MX2007005274A - Methods for treating obesity and obesity related diseases and disorders - Google Patents

Abstract

Methods for treating obesity or obesity related disorders are disclosed. These methods include the use of anti-obesity agents directed to the forebrain in combination with anti-obesity agents directed to the hindbrain.

Description

METHODS FOR THE TREATMENT OF OBESITY AND DISEASES AND DISORDERS RELATED TO THE OBESITY CROSS REFERENCE TO RELATED REQUESTS This application claims the benefit of the provisional patent application of E.UTA. number 60 / 624,357, filed on November 1, 2004, whose content is incorporated in its entirety for all purposes.

FIELD OF THE INVENTION The present invention relates to the medical field and in particular to the field of health, diet and nutrition. The invention relates to the use of anti-obesity agents.

BACKGROUND OF THE INVENTION Obesity and its associated disorders are common and very serious public health problems in the United States and around the world. Higher body obesity is the strongest known risk factor for type 2 diabetes mellitus and is a strong risk factor for cardiovascular disease. Obesity is a known risk factor for hypertension, atherosclerosis, congestive heart failure, stroke, gallbladder disease, osteoarthritis, sleep apnea, reproductive disorders such as polycystic ovarian syndrome, cancers of the breast, prostate and colon, and increased incidence of complications of general anesthesia (see, p. .gr., Kopelman, Nature 404: 635-43 (2000)). Obesity reduces the duration of life and carries with it a severe risk of the co-morbidities listed above, as well as disorders such as infections, varicose veins, acanthosis nigrícans, eczema, intolerance to exercise, insulin resistance, hypercholesterolemia due to hypertension, cholelithiasis, orthopedic injury and thromboembolic disease (Rissanen et al., Br. Med. J. 301: 835-7 (1990)). Obesity is also a risk factor for the group of conditions called insulin resistance syndrome, or "Syndrome X" and metabolic syndrome. The worldwide medical cost of obesity and associated disorders is enormous. It is believed that the pathogenesis of obesity is multifactorial. One problem is that, in obese subjects, the availability of nutrients and energy expenditure is not in balance until there is excess adipose tissue. The central nervous system (CNS) controls the energy balance and coordinates a variety of behavioral, autonomous and endocrine activities appropriate to the metabolic state of the animal. The mechanisms or systems that control these activities are widely distributed through the anterior brain (eg, hypothalamus), posterior brain (eg, brainstem), and spinal cord. Finally, the metabolic information (that is, availability of fuel) and cognitive (that is, learned preferences) of these systems is integrated and the decision to engage in appetitive behaviors (search for food) and consummatory (ingestion) is either activated (obtaining and starting food) or deactivated ( termination of food). It is thought that the hypothalamus is primarily responsible for integrating these signals and then issues commands to the brainstem. The brainstem nuclei that control the elements of the motor control system consummatorio (e.g., muscles responsible for chewing and swallowing). As such, these CNS nuclei have literally been referred to as constituting the "final common pathway" for ingestive behavior. Neuroanatomical and pharmacological evidence support that energy signals and nutritional homeostasis are integrated into the nuclei of the anterior brain and that the motor control system resides in the nuclei of the anterior brain, probably in regions surrounding the trigeminal motor nerve. There is extensive reciprocal connection between the hypothalamus and the brainstem. A variety of anti-obesity therapeutic compounds directed to the CNS (e.g., small molecules and peptides) are predominantly focused on substrates of the forebrain that reside in the hypothalamus and / or on substrates of the hindbrain that reside in the brainstem. Obesity remains a poorly treatable, chronic, essentially intractable metabolic disorder. Accordingly, there is a need for new useful therapies for weight reduction and / or maintenance of weight in a subject. Such therapies would lead to a profound beneficial effect on the health of the subject. All patents, patent applications and publications cited herein are incorporated herein by reference in their entirety.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides methods and compositions useful in the control, treatment and prevention of obesity and conditions, disorders and diseases related to obesity. The methods of the invention involve the administration of at least two anti-obesity agents to a subject in effective amounts to control, treat and prevent obesity and conditions related to obesity, disorders and diseases. In one aspect, the present invention provides methods for reducing the availability of nutrients in a subject. In another aspect, the invention provides methods for reducing the weight of a subject. In one aspect, the present invention provides methods for inducing a synergistic anti-obesity effect between the compounds. In one aspect, the present invention provides methods of treating obesity in a subject comprising peripherally administering therapeutically effective amounts of at least two different anti-obesity agents, wherein at least one anti-obesity agent acts on structures in the forebrain involved in food intake or modulation of body weight and at least one anti-obesity agent acting on structures in the hindbrain involved in food intake or modulation of body weight, where when an anti-obesity agent is a PYY (3-36), an analogue of PYY (3-36), or a PYY agonist (3-36), then another anti-obesity agent is not an amylin, an amylin agonist, an amylin analog, a CCK, a CCK analog, or a CCK agonist, and wherein when an anti-obesity agent is an exendin, an exendin derivative or an exendin agonist, then another anti-obesity agent is not an amylin, an amylin agonist, an amylin analogue. In certain embodiments, the methods of the invention include administration to a subject of at least two different anti-obesity agents wherein at least one of the anti-obesity agents is selected from the group consisting of an NPY1 receptor antagonist, an NPY5 receptor antagonist, an NPY2 receptor agonist, an NPY4 receptor agonist, a leptin, a leptin derivative, a leptin agonist, a CNTF, an CNTF agonist / modulator, a CNTF derivative, a MCH1 R antagonist, an MCH2R antagonist, a melanocortin 4 agonist, an MV4 receptor agonist, a cannabinoid receptor antagonist / reverse agonist (CB-1), a ghrelin antagonist, a 5HT2c agonist, an inhibitor of serotonin reuptake, a serotonin transport inhibitor, an exendin, an exendin derivative, an exendin agonist, a GLP-1, a GLP-1 analog, a GLP-1 agonist, a DPP-V inhibitor , an opioid antagonist, an antagonist orexin, a metabotropic glutamate receptor antagonist of subtype 5, an inverse antagonist / agonist of histamine 3, topiramate, a CCK, a CCK analogue, a CCK agonist, an amylin, an amylin analog and an amylin agonist. In certain embodiments, the anti-obesity agent administered is phentermine, rimonabant, sibutramine or pramlintide. In one embodiment, the invention provides a method of treating obesity in a subject which comprises peripherally administering therapeutically effective amounts of at least two anti-obesity agents, wherein the first anti-obesity agent is selected from the group consisting of a receptor antagonist. of NPY1, an NPY5 receptor antagonist, an NPY2 receptor agonist, an NPY4 receptor agonist, a leptin, a leptin derivative, a leptin agonist, a CNTF, an CNTF agonist / modulator, a derivative of CNTF, an antagonist of MCH1R, an antagonist of MCH2R, a melanocortin agonist 4, an MV4 receptor agonist, a cannabinoid receptor antagonist / inverse agonist (CB-1), a ghrelin antagonist, a 5HT2c agonist, a serotonin reuptake inhibitor, a transport inhibitor of serotonin, an exendin, an exendin derivative, an exendin agonist, a GLP-1, a GLP-1 analogue, a GLP-1 agonist, a DPP-V inhibitor, an opioid antagonist, an opioid antagonist, orexin, a metabotropic glutamate receptor antagonist of subtype 5, an inverse antagonist / agonist of histamine 3, topiramate, wherein the second anti-obesity agent is selected from the group consisting of a CCK, a CCK analogue, a CCK agonist, an amylin, an amylin analogue, and an amylin agonist, wherein when the first anti-obesity agent is not a PYY (3-36), an analog of PYY (3-36) ), or a PYY agonist (3-36), and wherein when the first anti-obesity agent is an exendin, an exendin derivative or an exendin agonist, then the second anti-obesity agent is not an amylin, an agonist of amylin, an analogue of amylin. In one embodiment, the invention provides methods of treating obesity comprising administering a first anti-obesity agent selected from an amylin, an amylin analog or an amylin agonist in combination with a second anti-obesity agent selected from a leptin, a Leptin derivative or a leptin agonist, wherein the administration of the agents results in a synergistic effect compared to administration of any of them alone. In certain embodiments, the invention provides methods by which the subject reduces body weight by at least 10%, the subject reduces body fat mass, the subject loses ectopic fat, or any combination thereof. In some embodiments, the methods are directed to a subject suffering from obesity, a disorder related to obesity, a disease related to obesity, a condition related to obesity, diabetes, insulin resistance syndrome, lipodystrophy, nonalcoholic steatohepatitis. , a cardiovascular disease, polycystic ovary syndrome, metabolic syndrome or a desire to lose body weight.

In one aspect, the administration of anti-obesity agents in combination can be simultaneous, concurrent, or sequential administration. The present invention also relates to the treatment of obesity and conditions, disorders and diseases related to obesity, and the use of the anti-obesity agents and compositions of the present invention for the manufacture of a medicament useful for treating these conditions.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph illustrating an effect of the administration of leptin and amylin on food intake. Figure 2 is a graph illustrating an effect of the administration of leptin and amylin on body weight. Figure 3 is a graph illustrating an effect of the administration of leptin and amylin on body composition. Figure 4 is a graph illustrating an effect of the administration of leptin and amylin on body composition. Figure 5 is a graph illustrating an effect of the administration of leptin and amylin on energy expenditure. Figure 6A is a graph illustrating an effect on body weight of the administration of leptin (500 μg / kg / day) and amylin (100 μg / kg / day), either alone or in combination for two weeks. Figure 6B is a graph illustrating an effect on body fat by administering two weeks of leptin (500 μg / kg / day) and amylin (100 μg / kg / day), either alone or in combination. Figure 6C is a graph illustrating an effect on body protein of a two week administration of leptin (500 μg / kg / day) and amylin (100 μg / kg / day), either alone in combination. Figure 7 is a graph illustrating an effect on body weight of administration of leptin alone (500 μg / kg / day), leptin fed in pairs alone (500 μg / kg / day), and leptine (50O- μg / kg 7day) ) and amylin (100 μg / kg / day) in combination for two weeks. Figures 8A-8B show graphs illustrating concentrations of leptin in serum in normal HSD animals and in animals subject to DIO either receiving vehicle, being fed in pairs to the amylin-treated group, or receiving amylin (100 μg / kg / day) for two weeks. Figure 9A is a graph illustrating an effect on body weight of vehicle or leptin administration (500 μg / kg / day) in normal animals. Figure 9B is a graph illustrating an effect on body weight of vehicle or leptin administration (500 μg / kg / day) in animals subject to DIO. Figure 10A is a graph illustrating an effect on body weight of the administration of sibutramine (3 mg / kg / day) and amylin (100 μg / kg / day), either alone or in combination for two weeks. Figure 10B is a graph illustrating an effect on body fat of administration of two weeks of sibutramine (3 mg / kg / day) and amylin (100 μg / kg / day), either alone or in combination. Figure 10C is a graph illustrating an effect on body protein of a two week administration of sibutramine (3 mg / kg / day) and amylin (100 μg / kg / day), either alone or in combination. Figure 11A is a graph illustrating an effect on body weight of the administration of phentermine (10 mg / kg / day) and amylin (100 μg / kg / day), either alone or in combination for two weeks. Figure 11B is a graph illustrating an effect on body fat of a two week administration of phentermine (10 mg / kg / day) and amylin (100 μg / kg / day), either alone or in combination. Figure 11 C is a graph illustrating an effect on the body protein of two weeks' administration of phentermine (10 mg / kg / day) and amylin (100 μg / kg / day), either alone or in combination. Figure 12A is a graph illustrating an effect on the body weight of administration of rimonabant (3 mg / kg / day) and amylin (100 μg / kg / day), either alone or in combination for two weeks. Figure 12B is a graph illustrating an effect on body fat of a two week administration of rimonabant (3 mg / kg / day) and amylin (100 μg / kg / day), either alone or in combination. Figure 12C is a graph illustrating an effect on body protein of a two week administration of rimonabant (3 mg / kg / day) and amylin (100 μg / kg / day), either alone or in combination.

Figure 13 is a graph illustrating the effect of administering a dose range of a CB-1 antagonist, either alone or in combination with amylin (100 μg / kg / day), on body weight. The time course of the combinations in the enclosed circle area is illustrated in Figures 14A and 14B. Figure 14A is a graph illustrating the effect of administration of a CB-1 antagonist (1 mg / kg / day) and amylin (100 μg / kg / day), either alone or in combination, on body weight . Figure 14B is a graph illustrating the effect of administration of a CB-1 antagonist (3 mg / kg / day) and amylin (100 μg / kg / day), either alone or in combination, on the weight bodily. Figure 15A is a graph illustrating an effect on body weight of the administration of an exendin-4 analogue (10 μg / kg / day) and amylin (100 μg / kg / day), either alone or in combination during two weeks. Figure 15B is a graph illustrating an effect on body fat of a two week administration of an exendin-4 analogue (10 μg / kg / day) and amylin (100 μg / kg / day), either alone or in combination. Figure 15C is a graph illustrating an effect on body protein of a two week administration of exendin-4 (10 μg / kg / day) and amylin (100 μg / kg / day), either alone or in combination . Figure 16A is a graph illustrating an effect on body weight of administration of PYY (3-36) (1 mg / kg / day) and amylin (100 μg / kg / day), either alone or in combination During two weeks. The figure 16B is a graph illustrating an effect on body fat of a two-week administration of PYY (3-36) (1 mg / kg / day) and amylin (100 μg / kg / day), either alone or in combination . Figure 16C is a graph illustrating an effect on body protein of a two week administration of PYY (3-36) (1 mg / kg / day) and amylin (100 μg / kg / day), either alone or in combination.

DETAILED DESCRIPTION D? ? INVENTION The inventors of the present have discovered that the administration of an anti-obesity agent acting on structures in the forebrain involved in the modulation of food intake and / or body weight in combination with an anti-obesity agent acting on structures in The posterior brain involved in modulation of food intake and / or body weight is surprisingly effective in reducing the availability of nutrients and in the treatment of obesity and conditions., disorders and diseases related to obesity. It has been found that when the administration of said anti-obesity agents is combined in this manner, the anti-obesity agents are more effective in reducing the availability of nutrients in the recipient than the use of one of the agents alone. As used herein, for example, a combination of anti-obesity agents can act synergistically to reduce nutrient availability, e.g., to reduce weight, reduce fat, reduce intake of food, or any combination of these three. The particular areas of the anterior brain (telencephalon and diencephalic constituents of the brain) and the posterior brain or brainstem (including the midbrain, pons and marrow bridge) have been identified as those involved in the control of the brain. energy balance Structures or nuclei of the forebrain that reside in the hypothalamus involved in the modulation of food intake and / or body weight include, for example, the arcuate nucleus (ARC), the paraventricular nucleus (PVN), the dorsomedial nucleus (DMH) , the ventromedial nucleus (VMH), and the lateral hypothalamus nucleus (LHA). Posterior brain structures or nuclei that reside in the brainstem involved in the modulation of food intake and / or body weight include, for example, the solitary tract nucleus (NST), the postrema area (AP), and the nucleus. lateral parabrachial (IPBN). The brainstem nuclei that control the elements of the motor control system are probably controlled by primary or secondary projections of brain stem regions such as NST, AP and IPBN. It should be noted that the AP, NST and IPBN have shown all of them (collectively and independently) to have their own integrative activities. A variety of anti-obesity agents directed to the CNS act on these structures of the forebrain that reside in the hypothalamus involved in the modulation of food intake and / or body weight. In addition, the anti-obesity agents directed to the CNS act on the posterior brain structures that reside in the brainstem involved in the modulation of food intake and / or body weight. Examples of said anti-obesity agents are described herein. See table 1 for examples. Such agents include, for example, neuropeptide receptor Y1 (NPY1) antagonists, NPY5 receptor antagonists, leptin and leptin agonists, ciliary neurotrophic factor (CNTF) and CNTF agonists, melanin concentrating hormone (MHC) and antagonists of MCH, melacortins (MCJs and MC agonists, cannabinoid receptor antagonists (CB-1), serotonin (5-HT) and 5-HT agonists, peptide YY (PYY) and PYY agonists, exendin and exendin agonists, GLP-1 and GLP-1 agonist, DPP-IV inhibitors, ghrelin and ghrelin antagonists, cholecystokinin (CCK) and CCK agonists, and amylin and amylin agonists.

TABLE 1 Individual anti-obesity targets and location CNS Region System Role in Anti-signaling Agents Food Obesity Ingestion Neuropeptide And Anterior Brain Increases Antagonists (NPY) (ARC / PVN) NPY1 and NPY5 receptor intake Leptin Previous brain Reduce intake Leptin or (ARC) agonists Neurotrophic factor Anterior brain Reduces intake CNTF (Axokine®) ciliary (CNFT) (ARC) Hormone Anterior brain Increases Concentrator antagonists (ARC / PVN) MCH melanin (MCH) intake Melanocortins Previous brain Agonists reduce MC4 agonists (MC) (PVN / ARC) intake Canabinoides Cerebro anterior Increases the Antagonist of (CB) (widely distributed receptor intake) cannabinoid Serotonin (5-HT) Previous brain Reduces intake Agonists of 5- (VH) HT2C Peptide YY (PYY) Previous brain Reduces intake Agonists (ARC) PYY (3-36) Epidermis similar to previous brain Reduces intake Exenatide and other glucagon (GLP-1) (PVN) ligands of GLP-1, inhibitors of DPP-IV Greiina Anterior brain Increases the Antagonists of (ARC) intake grist cholecystokinin Posterior brain Reduces intake CCK agonists (CCK) (AP) Amiline Posterior brain Reduces intake Agonists of (AP) amylin, pramlintide, amylin analogues In certain modalities, the methods include a first compound that is predominantly directed towards equilibrium centers of energy of the hypothalamus, such as the ARC, PVN, VM and LH. In certain modalities, the methods include a second compound that predominantly it is directed towards the centers of energy balance of the posterior brain such as the NST, the AP and the IPBN.

In certain embodiments, these compounds are anti¬ agents obesity. In certain modalities, the methods may include the use of one or more anti-obesity agents that act predominantly in the brain previous. In other modalities, the methods may include the use of one or more anti-obesity agents that act predominantly in the brain later. Illustrative anti-obesity agents include an antagonist of NPY1 receptor, an NPY5 receptor antagonist, a leptin or a Leptin agonist or analog, a CNTF (e.g., AXOKINE®), an antagonist of MCH, an MC4 agonist, a CB-1 antagonist (e.g., rimonabant), a 5-HT2C agonist, an NPY2 receptor agonist (e.g., a PYY (3-36) or a PYY agonist (3-36)), an exendin or an exendin or analog agonist, a GLP-1 or a GLP-1 agonist or analogy of a DPP-V inhibitor, a ghrelin antagonist, a CCK or a CCK agonist or analog, and an amylin or an amylin agonist or analogue. As illustrated herein, agonists and antagonists which are anti-obesity agents of the invention include, for example, molecules such as peptides, polypeptides and small molecule agents The details of one or more embodiments of the invention are set forth in Annex drawings and the following description Other features, objects and advantages of the invention will be apparent from the description and drawings, and from the claims.

Definitions An "anti-obesity agent" is a compound that is capable of reducing the availability of nutrients to the body under administration. A "Weight-inducing agent" is a compound that would increase the availability of nutrients to the body. In one aspect, a weight-inducing agent is an antagonist of an anti-obesity agent. As used herein, an anti-obesity agent that "acts on a structure of the forebrain involved in the modulation of food intake and / or body weight" stimulates or suppresses the activity of a region particular, e.g., particular nuclei and / or neural circuits, in the forebrain. This stimulation or suppression of the forebrain leads to a reduction in the availability of nutrients to the body. An anti-obesity agent that "acts on a posterior brain structure involved in the modulation of food intake and / or body weight" stimulates or suppresses the activity of a particular region, e.g., particular nuclei and / or neuronal circuits, in the posterior brain. This stimulation or suppression of the posterior brain results in a reduction in the availability of nutrients to the body. "Reduced nutrient availability" includes any means by which the body reduces the nutrients available to the body to be stored as fat. In other words, the reduction of nutrient availability may be by means including, but not limited to, appetite reduction, increased satiety, affectation of aversion to choice / taste of foods, increase in metabolism, and / or decrease or inhibition in the absorption of food. Illustrative mechanisms that may be affected include delayed gastric emptying or decreased absorption of food in the intestines. "Increased nutrient availability" includes any means by which the body increases the nutrients available to the body to be stored as fat. In other words, the increase in nutrient availability may be by means that include, but are not limited to, increased appetite, decreased satiety, impairment of aversion to food, decreased aversion to taste, decreased metabolism, and / or increased absorption of food. Illustrative mechanisms that may be affected include decreased gastric hypomotility or increased absorption of food in the intestines. Although "obesity" is generally defined as a body mass index (BMI) above 30, for the purposes of this description, any subject, including those with a body mass index of less than 30, who needs or wishes to reduce body weight or prevent gain of body weight is included in the scope of "obese". Therefore, subjects with a BMI less than 30 and 25 and above (considered overweight) or below 25 are also included in the subjects of the invention. Morbid obesity refers to a BMI of 40 or greater. With respect to methods for reducing nutrient availability, as used herein, a "subject in need thereof" includes subjects who are overweight or obese or morbidly obese, or who wish to lose weight. insulin, glucose intolerant, or have some form of diabetes mellitus (eg, type 1, 2, or gestational diabetes) can benefit from these methods to reduce nutrient availability. nutrient availability, as used herein, a "subject who needs them" includes subjects who are overweight or who wish to gain weight.A "subject" includes any animal, including humans, primates, and other mammals including rats, mice, pets such as cats, dogs, livestock animals such as horses, cattle, sheep and goats, as well as chickens, turkeys and any other animal for which the body weight or alteration of the composition of the body can be a problem. "Metabolic rate" means the amount of energy released / spent per unit of time. Metabolism per unit time can be estimated by food consumption, energy released as heat, or oxygen used in metabolic processes. It is generally desirable to have a higher metabolic rate when you want to lose weight. For example, a person with a high metabolic rate may be able to spend more energy (eg, the body burns more calories) to perform an activity than a person with a low metabolic rate for that activity. As used herein, "lean mass" or "lean body mass" refers to muscle and bone. Lean body mass does not necessarily indicate fat-free mass. Lean body mass contains a small percentage of fat (approximately 3%) within the central nervous system (brain and spinal cord), bone marrow, and internal organs. Lean body mass is measured in terms of density. Fat mass and lean mass measurement methods include, but are not limited to, underwater weight, air displacement plethysmography, x-rays, DEXA scanners, MRIs, and CT scans. In one embodiment, fat mass and lean mass are measured using weight under water.

By "fat distribution" is meant the location of fat deposits in the body. Such fat deposition sites include, for example, subcutaneous, visceral and ectopic deposits. By "subcutaneous fat" is meant the deposition of lipids just below the surface of the skin. The amount of subcutaneous fat in a subject can be measured using any method available for the measurement of subcutaneous fat. Methods of measuring subcutaneous fat are known in the art, for example, those described in the patent of E.U.A. No. 6,530,886, the entirety of which is incorporated herein by reference. By "visceral fat" is meant the deposit of fat as intra-abdominal adipose tissue. Visceral fat surrounds vital organs and can be metabolized by the liver to produce cholesterol in the blood. Visceral fat has been associated with increased risks of conditions such as polycystic ovary syndrome, metabolic syndrome and cardiovascular diseases. By "ectopic fat storage" is meant lipid deposits in and around tissues and organs that constitute lean body mass (e.g., skeletal muscle, heart, liver, pancreas, kidneys, blood vessels). Generally, the storage of ectopic fat is an accumulation of lipids outside the classical adipose tissue deposits in the body. As used herein, and as is well understood in the art, "treatment" is an approach to obtain beneficial or desired results, including clinical results. "Treatment" or "palliation" of a disease, disorder or condition means that the degree and / or undesirable clinical manifestations of a condition, disorder or a disease state are reduced and / or the time course of the progression becomes more slow or lengthened, compared to lack of treatment of the disorder. For example, in the treatment of obesity, a decrease in body weight, e.g., at least a 5% decrease in body weight, is an example of a desirable treatment outcome. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, alleviation or mitigation of one or more symptoms, decrease in the extent of the disease, stabilized disease status (i.e., not worsened, delayed or slowness of disease progression, mitigation or palliation of disease status, and remission (either partial or total), either detectable or undetectable. "Treatment" can also mean prolongation of survival compared to expected survival if treatment is not received. In addition, treatment does not necessarily occur by the administration of a dose, but often occurs under the administration of a series of doses. Therefore, a therapeutically effective amount, an amount sufficient to palliate, or an amount sufficient to treat a disease, disorder or condition can be administered in one or more administrations. As used herein, the term "therapeutically effective amount" means the amount of the active compounds in the composition which will induce the biological or medical response in a tissue, system, subject, or human that is being sought by the researcher, veterinarian, physician or other clinician, which includes relief of the symptoms of the disorder being treated. The novel treatment methods of this invention are for disorders known to those skilled in the art. As used herein, the term "prophylactically effective amount" means the amount of the active compounds in the composition that will induce a biological or medical response in a tissue, system, subject or human that is being sought by the researcher, veterinarian, physician or other clinical doctor, to prevent the onset of obesity or a disorder, condition or disease related to obesity in subjects such as risk for obesity or the disorder, condition or disease related to obesity. As used herein, the singular form "a", "an", "the" and "the" include plural references unless otherwise indicated or is clear from the context. For example, as will be evident from the context, "an" amylin agonist may include one or more amylin agonists. As used herein, an "analogue" refers to a peptide whose sequence was derived from that of a base reference peptide, eg, amylin and calcitonin, and includes insertions, substitutions, extensions, and / or deletions of the reference amino acid sequence, for example, having at least 50 or 55% amino acid sequence identity with the base peptide, in other cases, for example, having at least 70%, 80%, 90 % ó 95% amino acid sequence identity with the base peptide. Such analogs may comprise conservative or non-conservative amino acid substitutions (including non-natural amino acids and L and D forms). Analogs include compounds that have agonist activity and compounds that have antagonist activity. Analogs, as defined herein, also include derivatives. A "derivative" is defined as a reference peptide or analogs, described above, having a chemical modification of one or more of its amino acid side groups, carbon a-atoms, terminal amino group, or terminal carboxylic acid group. A chemical modification includes, but is not limited to, adding chemical portions, creating new bonds, and removing chemical portions. Modifications in the amino acid side groups include, without limitation, acylation of lysine e-amino groups, arginine N-alkylation, histidine or lysine, alkylation of glutamic or aspartic carboxylic acid groups, and deamidation of glutamine or asparagine. Modifications of the amino terminus include, without limitation, the modifications of amino, N-lower alkyl, N-di-lower alkyl, and N-acyl. Modifications of the amino terminus include, without limitation, the modifications desamino, N-lower alkyl, N-di-lower alkyl and N-acyl, such as alkylaryls, branched alkylacyls, alkylaryl-acyls. Modifications of the terminal carboxyl group include, without limitation, the modifications of amide ester, lower alkylamide, dialkylamide, arylamide, alkylarylamide, and lower alkyl. The lower alkyl is C 1 -C 4 -alkyl. In addition, one or more groups Lateral, or terminal groups, can be protected by protecting groups known to the expert in synthesis chemistry. The α-carbon of an amino acid can be mono- or dimethylated. In general, with respect to an amino acid sequence, the term "modification" includes substitutions, insertions, elongations, deletions, and derivations alone or in combination. The polypeptides of the invention can include one or more modifications of a "non-essential" amino acid residue In the context of the invention, a "non-essential" amino acid residue is a residue that can be altered, e.g., deleted or substituted, in the novel amino acid sequence without canceling or substantially reducing the activity (e.g., the agonist activity) of the polypeptide (e.g., the analogous polypeptide). The polypeptides of the invention may include deletions of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more non-essential amino acid residues. The polypeptides of the invention may include additions of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids without canceling or substantially reducing the activity of the polypeptide. The substitutions include conservative amino acid substitutions. A "conservative amino acid substitution" is one in which the amino acid residue is replaced by an amino acid residue having a similar side chain, or physicochemical characteristics (e.g., electrostatic, hydrogen bonding, isosteric, hydrophobic characteristics) ). Amino acids can be those that occur naturally or unnaturally (unnaturally). The families of amino acid residues that have similar side chains are known in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acid side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, methionine, cysteine), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan), β-branched side chains (e.g. , threonine, valine, isoleucine) and aromatic side chains (eg, tyrosine, "féñilalanina, tryptophan, histidine.) Substitutions may also include non-conservative changes." "amino acid" or "amino acid residue" means natural amino acids , unnatural amino acids, and modified amino acids Unless otherwise stated, any reference to an amino acid, usually or specifically by name, includes reference to stereoisomers D and L if its structure allows such stere forms Natural amino acids include alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine ( His), isoleucine (He), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine ( Tyr) and valina (Val). Non-natural amino acids include, but are not limited to homolysin, homoarginine, homoserin, azetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6- aminocaproic acid 2- aminoheptanoic, 2-aminoisobutyric acid, 3-aminoisbutyric acid, 2-aminopimelic acid, tert-butylglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2'-diaminopimelic acid, 2,3-diaminopropionic acid, N-ethylglycine, N -ethylarparagine, homoproline, hydroxylysine, alo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylalanine, N-methylglycine, N-methyl isoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, norvaline, norleucine , omitin, pentylglycine, pipecolic acid and thioproline. Additional non-natural amino acids include modified amino acid residues that are chemically blocked, reversibly or irreversibly, or chemically modified in their N-terminal amino group or their side chain groups, such as amino acids or N-methylated D and L residues in where the side chain functional groups are chemically modified to another functional group. For example, the modified amino acids include methionine sulfoxide; methionine sulfone; aspartic acid- (beta-methyl ester), a modified amino acid of aspartic acid; N-ethylglycine, a glycine modified amino acid; or alanine carboxamide, a modified amino acid of alanine. Additional residues that can be incorporated are described in Sandberg et al, J. Med. Client. 41: 2481-91, 1998. It should be noted that throughout the application, those alternatives are written in Markush groups, for example, each amino acid position containing more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thus comprising another embodiment of the invention, and the Markush group should not be read as a single unit.

Methods of the invention In a general aspect, the invention provides methods for reducing the availability of nutrients through the administration of a combination of anti-obesity agents. Therefore, the invention provides methods for treating obesity and diseases, disorders and / or conditions related to obesity that will benefit from a reduction in the availability of nutrients. Given the increase in effectiveness when used in combinations, the methods of the invention may allow administration of lower doses of one or more of the anti-obesity agents used in combination compared to the use of the agent alone., as in monotherapy. The methods of the invention provide for the administration of a combination of anti-obesity agents. The administration of agents "in combination" should be understood as providing each of the agents to a subject in need of treatment. The administration of the agents could occur as a single pharmaceutical dosage formulation containing all the anti-obesity agents intended or separately with each agent intended in its own dosage formulation. Where separate dose formulations are used, individual anti-obesity agents can be administered essentially at same time, that is, concurrently, or at separately staggered times, ie, sequentially before or subsequent to the administration of the other anti-obesity agent of the method. In some embodiments, administration in combination involves the administration of separate dose formulations during overlapping intervals. For example, the anti-obesity agent 1 is administered from day 1 to day 30 and the anti-obesity agent 2 is administered from day 20 to day 50. In other embodiments, administration in combination involves the administration of separate dose formulations in sequential intervals not overlapping. For example, anti-obesity agent 1 is administered from day 1 to day 30 and anti-obesity agent 2 is administered from day 35 to day 50. The present invention therefore should be understood as including all simultaneous treatment regimens, alternating, or completely separate over the course of total treatment, and the terms "administration," "administering," "administration in combination," and "administering in combination" should be interpreted accordingly. In one embodiment, the invention provides methods for reducing nutrient availability through the administration of at least one anti-obesity agent that acts on the structures of the forebrain involved in modulation of food intake and / or body weight in combination. with the administration of at least one anti-obesity agent acting on posterior brain structures involved in modulation of food intake and / or body weight. In some cases, the methods of invention increase or improve the effectiveness of an anti-obesity agent that has Imitated effectiveness, if any, when used alone (monotherapy). In such cases, the methods of the invention increase or improve the effectiveness of an anti-obesity agent, for example, by preventing or delaying the loss of effectiveness through continuous use or by increasing potency. The methods of the invention may allow administration of lower doses of one or more of the anti-obesity agents used in combination compared to the use of any agent alone. In one aspect, the methods of the invention provide a synergistic anti-obesity effect among the agents administered. Accordingly, in one embodiment, the administration of a combination of anti-obesity agents results in an effect, e.g., a reduction in nutrient availability, reduction in body weight, reduction in food intake, increase in metabolism, which is greater than the combination of the results of the anti-obesity agent administration alone (monotherapy). In another aspect of the invention, methods are provided that reduce or eliminate the resistance of a subject to an anti-obesity agent so that when the agent is administered, it will be able to induce an anti-obesity response (e.g., reduces the availability of nutrients). , reduces weight, reduces fat mass). For example, and without wishing to be bound by this or any other theory, it is postulated that leptin resistance may be due to the high levels of leptin found in obese subjects (ie, the body has been desensitized to leptin). Therefore, a method of invention comprises administering an anti-obesity agent other than leptin (e.g., amylin or an amylin agonist) to reduce the weight of the subject in order to reduce or remove resistance to leptin. Once this has been achieved, the leptin is then administered, either alone or in combination with an anti-obesity agent (e.g., amylin or an amylin agonist), for an additional anti-obesity effect. Other means of weight reduction are contemplated to mitigate resistance to leptin, such as diet, exercise, other diet drugs, and surgical devices. In one embodiment, the invention is directed to the delivery of a first anti-obesity agent that acts on the posterior brain structures involved in the modulation of food intake and / or body weight to prepare the body prior to the administration of a second agent anti-obesity that acts on the structures of the anterior brain involved in the modulation of food intake and / or body weight. In certain modalities, the administration of the first agent is for a number of days, weeks or even months before the administration of the second agent. At this point, the second agent can be administered alone or in combination with the first agent. In certain embodiments, the first anti-obesity agent is amylin or an amylin agonist and the second agent is a leptin or a leptin agonist. In some embodiments, the concentration in the leptin serum of a subject before administration of the anti-obesity agents is greater than 10 ng / ml, in other embodiments, it is greater than 20 ng / ml.

In one embodiment, an amylin or an amylin agonist is administered to the subject at least 1 day, 2 days, 3 days, 5 days, 7 days, 10 days, 14 days, 21 days, 28 days or more before administration of a leptin or leptin agonist. In some embodiments, prior to the administration of a leptin or a leptin agonist, an amylin or an amylin agonist is administered to the subject until the concentration in the leptin serum in the subject is approximately 4 ng / ml, less than 4 ng / ml, less than 2 ng / ml, less than 1 ng / ml, or less than about 0.5 ng / ml. In some embodiments, a leptin or a leptin agonist is administered in a quantity of replacement therapy to achieve near-physiological concentrations of leptin in the plasma. In another aspect of the present invention, methods are provided to reduce the risk of developing metabolic disorders, wherein the method comprises administering to the subject a combination of anti-obesity agents in effective amounts to reduce the weight of a subject. In some embodiments of the invention, the methods of the invention are used to increase the metabolic rate in a subject, decrease a reduction in the metabolic rate in a subject, or maintain the metabolic rate in a subject. In one embodiment, the metabolic rate may involve the preferential use of body fat as a source of energy over lean body tissue. In one aspect, lean body mass does not decrease after administration of the combination of anti-obesity agents. In another aspect, a reduction in lean body mass is reduced or prevented after administration of the combination of anti-obesity agents. In yet another aspect, lean body mass is increased after administration of the combination of anti-obesity agents. This preference for fat as the source of energy can be determined by comparing the amount of fat tissue with lean body tissue, achieved by measuring the total body weight and fat content at the beginning and end of the treatment period. An increase in the metabolic rate is a level of the use of calories or other higher energy source by a subject during a period as compared to the level of use of calories or other energy source by the subject during another period under substantially similar conditions or identical without administration of the combination of anti-obesity agents. In one embodiment, the metabolic rate increases by at least about 5% in one subject, in other modalities, the metabolic rate increases by at least approximately 10%, 15%, 20% 25%, 30% or 35% in one subject compared to the level of calorie use or other energy source by the subject during another period under substantially similar or identical conditions without administration of the combination of anti-obesity agents. The increase in the metabolic rate can be measured using, for example, a respiratory calorimeter. An effective amount of the anti-obesity agents as used in this embodiment is an amount of each agent effective to increase the metabolic rate in a subject when administered in combination as compared to a subject not receiving the agents or only one of the agents.

In another embodiment, a method is provided to reduce a decrease in the metabolic rate in a subject. Said decrease in the metabolic rate can be the result of any nutritional or physical condition or diet that leads to a reduction in the metabolic rate, for example, due to a reduced calorie diet, a restricted diet, or weight loss. A restricted diet includes tolerances or prohibitions, or both on the types of food or the amounts of food or both allowed in a diet, not necessarily based on calories. For example, as in individual diets, the body compensates with a reduced metabolic rate based on lower caloric intake. In essence, the body down-regulates the requirement of food, subsisting with less food. As the diet continues, the threshold for caloric intake is reduced. When the diet is over, the individual typically gains weight while eating a normal diet due to the threshold of reduced caloric intake and lower basal metabolic rate (NIH Technology Assessment Conference Panel (1992) Ann. Intern Med. 116: 942-949; Wadden (1993) Ann. Intern. Med. 119: 688-693). In one aspect, a method is provided for reducing the loss of metabolic rate in a subject, wherein the loss of metabolic rate is the result of a reduced calorie diet or weight loss. When using said method, the reduction in the metabolic rate the subject is decreased by at least approximately 10%, 15%, 20% 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80 %, 90% or 95% in a subject. For such methods, it may be desirable to administer the combination of anti-obesity agents at the time when the condition or nutritional or physical regimen is initiated which leads to a loss or reduction in the metabolic rate. However, it is also contemplated that the administration of the agents starts before the nutritional or physical condition or diet is initiated. In one case, the metabolic rate is measured using a respiratory calorimeter. An effective amount of the anti-obesity agents as used in this embodiment is an amount of each agent effective to decrease the reduction of the metabolic rate in a subject when administered in combination. In another aspect, methods are provided for reducing metabolic plateaus, wherein one method comprises administering effective amounts of anti-obesity agents in combination to a subject. In one embodiment, the subject is losing weight, or has lost weight, for example, due to a reduced calorie diet, increased exercise or a combination thereof. By "metabolic plateau" are understood intervals of time of constant metabolic rate while the body adjusts to changes in caloric input or energy. The changes in caloric intake or expenditure may be the result of, for example, reduced calorie diet or increased physical activity. Such plateaus can be observed, for example, during a weight loss regime when the weight loss becomes slow or stops. In one embodiment, a method of the present invention reduces the duration of a metabolic plateau in a subject compared to the duration of the metabolic plateaus in an otherwise identical subject during the same period under substantially similar conditions or identical without administration of the combination of anti-obesity agents. In another embodiment, a method of the present invention reduces the frequency of metabolic plateaus as compared to the frequency of metabolic plateaus in an otherwise identical subject during the same period under substantially similar or identical conditions without administration of the combination of anti-aging agents. obesity. In yet another embodiment, a method of the present invention delays the onset of a metabolic plateau compared to the initiation of a metabolic plateau in an otherwise identical subject during the same period under substantially similar or identical conditions without administration of the combination of antiobesity agents. In one modality, the metabolic plateaus are identified by tabulated periods of reduced weight loss or without weight loss. In one embodiment, at least one metabolic plateau is reduced. In other modalities, at least two, three, four, five, six, seven, eight, nine or ten metabolic plateaus are reduced. In another aspect, the metabolic plateaus are delayed one day in comparison to a subject to whom the combination of anti-obesity agents was not administered under identical or similar conditions. In other aspects, the metabolic plateaus are delayed 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 10 days, 2 weeks or 3 weeks in a subject. In yet another embodiment, a method is provided for preserving the metabolic rate in a subject. In one modality, the subject may be at risk of losing metabolic rate, for example, due to the initiation of a diet of reduced calories, restricted diet, or anticipated weight loss. A preservation of the metabolic rate is a maintenance of the level of use of calories or other energy source by a subject during a period as compared to the level of calorie use or other source of energy by an otherwise identical subject during the same period. period under substantially similar or identical conditions without administration of the combination of anti-obesity agents. In one aspect, the metabolic rate is maintained within 15% of the metabolic rate of the subject before the onset of the event which results in the decrease in the metabolic rate. In other aspects, the metabolic rate remains within 10%, within 7%, within 5%, within 3% or less of the subject's metabolic rate. In one aspect, the combination of anti-obesity agents is administered at the start of a reduced-calorie diet regimen, restricted diet or exercise. Metabolic rates can be assessed using any available method to determine such rates, for example using a respiratory calorimeter. Said methods and devices for evaluating the metabolic rate are known in the art and are described, for example, in the U.S. Patents. Nos. 4,572,208, 4,856,531, 6,468,222, 6,616,615, 6,013,009 and 6,475,158. Alternatively, the metabolic rate of an animal can be assessed by measuring the amount of lean tissue versus fatty tissue catabolized by the animal after the diet period. Therefore, the content of body weight and total fat can be measured at the end of the diet period. In rats, a method frequently used to determine fat The total body is removed surgically and weigh the retroperitoneal fat pad, a body of fat located in the retroperitoneum, the area between the posterior abdominal wall and the posterior parietal peritoneum. The weight of the pad is considered to be directly related to the percent body fat of the animal. Since the relationship between body weight and body fat in rats is linear, obese animals have correspondingly higher per cent body fat and retroperitoneal fat pad weight. In another aspect of the present invention, methods are provided for reducing fat mass by increasing the metabolic rate in a subject, wherein the methods comprise administering a combination of antiobesity agents in effective amounts to reduce the fat mass by increasing the metabolic rate of the subject. The fat mass can be expressed as a percentage of the total body mass. In some aspects, the fat mass is reduced by at least 1%, by at least 5%, by at least 10%, by at least 15%, by at least 20% or by at least 25% during the course of the treatment. In one aspect, the subject's lean mass does not decrease during the course of treatment. In another aspect, the lean mass of the subject is maintained or increased during the course of treatment. In another aspect, the subject is on a diet of reduced calories or restricted diet. By "reduced calorie diet" is meant that the subject is eating fewer calories per day than compared to the normal diet of the same subject. In one case, the subject is consuming at least 50 less calories per day. In other cases, the subject is consuming at least 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900 or 1000 fewer calories per day. In one embodiment of the present invention, a method is provided for altering the distribution of fat in a subject, wherein the method comprises administering a combination of anti-obesity agents in effective amounts to alter the distribution of fat in the subject. In one aspect, the result of an increased metabolism of visceral or ectopic fat, or both in the subject. In some embodiments, the method involves the metabolism of visceral or ectopic fat or both at a rate of at least about 5%, 10%, 15%, 20%, 25%, 30%, 40% or 50% greater than for subcutaneous fat. In one aspect, the methods result in a favorable fat distribution. In one embodiment, the favorable fat distribution is an increased ratio of subcutaneous fat to visceral fat, ectopic fat, or both. In one aspect, the method involves an increase in lean body mass, for example, as a result of an increase in mass of muscle cells. In another embodiment, methods are provided for reducing the amount of subcutaneous fat in a subject, wherein the method comprises administering, to a subject in need thereof, a combination of anti-obesity agents in effective amounts to reduce the amount of subcutaneous fat. in the subject. In one case, the amount of subcutaneous fat is reduced in a subject by at least about 5%. In other cases, the amount of subcutaneous fat is reduced by at least about 10%, 15%, 20%, 25%, 30% 40% or 50% compared to the subject before the administration of anti-obesity agents. The methods described herein can be used to reduce the amount of visceral fat in a subject. In one case, visceral fat is reduced in a subject by at least about 5%. In other cases, the visceral fat is reduced in the subject by at least about 10%, T5% 20%, 25%, 30% 40% or 50% compared to the subject before administration of the combination of anti-aging agents. -obesity. Visceral fat can be measured through any means available to determine the amount of visceral fat in a subject. Such methods include, for example, abdominal tomography by means of CT scanning and MRI. Other methods to determine visceral fat are described, for example, in the patents of E.U.A. Nos. 6,864,415, 6,850,797 and 6,487,445. In one embodiment, a method is provided for preventing the accumulation of ectopic fat or reducing the amount of ectopic fat in a subject, wherein the method comprises administering, to a subject in need thereof, a combination of anti-obesity agents in effective amounts to prevent the accumulation of ectopic fat or to reduce the amount of ectopic fat in the subject. In one case, the amount of ectopic fat is reduced in a subject by at least about 5% compared to the subject prior to administration of the combination of anti-obesity agents. In other cases, the amount of ectopic fat is reduces in a subject by at least about 10%, or by at least about 15%, 20%, 25%, 30% 40% or 50%. Alternatively, the amount of ectopic fat is proportionally reduced by 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% in comparison with subcutaneous fat in a subject. Ectopic fat can be measured in a subject using any method available to measure ectopic fat. In another embodiment, methods are provided for producing a more favorable fat distribution in a subject, wherein the method comprises administering to a subject a combination of anti-obesity agents in effective amounts to produce a favorable fat distribution. In one embodiment, administration of a combination of anti-obesity agents reduces the amount of visceral fat or ectopic fat, or both, in a subject. For example, the administration of a combination of anti-obesity agents, wherein at least one anti-obesity agent acts on the structures of the forebrain involved in modulation of food intake or body weight or both in combination with administration of at least one anti-obesity agent acting on the structures of the posterior brain involved in modulation of food intake or body weight or both. In one embodiment, the methods preferably reduce the amount of visceral or ectopic fat, or a combination of both, on the reduction in subcutaneous fat. These methods result in a greater ratio of subcutaneous fat to visceral fat or ectopic fat. These relationships Improved results may result in a reduced risk of the development of cardiovascular diseases, polycystic ovary syndrome, metabolic syndrome, or any combination thereof. In one embodiment, ectopic or visceral fat is metabolized at a rate 5% higher than subcutaneous fat. In other modalities, ectopic or visceral fat is metabolized at a rate of at least 10% 15%, 20%, 25%, 30% 50%, 60%, 70%, 80%, 90% or 100% greater than fat. subcutaneous In still another aspect, the methods of the invention include the use of a therapeutically effective amount of a combination of anti-obesity agents administered in combination with glucocorticosteroids. Glucocorticosteroids have the adverse effect of increasing fat mass and reducing lean mass. Accordingly, it is contemplated that the combination of anti-obesity agents may be used in conjunction with glucocorticosteroids under conditions where the use of the glucocorticosteroid is beneficial. Methods for reducing weight in a subject with morbid obsession are also provided by first reducing the subject's weight to a level below having morbid obesity, then administering to the subject a combination of anti-obesity agents in effective amounts to further reduce the weight of the subject. subject. Methods for reducing the weight of a subject to below morbid obesity include reducing caloric intake, increasing physical activity, drug therapy, bariatric surgery, such as gastric bypass surgery, or any combination of the above methods.

In one aspect, administration of the combination of anti-obesity agents further reduces the subject's weight. In another embodiment, methods are provided for reducing the body mass index in a subject having a body mass index of 40 or less by administering a combination of anti-obesity agents in effective amounts to further reduce the weight of the subject. By reducing weight, it is understood that the subject loses a portion of his total body weight during the course of treatment, whether the course of treatment is days, weeks, months or years. Alternatively, weight reduction can be defined as a decrease in the ratio of fat mass to lean mass (in other words, the subject has lost fat mass, but maintained or gained lean mass, without there necessarily being a corresponding loss in total body weight). An effective amount of anti-obesity agents administered in combination in this embodiment is an amount effective to reduce a subject's body weight during the course of treatment., or alternatively an amount effective to reduce the percentage of fat mass of the subject during the course of the treatment. In certain embodiments, the subject's body weight is reduced, during the course of treatment, by at least about 1%, by at least about 5%, by at least about 10%, by at least about 15% or in at least about 20%. Alternatively, the percentage of fat mass of the subject is reduced, during the course of treatment, by at least 1%, at least 5%, so less 10%, at least 15%, at least 20%, or at least 25%. In certain embodiments, methods of reducing the availability of nutrients, eg, weight reduction, in a subject comprise administering to the subject an effective amount of the anti-obesity agents in a bolus dose one or more times per day. . A bolus dose is an intermittent dose of medicine (as opposed to a continuous infusion). One or more bolus doses per day can be administered to a subject. The bolus dose may be the same regardless of when it is administered to the subject, or it may be adjusted in such a way that the subject is administered a larger bolus dose at certain times of day compared to others. The administration of an agent in certain formulations, e.g., sustained-release formulations, a bolus dose may be administered less frequently, for example, once every three days, once a week, twice a month, a every month. In addition, the time between the bolus doses is preferably long enough to allow the drug to be administered at the previous bolus dose to clear the bloodstream of the subject. In other embodiments, methods of reducing the availability of nutrients, e.g., weight reduction, in a subject comprise administering to the subject an effective amount of the anti-obesity agents in continuous doses. By "continuous dose" is meant the continuous infusion of the drug, for example, by intravenous injection or a transdermal patch. Alternatively, a continuous dose can be administered orally in form of a controlled release capsule or tablet that releases the drug into the subject's system for a period. When administered by a continuous dose, the drug is released over a period of about 1 hour. In some cases, the drug is released over a period of approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18 or 24 hours. By "administered in combination" it is meant that the anti-obesity agents are administered as a single administration, simultaneously as separate doses, or as administered sequentially. Sequential administration refers to administering one of the anti-obesity agents either before or after an anti-obesity agent. In one embodiment, the first anti-obesity agent is administered approximately 30 minutes before or after at least one other anti-obesity agent, in other modalities approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours before or after at least other anti-obesity agents. Any of the anti-obesity agents administered can be administered as a bolus dose or as a continuous dose. The present invention is further directed to methods for increasing thermogenesis in a subject, the method comprising administering to a subject in need thereof an effective amount of at least one anti-obesity agent acting on the structures of the forebrain involved in modulation of food intake, body weight or both in combination with the administration of at least one anti-obesity agent which acts on posterior brain structures involved in the modulation of food intake, body weight or both. Thermogenesis is the process of releasing calories as heat by increasing the metabolic rate of the body. Thermogenesis is activated by mechanisms, including supplements, nutrition, exercise and exposure to cold. The present invention is further directed to methods for increasing oxidative metabolism in a subject, the method comprising administering to a subject in need thereof an effective amount of at least one anti-obesity agent acting on the structures of the forebrain involved in the modulation of food intake, body weight or both in combination with the administration of at least one antiobesity agent acting on the structures of the posterior brain involved in the modulation of food intake, body weight or both. Oxidative metabolism is the process by which oxygen is used to make energy from carbohydrates (sugars). In another aspect, a method for inducing a feeling of satiety in a subject is provided, wherein the method comprises administering an effective amount of at least one anti-obesity agent acting on the structures of the forebrain involved in the modulation of intake. of food, body weight or both in combination with administration of at least one anti-obesity agent acting on the structures of the posterior brain involved in the modulation of food intake, body weight or both to said subject.

In yet another aspect, a method for controlling hunger in a subject is provided, wherein the method comprises administering an effective amount of at least one anti-obesity agent acting on the structures of the forebrain involved in the modulation of food intake. food, body weight or both in combination with the administration of at least one anti-obesity agent that acts on the structures of the posterior brain involved in the modulation of food intake, body weight or both to said subject. In yet another aspect, a method is provided for prolonging a satiety sensation in a subject, wherein the method comprises administering an effective amount of at least one anti-obesity agent acting on the structures of the forebrain involved in the modulation of food intake, body weight or both in combination with the administration of at least one anti-obesity agent that acts on the structures of the posterior brain involved in the modulation of food intake, body weight or both to said subject. In a further aspect, a method for reducing caloric intake by reducing the size of a food is provided, wherein the method comprises administering an effective amount of at least one anti-obesity agent acting on the structures of the forebrain involved in the modulation of food intake, body weight or both in combination with the administration of at least one anti-obesity agent acting on the posterior brain structures involved in the modulation of food intake, body weight or both to said subject. In another aspect, a method for controlling food intake is provided, wherein the method comprises administering an effective amount of at least one anti-obesity agent acting on the structures of the forebrain involved in the modulation of increase intake, body weight or both in combination with the administration of at least one anti-obesity agent acting on the structures of the posterior brain involved in the modulation of food intake, body weight or both to said subject. In yet another aspect, a method is provided for securing or assisting compliance with a reduced or restricted calorie diet, wherein the method comprises administering an effective amount of at least one anti-obesity agent acting on the structures of the brain. previous involved in the modulation of food intake, body weight or both in combination with the administration of at least one anti-obesity agent acting on the structures of the posterior brain involved in the modulation of food intake, body weight or both to said subject . In a further aspect, a method is provided for adjusting the fixation point of a subject in such a way that the propensity of the body for homeostasis is adjusted to a healthier fixation point, wherein the method comprises administering an effective amount of less an anti-obesity agent that acts on the structures of the forebrain involved in the modulation of food intake, body weight or both in combination with the administration of at least one anti-obesity agent acting on the structures of the posterior brain involved in the modulation of food intake, body weight or both to said subject. In yet another aspect, a method for maintaining weight loss or maintaining lost weight is provided, wherein the method comprises administering an effective amount of at least one anti-obesity agent that acts on the structures of the forebrain involved in the optimization. ~ of food intake, body weight or both in combination with the administration of at least one anti-obesity agent acting on the posterior brain structures involved in the modulation of food intake, body weight or both to said subject. In an embodiment of this aspect of the invention, the weight loss is maintained by re-establishing the fixation point of the subject. In addition, in certain embodiments, the administration of anti-obesity agents in combination results in a synergistic effect in any of the methods described herein. In addition, in certain embodiments, the administration of the anti-obesity agents in combination results in a lower dose requirement for at least one of the agents, with the same effect. In one embodiment, the methods of the invention are used in the treatment and / or prevention of metabolic conditions or disorders that benefit from a reduction in nutrient availability. Accordingly, these methods may be useful in the treatment and / or prevention of obesity, diabetes (eg, type 2 or non-insulin dependent diabetes, type 1 diabetes, and gestational diabetes), eating disorders, insulin resistance syndrome, and cardiovascular disease. In one embodiment, methods are provided for use in altering the fat distribution, reducing the fat mass, or both in a subject. Therefore, subjects for whom the alteration of body composition is beneficial may also benefit from the present methods. Altered body composition, as claimed herein, includes loss or maintenance of body fat, with minimal reduction in loss, maintenance, or gain of lean body mass. In such situations, the weight can be increased as well as reduced. Therefore, the subjects can be slender, overweight or obese as these terms are generally used in the art. The methods of the invention may also include fat reduction in non-adipose tissue while having little lean mass. Uses for this method include treatment of diseases such as nonalcoholic steatohepatitis (NASH) or lipodystrophy. The methods described herein use the administration of at least one anti-obesity agent that acts on the structures of the forebrain involved in the modulation of food intake, body weight or both in combination with the administration of at least one anti-obesity agent that acts on the structures of the posterior brain involved in the modulation of food intake, body weight or both for control, prevention and / or treatment of said conditions or disorders. In another aspect, methods are provided that stimulate food intake, promote body weight gain, or both through the administration of agents that act on the forebrain and the posterior brain. In such methods, the weight-inducing agents are administered to a subject in combination and in effective amounts to stimulate food intake, promote weight gain or both in the subject. These methods are particularly beneficial for diseases and disorders such as cachexia and anorexia, and other wasting diseases characterized by loss of appetite, decreased food intake, and loss of body weight in a subject. Exemplary weight-inducing agents include NPY1 receptor agonists, NPY5 receptor agonists, leptin antagonists, MCH agonists, MC4 antagonists, cannabinoid receptor agonists, 5-HT2C antagonists, exendin antagonists, GLP-antagonists 1, ghrelin agonists, CCK antagonists, and amylin antagonists. Accordingly, one embodiment provides methods for stimulating food intake, promoting body weight gain or both in a subject in need thereof comprising administering to the subject at least two or more weight-inducing agents. With respect to the administration of weight-inducing agents, the weight-inducing agents are administered as a single administration, simultaneously as separate doses, or as sequentially administered. Where the separate dose formulations are used, the Individual weight-inducing agents can be administered essentially at the same time, i.e., concurrently, or in staggered times, eg, sequentially before or subsequent to the administration of the other weight-inducing agent of the method. In one embodiment, the first weight-inducing agent is administered approximately 30 minutes before or after at least one other weight-inducing agent, in other embodiments approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours before or after de-porl? "Mepos-otrss" "weight-inducing agents". In some embodiments, administration in combination involves the administration of separate dose formulations during overlapping intervals. For example, the weight-inducing agent 1 is administered from day 1 to day 30 and the weight-inducing agent 2 is administered from day 20 to day 50. In other modalities, administration in combination involves administration of separate dose formulations at sequential, non-overlapping intervals. For example, the weight-inducing agent 1 is administered from day 1 to day 30 and the weight-inducing agent 2 is administered from day 35 to day 50. Therefore, it is to be understood that the present invention includes all such simultaneous treatment regimens , alternating or completely separated during the course of total treatment. Any of the weight-inducing agents administered can be administered as a bolus dose or as a continuous dose. Furthermore, in certain embodiments, the administration of the weight-inducing agents in combination results in an effect synergistic in any of the aspects of the invention. In addition, in certain embodiments, the administration of the weight-inducing agents in combination results in a lower dose requirement for at least one of the agents, with the same effect. Anti-obesity agents for use in the present invention include leptin, leptin derivatives, recombinant leptin, and leptin agonists. Leptin (derived from leptose, meaning thin) is a hormone produced predominantly by fat cells. In obese humans, leptin levels in the blood usually correlate with the amount of fat stored in the body. Generally, the greater the amount of fat, the greater the amount of leptin. The levels of leptin concentration in serum in most obese humans are high, and it is thought that there is a state of resistance to leptin (Mantzoros et al. (2000) J. Endocrinol Clin. 4000-4002). Despite therapeutic attempts to use leptin to treat obesity, the effect of recombinant human leptin has been limited, if at all, to causing weight loss in obese individuals. Exceptions to this include the treatment of individuals with congenital leptin deficiency and the treatment of individuals with lipoatrophy. See, for example, Heymsfield et al. (1999) JAMA 282: 1568-1575, Farooqi et al. (1999) N. Engl J. Med. 341: 879-884, and patent publication of E.U.A. No. 2005/0020496. In certain embodiments, leptin is administered in the form of replacement therapy to achieve close physiological concentrations of leptin in the plasma. It is estimated that the physiological replacement dose of leptin is approximately 0.02 mg / kg of body weight per day for male individuals of all ages, approximately 0.03 mg / kg of body weight per day for female individuals under 18 years of age. years and approximately 0.04 mg / kg of body weight per day for adult female individuals. When attempting to achieve close physiological concentrations of leptin, it can be treated, for example, "apsrrsujetercOt? ~ '5O" percent of the estimated replacement dose during the first month of treatment, 100 percent of the replacement dose during the second month month of treatment, 200 percent of the replacement dose during the third month of treatment, etc. Leptin levels in serum can be measured by methods known in the art, including, for example, the use of commercially available immunoassays. One aspect of the invention is that the fat is reduced by such means as administering amylin to treat resistance to eptina. Once resistance to leptin is mitigated (reduced), leptin can be administered to further treat obesity. The leptin proteins and the leptin protein containing compositions suitable for use in the methods described herein are known in the art and include, but are not limited to, recombinant human leptin (PEG-OB, Hoffman La Roche) and human methionine leptin. recombinant (Amgen). Leptin proteins, analogs, derivatives, preparations, formulations, pharmaceutical compositions, doses, and routes of administration have been described above in the following patent publications and are incorporated herein by reference in their entirety: US Patents. Nos. 5,552,524; 5,552,523; 5,552,522; 5.521, 283; and PCT application publications Nos. WO 96/05309, WO 96/40912; WO 97/06816, WO 00/20872, WO 97/18833, WO 97/38014, WO 98/08512, and WO 98/284427. Leptin agonists and antagonists are known in the art and can also be found through a search of patent databases. For example, leptin agonists are described in PCT application publications Nos. 2004/0072219, 2003/049693, 2003/0166847, 2003/0092126 and U.S. Pat. Nos. 6,777,388 and 6,936,439. Leptin antagonists are described in PCT application publications Nos. 2004/0048773, 2002/0160935 and patent of E.U.A. No. 6,399,745. Test media for leptin agonism or antagonism are described in the U.S. Patents. Nos. 6,007,998 and 5,856,098. These patents are illustrative and are incorporated herein by reference in their entirety. Anti-obesity agents for use in the present invention also include amylin and amylin agonists. Amylin is a peptide hormone of 37 amino acids that is co-secreted with insulin from pancreatic beta cells in response to nutrient stimuli. Human amylin (hAmilin) has the following amino acid sequence: Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser -Ser-Asn-Asn-Phe-Gly-Ala-lle-Leu-Ser-Ser-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr (SEQ ID NO: 1). Rat amylin (rAmilin) has the following sequence: KCNTATCATQRLANFLVRSSNNLGPVLPPTNVGSNTY (SEQ ID NO: 2). The use of amylin of any species is contemplated. It has surprisingly been found that modulation of effective amylin levels in vivo such as through the use of amylin, amylin agonists, and amylin antagonists, can modulate effective levels of ghrelin in vivo. Amylin agonists contemplated in the use of the invention include those described in the U.S.A. Nos. 5,686,411, 6,114,304 and 6,410,511, which are incorporated herein by reference in their entirety. Such compounds include those having the formula I: ^ X-Asn-Thr- ^ la-Thr-Y-Ala-Thr- ^ GIn-Arg-Leu-BrAsn- ^ Phe-Leu-dD Er ^ F GrAsn-HrGIy- ^ lrJ Leu-KrLr ^ Thr-MrVal-Gly-Ser- 35Asn-Thr-Tyr-Z (SEQ ID NO: 3) where Ai is Lys, Ala, Ser or hydrogen; BT is Ala, Ser or Thr; Ci is Val, Leu or He; G-? is Asn, Gln or His; J-i is lie, Val, Ala or Leu; K-i is Ser, Pro, Leu, lie or Thr; L-i is Ser, Pro or Thr; M-i is Asn, Asp, or Gln; X and Y are independently selected amino acid residues having side chains that chemically bind to each other to form an intramolecular linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy. Suitable side chains for X and Y include groups derived from alkylsulfhydryls which can form disulfide bonds; alkyl acids and alkylamines which can form cyclic lactams; alkyl aldehydes or alkyl halides and alkylamines which can be condensed and reduced to form an alkylamine bridge; or side chains which can be connected to form an alkyl, alkenyl, alkynyl, ether or thioether bond. Preferred alkyl chains include lower alkyl groups having from about 1 to about 6 carbon atoms. A further aspect of the present invention is directed to agonist analogs of SEQ ID NO: 3 which are not bridging, and wherein X and Y are independently selected from Ala, Ser, Cys, Val, Leu and lie or esters and ethers Alkyl, aryl or aralkyl of Ser or Cys. Biologically active derivatives of the above agonist analogs are also included within the scope of this invention in which the stereochemistry of individual amino acids can be inverted from (L) / S to (D) / R at one or more specific sites.

Analogs of agonists modified by glycosylation of Asn, Ser and / or Thr residues are also included within the scope of this invention. Biologically active amylin agonist analogs are included within the scope of this invention that contain less peptide character. Said peptide simulants may include, for example, one or more of the following substitutions for amide bonds -CO-NH-: depsipeptides (-0-0-), iminomethylenes (-CH2-NH-), trans-alkenes (~ CH = CH ~), beta-enaminonitriles (~ C (= CH ~ CN) - NH-), thioamides (--CS - NH-), thiomethylenes (--S-CH2-- or -CH2-S-- ), methylenes (-CH2-C2-) and retro-amides (-NH- CO-). The compounds of this invention form salts with various inorganic and organic acids and bases. Said salts include salts prepared with organic and inorganic acids, for example, HCl, HBr, H2S04, H3P04, trifiuoroacetic acid, acetic acid, formic acid, methanesulfonic acid, toluene sulfonic acid, maleic acid, fumaric acid and camphor sulfonic acid. Salts prepared with bases include, for example, ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as calcium and magnesium salts). The acetate, hydrochloride and trifluoroacetate salts are preferred. Throughout the application, the amino acid sequence can be referred to as amino acids in position a to position b adjacent to a reference peptide. For example, 1-7 hAmiline refers to the sequence of amino acids from position 1 to position 7, inclusive, of human amylin (SEQ ID NO: 1), the reference peptide in this example. The modification to the reference peptide can be shown as the modification position adjacent to the modification. For example, (2Asp 7Lys) 1-7 hAmiline represents the amino acid sequence in positions 1 to 7 of human amylin with a modification of Cys to Asp in position 2 and a modification of Cys to Lys in position 7. As another example, 18Arg25'28Pro-h-amylin represents the amino acid sequence of human amylin with a modification of His to Arg at position 18, a modification of Ala to Pro at position 25, and a modification of the Ser a Pro at position 28. Illustrative compounds include, but are not limited to, des-1Lys-h-amylin (SEQ ID NO: 4), 28Pro-h-amylin (SEQ ID NO: 5), 25'28'29Pro- h-amylin (SEQ ID NO: 6), 18Arg25'28Pro-h-amylin (SEQ ID NO: 7), and des-1Lys18Arg25'28Pro-h-amylin (SEQ ID NO: 8), all show amylin activity in I live in treated test animals, (e.g., causing marked hyperlactemia followed by hyperglycemia). In addition to having characteristic activites of amylin, it has been found that certain of the preferred compounds of the invention possess more desirable solubility and stability characteristics when compared to human amylin. Examples of these compounds include 25Pm26Val28.29 Pro-h-amylin (SEQ ID NO: 9), 25'28'29pro-h-amylin (SEQ ID NO: 10), and 18Arg25'28Pro-h-amylin (SEQ ID NO. : 7).

Other compounds include 18Arg25 '8.29Pro-h-amylin (SEQ ID NO: 11), des-1Lys18Arg25'28'29Pro-h-amylin (SEQ ID NO: 12), des-1Lys25'28'29Pro-h-amylin (SEQ ID NO: 13), 25Pro26Val28'29Pro-h-amylin (SEQ ID NO: 14), 23Leu25Pro26Val28.29Pro-h-amylin (SEQ ID NO: 15), 23Leu25Pro26Val28Pro-h-amylin (SEQ ID NO: 16) , des- 1Lys23Leu25Pro26Val 8Pro-h-amylin (SEQ ID NO: 17), 18Arg23Leu25Pro26Val28Pro-h-amylin (SEQ ID NO: 18), 18Arg23Leu25'28'29Pro-h-amylin (SEQ ID NO: 19), 18Arg23Leu25 '8Pro -h-amylin (SEQXD NOT20), 17lle23Leu25'28'29Pro-h-amylin (SEQlD ~ NO? 21), 7lle 5'28'29Pro-h-amylin (SEQ ID NO: 22), des-1Lys17lle23Leu25'28 ' 29Pro-h-amylin (SEQ ID NO: 23), 17IIe18Arg23Leu-h-amylin (SEQ ID NO: 24), 17IIe18Arg23Leu26Val29Pro-h-amylin (SEQ ID NO: 25), 17lle18Arg23Leu25Pro26Val28'29Pro-h-amylin (SEQ ID NO : 26), 13Thr21His23Leu26Ala28Leu29Pro31Asp-h-amylin (SEQ ID NO: 27), 13Thr21His23Leu26Ala29Pro31Asp-h-amylin (SEQ ID NO: 28), des- ys 13Hi? ^ 1His23Leu26Ala28Pro31Asp-h-amylin (SEQ ID NO: 29), 13Thr18 Arg21His23Leu26Ala29Pro31Asp-h-amiline (SEQ ID NO: 30), 13Thr18Arg21His23Leu28'29Pro31Asp-h-amylin (SEQ ID NO: 31), and 13Thr18Arg21His23Leu25Pro26Ala28'2 Pro31Asp-h-amylin (SEQ ID NO: 32). Useful amylin agonist analogs include those identified in PCT application publication No. WO 93/10146, the content of which is incorporated herein by reference. Amylin agonists useful in the invention may also include fragments of amylin and their analogs as described above as well as those described in EP 289287, the content of which is incorporated herein by reference. reference. Amylin agonists can also be compounds having at least 60, 65, 70, 75, 80, 85, 90, 95 or 99% amino acid sequence identity to SEQ ID NO: 1 having amylin activity. Amylin agonists also include small molecules, non-peptide molecules, for example, those based on small molecule chemistry. "Amylin activity," as used herein, includes the ability of amylin to affect ghrelin levels in a body. Amylin agonists also include amylin analogs having insertions, deletions, extensions and / or substitutions in at least one or more amino acid positions of SEQ ID NO: 1. The number of amino acid insertions, deletions or substitutions may be greater than 5, 10, 15, 20, 25 or 30. The inserts, extensions or substitutions may be with other natural amino acids, synthetic amino acids, peptidomimetics, or other chemical compounds. The amylin agonists, as contemplated in the invention may also be calcitonins, such as teleost calcitonins, and their analogues, as well as peptides related to the calcitonin gene (CGRP) and its analogues. Amylin agonists also include polypeptides (referred to herein as LHC peptides (C-terminal loop helix)) described in the U.S. patent application. No. 60 / 543,275 and in PCT application No. PCT / US2005 / 004631, filed on February 11, 2005, each of which is incorporated herein by reference, as well as its analogues and derivatives. The LHC peptides for use in the Invention act as an agonist for at least one biological effect of calcitonin, amylin, CGRP or any combination of the three described herein or linked to at least one of the amylin, calcitonin or CGRP receptors. The binding activity of the receptor and the biological activity of illustrative LHC peptides are described in the patent application of E.U.A. No. 60 / 543,275 and in the PCT application No. PCT / US2005 / 004631. In a general aspect, these polypeptide agonists have at least one loop region of amylin or calcitonin and analogs thereof, a helical region a of at least a portion of a helix region a of calcitonin or analogs of the same or a helical region a having a portion of a helical region of amylin and a helical region of calcitonin or its respective analogs, and a C-terminal tail of amylin or calcitonin or analogues thereof, with the proviso that the tail C-ends! of calcitonin or a calcitonin analogue is not proline (Pro), hydroxyproline (Hyp), homoserin (Hse) or derivatives of Hse. In certain embodiments, these LHC peptides have an amylin or amylin analogue loop region, at least a portion of a calcitonin a or calcitonin analogue helix region, and a C-terminal amylin or amylin analogue tail. . In other embodiments, these LHC peptides have a calcitonin or calcitonin analogue loop region, at least a portion of a calcitonin a or calcitonin analogue helix region, and a C-terminal amylin or amylin analogue tail. In still other embodiments, these LHC peptides have a loop region of amylin or amylin analogue, at least a portion of a amilin or analogous amylin and at least a portion of a calcitonin a or calcitonin analogue helix region, and a C-terminal amylin or amylin analogue tail. In still other embodiments, these LHC peptides have a calcitonin or calcitonin analogue loop region, at least a portion of an amylin a or amylin analogue helical region and at least a portion of a helical region a calcitonin or calcitonin analog, and a C-terminal tail of amylin or amylin analogue. In other additional embodiments, these LHC peptides have an amylin or amylin analogue loop region, a portion of a calcitonin a helical region or calcitonin analogue or at least a portion of a helical region of amylin or analogue of amylin and at least a portion of a helix region of calcitonin or calcitonin analog, and a C-terminal tail of caicitonin or caicitonin analogue. In certain embodiments, the loop region of these LHC peptides may further comprise no more than one, two, three or four modifications including substitutions, insertions or loop deletions of amylin or calcitonin, and analogs thereof. Furthermore, it is contemplated that these LHC peptides may have additional modifications in the N-terminal portion of the loop comprising a N-cap region, which may have hydrophobic or hydrophilic characteristics such as acetyl, socaproyl, 3,6-dioxyoctanoic acid, or 1-amino-4,7,10-trioxa-13-tridecanaminsuccininic acid. Modifications may also include one, two, three or more additional amino acids. This is an area that allows many modifications too numerous to mention, but would be understood by a person skilled in the art on the basis of those illustrated by way of example later in this application. These LHC peptides can also be derived by chemical alterations such as amidation, glycosylation, acylation, sulfation, phosphorylation, acetylation and cyclization. Said chemical alterations can be obtained through chemical or biochemical methodologies, as well as through in vivo procedures, or any combination thereof. Derivatives of these LHC peptides may also include conjugation to one or more small molecule polymers or substituents. One type of polymer conjugation is the linking or linking of polyethylene glycol ("PEG") polymers, polyamino acids (e.g., poly-his, poly-arg, poly-lys, etc.) and / or fatty acid chains of various lengths to the N- or C-terminal or side chains of amino acid residues of the polypeptide. Small molecule substituents include short aiquiia and contracted alkyls (e.g., branched adamantyl, cyclic, fused), and aromatic groups. In addition, basic residues such as R and K can be replaced by homoR and homoK, citrulline or omitin to improve the metabolic stability of the peptide. Polypeptides for use in the invention include acid as well as basic forms. In certain modalities, the a-helix region of the peptides LHC comprises at least four consecutive amino acids of a calcitonin α-helical region or calcitonin analogue. In another embodiment, the a-helix region comprises at least 5, 6, 7 or 8 amino acids consecutive of a calcitonin helix region or calcitonin analogue. In other embodiments, the a helical region comprises at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or more consecutive amino acids from a helix region to calcitonin or analogue calcitonin. In certain embodiments, when the number of consecutive amino acids is less than 8, it is contemplated that the a-helical region further comprises at least 4, 5, 6, 7, 9, 10, 11, or more consecutive amino acids from a region of amylin or amylin analogue helix. In certain embodiments, it is contemplated that while fewer amino acids of calcitonin or calcitonin analogue, more amino acids of an amylin or amylin analogue may be found in the a helical region of the novel compounds. The number of amino acids comprising the helical region a may be from about 10 to 23 amino acids. Therefore, the a helical region may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 amino acids long. Furthermore, the amino acids must provide approximately three to approximately six turns of helix. Furthermore, it is contemplated that the helix region a of the compounds may further comprise no more than one, two, three, four, five, six, seven, eight, nine or ten modifications including substitutions, insertions or deletions of that region. of helix a of calcitonin and / or amylin, and analogues thereof. In certain embodiments, the C-terminal tail of the LHC peptides comprises at least the last six, five or four amino acids of either amylin or calcitonin, and analogs thereof. In certain modalities, the C-terminal tail of the novel compounds comprises at least a portion of the C-terminal end having a β-turn. In certain modalities, the ß turn is introduced by the amino acid combination of Gly-Ser. Accordingly, the LHC peptides may have a C-terminal end comprising a portion of a C-terminal tail of amylin or calcitonin (and analogs thereof) having Gly-Ser or starting on Gly-Ser. In certain embodiments, the C-terminal tail of the LHC peptides may further comprise no more than one, two or three modifications including substitutions, insertions or deletions of the amylin or calcitonin loop, and analogs thereof. In addition, it is contemplated that the LHC peptides may have additional modifications in the C-terminal portion of the C-terminal tail which may include, for example, L-octylglycine, 4ABU (4-aminobutyric acid), 9Anc (9-aminonanoic acid) , 3,6-dioxyoctanoic acid or 1-amino-4,7,10-trioxa-13-tridecanaminosuccinimic acid. The modification may also include one, two, three or more additional amino acids. The types of modification contemplated in this area would be understood by a person skilled in the art based on what is illustrated by way of example in the present application. In one aspect, a loop region is defined as that region found at the N-terminus comprising at least 5 to 8 amino acids, wherein the first and last amino acids are capable of creating a bond, for example, residues in the 2-7 positions of amylin or residues in positions 1-7 of calcitonin and their corresponding regions in their respective analogs. In another aspect, a helical region a is defined as the internal portion of amylin or calcitonin flanked by the loop region and the C-terminal tail that structurally forms a helix a, eg, residues at positions 8-23 of amylin or residues at positions 8-27 of calcitonin and their corresponding regions in their respective analogs. In yet another aspect, a C-terminal tail is defined as that region after helix a, eg, residues at positions 33-37 of amylin or longer such as residues at positions 27-37 or residues in positions 27 or 28 to 32 of calcitonin. Included in the LHC peptides are both the amide form and the acid form of the described compounds. Amylin and calcitonin, as defined herein, include all native and species variations. Examples of amylin and calcitonin include, but are not limited to: human amylin (SEQ ID NO: 1), rat amylin (SEQ ID NO: 2), salmon calcitonin (sCT) CSNLSTCVLGKLSQELHKLQTYPRTNTGSGTP (SEQ ID NO: 33), and human calcitonin (hCT) CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP (SEQ ID NO: 34). In a general aspect, the LHC peptides comprise at least a loop region, a helical region a, and a C-terminal tail. The loop region comprises an amino sequence comprising the formula (II) sequence X-Xaa1-Y wherein X and Y are capable of creating a bond and are independently selected residues having chains laterals that are, or are capable of being, chemically linked to each other to form an intramolecular bond such as, for example, a disulfide bond; an amide bond; a cyclic lactam formed, for example, by an alkyl acid and an alkylamine; an alkylamine or imine bridge formed, for example, by condensation and reduction of alkyl aldehydes or alkyl halides and alkylamines; and an alkyl or alkenyl, alkenyl, alkynyl ether or thioether bond formed, for example, by attachment of side chains. Side chains can include lower alkyl groups having from about 1 to about 6 carbon atoms. In certain embodiments, the intramolecular linkage can be a disulfide, amide, mine, amine, alkyl, and alkene bond. In certain embodiments, X and Y of formula (II) are independently selected from Ser, Asp, Glu, Lys, Orn (ornithine) or Cys. In certain embodiments, X and Y of formula (II) are Cys and Cys. In other embodiments, X and Y of formula (II) are Ser and Ser. In other embodiments, X and Y of formula (II) are Asp and Lys or Lys and Asp. The Xaa1 sequence of formula (II) comprises an amino acid sequence of 3, 4, 5 or 6 amino acids between X and Y. In certain embodiments, the Xaa1 sequence comprises an amino acid sequence having a region with one or more substituted or unsubstituted hydroxyl-containing residues proximate Y. For example, the hydroxyl-containing residue region may have at least 2 of the 3 adjacent amino acids Y that are either a Ser or Thr. The other amino acids in the Xaa1 sequence can be any amino acid. In certain modalities, the Xaa1 sequence is 3 amino acids. In other embodiments, the Xaa1 sequence is 4 amino acids. In still other embodiments, the Xaa1 sequence is 5 amino acids. In still other embodiments, the Xaa1 sequence is 6 amino acids. Accordingly, Xaa1 of the formula (II) can be represented by Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7 (SEQ ID NO: 35). In certain embodiments, Xaa2, Xaa3, Xaa4, any two, or all three may be absent. In certain embodiments, Xaa5, Xaa6 and Xaa7 comprise the residue region containing hydroxyTX. As such, at least two of the three amino acids may be a Ser, Hse, Thr, alloTreonine (aloThr), d-Threonine (d-Thr), or another unnatural analogue thereof. Xaa2 can be any amino acid or be absent, Xaa3 can be any amino acid or be absent, Xaa4 can be any amino acid or be absent, Xaa5 can be any amino acid if Xaa6 is a Ser or Thr and Xaa7 is a Ser or Thr, Xaa6 can be any amino acid if Xaa5 is a Ser or Thr and Xaa7 is a Ser or Thr, Xaa7 can be any amino acid if Xaa5 is Ser or Thr and Xaa6 is Ser or Thr. Accordingly, in some embodiment, Xaa1 can be represented as Xaa2 absent, Xaa3 is Ala, Gly, Ser, Asp or is absent, Xaa4 is Asn, Ala, Asp, Gly or is absent; Xaa5 is Ala, Leu, Thr, or Ser; Xaa6 is Ala, Ser, or Thr; and Xaa7 is Ala, Ser, Val, Hse, (S) -2-amio-3-hydroxy-methylbutanoic acid (Ahb), (2S, 3R) -2-amino-3-hydroxy-methylpentanoic acid (Ahp), d -Thr, Thr, or a derivative thereof. In other modalities, Xaa1 can be represented as Xaa2 is absent, Xaa3 is Ser, Gly, or is absent, Xaa4 is Asn or Asp, Xaa5 is Ala, Ser, Thr or Leu, Xaa6 is Ala, Thr or Ser, and Xaa7 is Ser, d-Thr, alloThr or Thr. In certain embodiments, the loop region of formula (II) comprises the above-described representations of Xaa1 wherein Xaa3 is Ala, wherein Xaa3 is Ser or wherein Xaa3 is Gly. Alternatively or additionally, the loop region comprises the above-described representations of Xaa1 wherein Xaa4 is Ala, wherein Xaa4 is Asn, wherein Xaa4 is Asp, or wherein Xaa4 is Gly. Alternatively or additionally, the loop region comprises the above-described representations of Xaa1 wherein Xaa5 is Ala, where Xaa5 is Thr, or where Xaa5 is Leu. Alternatively or additionally, the loop region comprises the above-described representations of Xaa1 wherein Xaa6 is Ser or wherein Xaa6 is Ala. Alternatively or additionally, the loop region comprises the above-described representations of Xaa1 wherein Xaa7 is Thr or wherein Xaa7 is d-Thr. In addition, it is contemplated that no more than one, two or three modifications such as substitutions, insertions, deletions, and / or derivations can be made to the loop region. Examples of the loop region of the invention include, but are not limited to, CNTATC (SEQ ID NO: 36); CATATC (SEQ ID NO: 37); CDTATC (SEQ ID NO: 38); CGTATC (SEQ ID NO: 39); CNAATC (SEQ ID NO: 40); CNTSTC (SEQ ID NO: 41); CNTA-dThr-C (SEQ ID NO: 42); CNTA-T (OP03H2) -C (SEQ ID NO: 43); CNTASC (SEQ ID NO: 44); CNTAAC (SEQ ID NO: 45); CNTAVC (SEQ ID NO: 46); CNTA-Hse-C (SEQ ID NO: 47); CNTA-Ahb-C (SEQ ID NO: 48); CNTA-Ahp-C (SEQ ID NO: 49); CSNLSTC (SEQ ID NO: 50); CGNLSTC (SEQ ID NO: 51); CANLSTC (SEQ ID NO: 52); CSALSTC (SEQ ID NO: 53); CSNASTC (SEQ ID NO: 54); CSNLATC (SEQ ID NO: 55); and CSNLSAC (SEQ ID NO: 56). As noted above, it is further contemplated that no more than one, two or three modifications such as substitutions, insertions, deletions and / or derivations can be made to the loop region. The loop region of the LHC peptides may further comprise modifications or additional amino acids at the N-terminus. Such modifications include the addition of compounds such as Lys, Ala, Phe, He, Ser, Octylglycine, Isocap, Fmoc-3,6-dioxo-octanoic acid, Fmoc-1-amino-4,7,10-trioxa-13-tr acid. Decanaminosuccinimic, acetyl, and / or groups for solubility, supply, signaling. Illustrative modified loops include the addition of Lys to the Xaa1 sequence or the addition of He to the Xaa1 sequence. For example, the modified loop region may be KCNTATC (SEQ ID NO: 57). In certain embodiments, additions and / or modifications at the N-terminal end of the loop region may change the loop region. For example, the loop region can be modified as follows: cycle (2.7) 1-7 hAmilin, cycle (2Asp 7Lys) 1-7 hAmilin, N-isocaproyl 1-7 hAmilin, N-3.6 dioxaoctanoyl 1- 7 hAmilina, L-Octilglicina 1-7 hAmilina, Acetil (2Agy, 7Agy) 1-7 hAmilina where Agy is Alilglicina, Acetil (1Ala) 1-7 hAmilina, (1Thr, 3Asp) 1-7 hAmilina, Isocap (7Ala) 5-7 sCT, Acetyl (2Agy, 7Agy) 1-7 sCT, and cycle (1, 7) (1ASp 7Lys) 1-7 sCT. Therefore, taking the example of Isocap (7Ala) 5-7 sCT, certain modalities include a modification in the N-terminal region of the loop region such that the amino acids Xaa2 to Xaa5 are absent. The a helix region of the LHC peptides may be about 8 to 23 amino acids in length. In certain embodiments, the helix region a is amphipathic. In certain embodiments, the a-helical region comprises approximately 3 to 6 helical turns. In certain embodiments, the a-helical region comprises 3, 4, 5 or 6 helical turns. In other embodiments, the helical region a is a rigid structure equivalent to approximately 3, 4, 5 or 6 helical turns. An example of an idealized helix is LLQQLQKLLQKLKQY (SEQ ID NO: 58). In certain modalities, helix a is an amphipathic structure. Accordingly, the desirable amino acid characteristics that would provide this type of structure can be selected. It has been found that the α-helix region of calcitonin, a combination of an amylin and a α-helical region of calcitonin, or parts thereof, and / or some CGRP elements are-desirable in the α-helix region of the peptides LHC. It is contemplated that, as with the loop region, the a helical region may be any amylin or calcitonin, and analogs thereof. Accordingly, in certain embodiments, the helical region a is at least a portion of a helical region a of a calcitonin or calcitonin analog. In other embodiments, the helix region a is at least a portion of a helix region a of a calcitonin or calcitonin analog and at least a portion of a helix a of a amylin or amylin analogue. In still other embodiments, the helix region a of the LHC peptides contain CGRP elements. In addition, it is contemplated that the novel compounds may have no more than one, two, three, four, five, six, seven, eight, nine or ten additional modifications such as substitutions, insertions, deletions, and / or derivations. In certain embodiments, the helical region a of the LHC may comprise a helix region of type I. Uns helical region of type I comprises amino acids from the 8 position of sCT to position 18, 19, 20, 21, 22 , 23, 24, 25, 26 or 27 of sCT. Moreover, the α-helix region of type I may comprise more than one portion of a helix region α of calcitonin or calcitonin analogue of the same or different species, for example 8-21 sCT 19-27 sCT; 8-21 sCT 18-27 sCT; or 8-16 hCT 17-27 sCT; or (1Arg) 8-16 hCT (18Arg) 17-27 sCT. Alternatively or additionally, the above described helix a of 8-18 sCT at 8-27 sCT may further comprise substitutions of one or more of (10Aib), (11Arg), (11Orn), (11hATg), (1Cit), ( 11hLyS), (Lys (-for -) -) ^ (^ A, b); (18Arg), (18Orn), (18hArg), (18Cit), (18hLys), (18Lys (for)), (18Lys (PEG5000)), (22Leu), (24Pro) or any combination thereof. In one embodiment, a helical region of type I of the LHC peptides can be represented by: X1 VL XaalO Xaa11 LSQ Xaa15 L Xaa17 Xaa18 LQT Xaa22 P Xaa24 TNT X1 (SEQ ID NO: 59), where XaalO is Gly or Aib; Xaa11 is Lys, Arg, Orn, hArg, Cit, hLys, or Lys (for); Xaa15 is Glu or Phe; Xaa17 is His or Aib; Xaa18 is Lys, Arg, Orn, hArg, Cit, hLys.Lys (for), Lys (PEG 5000); Xaa22 is Try or Leu; Xaa24 is Arg or Pro; or X1 is absent or comprises 1-4 additional amino acids. It must be remembered that each member of the Markush group, or a combination thereof, is another embodiment of the invention and should not be read as a single unit. This is an abbreviated method to establish, as an example, modalities of the LHC peptides include a helix a-type I formula where, Xaa18 can be a Lys, Arg, Om, hArg, Cit, hLys, or Lys ( for), and each variation is a separate embodiment of the invention. Accordingly, the helix region formula of type I has a mode where XaalS is Lys. Has another modality where Xaa1 8 is Arg, etc. In addition, it is contemplated that the a helical region may contain no more than one, two, three, four, five, six, seven, eight, nine or ten modifications such as substitutions, insertions, deletions and / or derivations. Accordingly, helix a-type I compounds may have additional deletions at the C-terminus. In certain embodiments, the amino acids of X1 are capable of forming a helical turn of a. Examples of a helical region of type I of the LHC peptides include, but are not limited to, 8-18 sCT, 8-21 sCT, 8-24 sCT, 8-27 sCT, (11Arg) 8-18 sCT, (18Arg) 8-18 sCT, (11Arg 18Arg) 8- 18 sCT, (1Orn 18Orn) 8-18 sCT, (11Arg 18Cit) 8-18 sCT, (11hArg 18hArg) 8-18 sCT, (11Arg 18Orn) 8-18 sCT, (11Cit 8Arg) 8-18 sCT, (1 Cit 18Cit) 8-18 sCT, (11hLys 18hLys) 8-18 sCT, (10Aib 11Arg 17Aib 18Arg) 8-18 sCT, (11Lys (for) 18Lys (for)) 8-18 sCT, (10Aib 11LyS (for) 17Aib 18Lys (for)) 8-18 sCT, (11Arg 18Lys (PEG 5000)) 8-18 sCT, (1 Arg) 8-21 sCT, (18Arg) 8-21 sCT, (11Arg 18Arg) 8-21 sCT, ( 11Orn 18Orn) 8-21 sCT, (11Arg 18Ct) -21 sCT, (1hArg 18hArg) 8-21 sCT, ('11Arg 18Om) 8-21 sCTTT'Oit 8Arg) 8-21 sCT, (11Cit 18Cit) 8 -21 sCT, (11hLys 18hLys) 8-21 sCT, (10Aib 11Arg 17Aib 18Arg) 8-21 sCT, (11Lys (for) 18Lys (for)) 8-21 sCT, (10Aib 1Lys (for) 17Aib 18Lys (for) ) 8-21 sCT, (11Arg 18Lys (PEG 5000)) 8-21 sCT, (11Arg) 8-24 sCT, (18Arg) 8-24 sCT, (11Arg 18Arg) 8-24 sCT, (11Arg 18Arg 22Leu) 8 -24 sCT, (11Arg 18Arg 24Pro) 8-24 sCT, (11Orn 18Orn) 8-24 sCT, (11Arg 18Cit) 8-24 sCT, ( 11hArg 18hArg) 8-24 sCT, (11Arg 18Orn) 8-24 sCT, (11Cit 18Arg) 8-24 sCT, (11Cit 18Cit) 8-24 sCT, (11hLys 18hLys) 8-24 sCT, (10Aib 11Arg 7Aib 18Arg) 8-24 sCT, (11Lys (for) 18Lys (for)) 8-24 sCT, (10Abs 11Lys (for) 17Aib 18Lys (for)) 8-24 sCT, (11Arg 18Lys (PEG 5000)) 8-24 sCT, (1Arg) 8-27 sCT, (8Arg) 8-27 sCT, (11Arg 18Arg) 8-27 sCT, (11Arg 18Arg 22Leu) 8-27 sCT, (11Arg l8Arg 24Pro) 8-27 sCT, (11Orn 18Orn) 8 -27 sCT, (11Arg 18Cit) 8-27 sCT, (11hArg 18hArg) 8-27 sCT, (11Arg 180m) 8-27 sCT, (11Cit 18Arg) 8-27 sCT, (11Cit 18Cit) 8-27 sCT, ( 11hLyS 18hLys) 8-27 sCT, (10Aib 11Arg 17Aib 18Arg) 8-27 sCT, (11Lys (for) 18Lys (for)) 8-27 sCT, (10Aib 11Lys (for) 17Aib 18Lys (for)) 8-27 sCT , (11Arg 18Lys (PEG 5000)) 8-27 sCT, (11Arg 18Arg) 8-21 sCT-19-27 sCT, and (11Arg 18Arg) 8-21 sCT- (18Leu) 18-27 sCT. In certain embodiments, the a helical region of the LHC peptides may comprise a helical region of type II. A helical region of type II comprises a portion of a helical region a of an amylin or analogue of amylin and a portion of a helical region a of a calcitonin or calcitonin analogue. The a-helix region type II can comprise amino acids from position 8 of hAmilin to 11, 12, 13, 14, 15, 16, 17, 18 or 19 of hAmilin and amino acids of position 13, 14, 15, 16, 17, 18, and 19 of sCT to position 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 of sCT. Alternatively or additionally, the previously described a helical region of amylin and calcitonin may further comprise substitutions of one or more of (8Val), (9Leu), (9Met), (10Gly), (10His), (12Thr), ( 13Thr), (13Asn), (13Phe), (13Tyr), (14Arg), (14Al), (14Asp), (14Giu), (14Gin), (4Thr), (14Giy), (15Leu), (15Ser) (15Glu), (15Al), (15Tyr), (16Asp), (17Ser), (17Phe), (18Arg), (17Aib), (18Arg), (180m), (18hArg), (18Cit), ( 18hLys), (8Lys (for)), (18Lys (PEG5000 -)) r (19Phe), (20His), (21Asn), - (22Met), (22Val), (22Phe), (22Leu), (24Pro) , or any combination thereof. In certain embodiments, the number of amino acids in the helix region of type II of the LHC peptides is at least 10 amino acids. In other embodiments, the number of amino acids in the helical region of type II of the LHC peptides is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23. In others embodiments, the number of amino acids in the type II helical region of the LHC peptides is 24 or more.

In one embodiment, a helix region of type II of the LHC peptides can be represented by: X1 Xaa8 Xaa9 XaalO Xa Xa12 Xaa13 Xaa15 Xaa16 Xaa17 Xaa18 Xaa19 Xaa20 Xaa21 Xaa22 P Xaa24 TNT X1 (SEQ ID NO: 60) where Xaad is Ala or Val; Xaa9 is Thr, Met or Leu; XaalO is Gln, Gly, His; Xaa12 is Leu, or Thr; Xaa13 is Ala, Thr, Asn, Phe, Tyr, Ser, or Thr; Xaa14 is Asn, Arg, Ala, Asp, Glu, Gln, Thr, or Gly; Xaa15 is Phe, Leu, Ser, Glu, Ala, Asp, or Tyr; Xaa16 is Leu or Asp; Xaa17 is Val, His, Ser, Phe, or Aib; Xaa18 is His, Arg, Lys, Orn, hArg, Cit, hLys, Lys (for), or Lys (PEG5000); Xaa19 is Leu, Ser or Phe; Xaa20 is Gln or His; Xaa21 is Thr or Asn; Xaa22 is Tyr, Val, Phe.Leu or Met; Xaa24 is Arg or Pro; and X1 is absent or comprises 1-4 additional amino acids. Again, each member in the Markush group, or a combination thereof, is another embodiment of the invention and should not be read as a single unit. In addition, it is contemplated that the a-helix region of type II may contain no more than one, two, three, four, five, six, seven, eight, nine or ten modifications such as substitutions, insertions, deletions and / or derivations of the compounds described herein. For example, in certain embodiments, the a-helix region of type II may have deletions at the C-terminal end resulting in the deletion of position 27, 26, 25, 24 or 22. In other embodiments, however, the deletions do not remove amino acids from positions 19, 20, 21 or 22. Examples of a helical region of type II of the LHC peptides include, but are not limited to, (8Val 9Leu 10Gly) 11-15 hAmilin 16-27 sCT, (8Val 9Leu 10Gly) 11-15 hAmilina (18Arg) 16-27 sCT, 8-12 hAmilina (18Arg) 13-27 sCT, 8-18 hAmilina 19-23 sCT, 8-18 HAmilina 19-27 sCT, (15Glu 18Arg) ) 8-18 hAmilina 19-24 sCT, (14Arg 15Ser) 8-18 hAmilina 19-22 sCT, (13Ala 4Ala 15Ala) 8-18 hAmilina 19-27 sCT, (13Ala 14Asp 15Ala) 8-18 hAmilina 19-22 sCT , (13Ala 14Asp) 8-18 hAmilina 19-23 sCT, (13Ala 14Asp) 8-18 hAmilina 19-27 sCT, (13Ala 14Ala) 8-18 hAmilina 19-22 sCT, (13A! A 14G! U) 8- 18 hAmiline 19-22 sCT, (13Thr 14Asp 15Tyr) 8-18 hAmiline 19-22 sCT, (13Ala 14Gln) 8-18 hAmilina 19-22 sCT, (13Asn 14Glu 15Tyr) 8-18 hAmilina 19-27 sCT, (13Phe 14Asp) 8-18 hAmilina 19-27 sCT, (13Ala 14Asp) 8-18 hAmilina (15Glu 18Arg) 8-18 hAmilina 19-24 sCT, (19Phe 22Phe) 19 -27 sCT, (13AIa 14Asp) 8-18 hAmilina (19Phe 20His 22Phe) 19-27 sCT, (13Ala 14Asp) 8-18 hAmilina (19Phe 22Phe) 19-27 sCT, (9Thr 10His) 8-18 hAmilina 19-22 sCT, (Thr 10His 14GIy 15Leu 17Ser 18Arg) 8-19 hAmiline 20-23 sCT, 8-18 hAmline (21Asn 22Phe 23Val) 19-23 sCT, 8-18 hAmiline (22Met) 19- 27 sCT, 8-18 hAmilina (22Val) 19-27 sCT, (9Met 12Thr 13Tyr 14Thr 15GIu 16Asp 7Phe) 8-17 hAmilina (18Arg) 18-20 sCT). In other embodiments, the novel compounds include variations of the above illustrative compounds with the helix a terminating in correspondence to 22, 23, 24, 25, 26 or 27 of sCT. In other words, the compound 8-18 hAmiline 19-24 sCT is also specifically described since this compound is simply 8-18 hAmiline 19-27 sCT described above truncated to position 24. As another example, the compound (13Ala 14Asp 15Ala ) 8-18 hAmiline 19-23 is specifically described due to the previous language applied to (13Ala 14Asp 15Ala) 8-18 hAmilina 19-22. In certain embodiments, the C-terminal tail of the LHC peptides comprises amino acids from position 27, 28, 29, 30, 31, 32 or 33 to position 36 or 37 of hAmilin. In other embodiments, the C-terminal tail of the LHC peptides comprises amino acids from position 27 or 28 to position 32 of sCT; however, when the loop region is of a calcitonin or calcitonin analogue and the helix region a is of a calcitonin or calcitonin analogue, the last position of the C-terminal tail is not Pro, Hyp, Hse or derivatives of Hse. Alternatively or additionally, the afore described amylin and calcitonin helix may further comprise substitutions of one or more of (27Tyr) hAmilin, (29Arg) hAmilin, (32Val) hAmilin, (32Thr) hAmilin, (34Glu) hAmylin, (35Lys ) hAmilin, (36Phe) hAmilin, (36Ala) hAmilin, (37Phe) hAmilin, (30Asn) sCT, (32Tyr) sCT, or any combination thereof.

In one embodiment, a C-terminal tail of the LHC peptides can be represented by Xaa28 Xaa29 Xaa30 Xaa31 Xaa32 Xaa33G Xaa35 Xaa36 Xaa37 Xaa38 (SEQ ID NO: 61), wherein Xaa28 is Lys, Tyr, or is absent; Xaa29 is Ser, Pro, or absent; Xaa30 is Ser, Pro, Arg, or is absent; Xaa31 is Thr, or is absent; Xaa32 is Asn or absent; Xaa33 is Val, Thr, or is absent; Xaa35 is Ser, Giu Xaa36 is Asn, Lys, or Gly; Xaa37 is Thr, Phe, or Ala; Xaa38 is Tyr, Phe, Pro, or is absent; with the proviso that when the loop region of the LHC agonist is of a calcitonin or calcitonin analogue and the helix region a is of a calcitonin or calcitonin analogue, the last position of the C-terminal tail is not Pro, Hyp, Hse or derivatives of Hse. Again, each member of the Markush group, or a combination thereof, is another embodiment of the invention and should not be read as a single unit. In addition, it is contemplated that the C-terminal tail may contain no more than one, two or three modifications such as substitutions, insertions, deletions and / or derivations of the compounds described herein.

Examples of the C-terminal tail of an LHC agonist include, but are not limited to, 27-37 rAmilin, (27Tyr 29Arg 32Thr) 27-37 rAmiiin, (29Arg 32Thr) 28-37 rAmilin, 30-37 hAmilin, ( 32Thr) 30-37 hAmilina, (35Lys 36Ala 37Phe) 30-37 hAmilina, 30-36 hAmilina, (32Val) 30-36 hAmilina, (34Glu 36Phe) 30-36 hAmilina, 31-37 hAmyin, 31-36 hAmilina, 33 -36 hAmilina, 33-37 hAmilina, 28-32 sCT, (30Asn 32Tyr) 28-32 sCT, and 27-32 sCT. In other embodiments, the C-terminal tail comprises the amino acid sequence KSNFVPTNTSEQ D ~ NO: 62) or SNFVPTNV (SEQ ID NO: 63). Furthermore, it is contemplated that no more than one, two or three modifications such as substitutions, insertions, deletions and / or derivations can be made to the C-terminal tail of the invention as described in the preceding paragraphs. The C-terminal tail of the LHC peptides may further comprise modifications or additional amino acids at the C-terminus. Such modifications include the addition of compounds such as Lys, up to 4 Lys, L-Octylglycine, 4ABU (4-aminobutyric acid), 9Anc (9-aminonanoic acid), and / or groups for solubility, stability, or delivery. Examples include, but are not limited to, 33-37 h-aminine L-octylglycine, 33-37 hAmilin 4ABU and 33-37 hAmilin 9Anc. In a general aspect, the LHC peptides for use in the invention comprise (a) any of the LHC agonist loop regions as described herein; (b) any of the LHC agonist helix regions as described here; and (c) any of the C-terminal LHC agonist tails described herein, with the proviso that when the loop region is of a calcitonin or calcitonin analogue and the helix regions a is of a calcitonin or calcitonin analogue , the last position of the C-terminal tail is not Pro, Hyp, Hse or derivatives of Hse. In another general aspect, the LHC peptides for use in the invention comprise (a) a loop region comprising formula (II) Xaa1 or Xaa1 with modifications at the N-terminus; (b) a helical region a comprising the helical region a of type I or type II; (c) a C-terminal tail represented by SEQ ID NO: 61, with the proviso that when the loop region is of a calcitonin or calcitonin analogue and the helix region a is of a calcitonin or calcitonin analogue, the The last position of the C-terminal tail is not Pro, Hyp, Hse or derivatives of Hse. The C-terminal end may comprise additional modifications. In yet another aspect, the LHC peptides for use in the invention comprise an amino acid sequence of the formula (III): Xaa1 X Xaa3 Xaa4 Xaa5 Xaa6 Xaa6 Xaa9 XaaO Xaa11 Xaa12 Xaa13 Xaa14 Xaa15 Xaa16 Xaa17 Xaa18 Xaa19 Xaa20 Xaa21 Xaa22 Xaa23 Xaa24 Xaa25 Xaa26 Xaa27 Xaa28 Xaa29 Xaa30 Xaa31 Xaa32 (SEQ ID NO: 64) where Xaa1 is A, C, hC, D, E, F, I, L, K, hK, R, hR, S, Hse, T, G, Q, N, M, Y, W, P, Hyp, H, V or is absent; Xaa3 is A, D, E, N, Q, G, V, R, K, hK, hR, H, I, L, M, or is absent; Xaa4 is A, I, L, S, Hse, T, V, M, or is absent; Xaa5 is A, S, T, Hse, Y, V, I, L, or M; Xaa6 is T, A, S, Hse, Y, V, I, L, or M; Xaa8 is AXVXI, IT, F, or M; Xaa9 is L, T, S, Hse, V, I, or M; XaalO is G, H, Q, K, R, N, hK, or hR; Xaa11 is K, R, Q, N, hK, hR, or H; Xaa12 is L, I, V, F, M, W, or Y; Xaa13 is A, F, Y, N, Q, S, Hse, or T; Xaa14 is A, D, E, G, N, K, Q, R, H, hR, or hK; Xaa15 is A, D, E, F, L, S, Y, I, V, or M; Xaa16 is L, F, M, V, Y, or I; Xaa17 is H, Q, N, S, Hse, T, or V; Xaa18 is K, hK, R, hR, H, u (Cit), or n (Orn); Xaa19 is F, L, S, Hse, V, I, T, or is absent; Xaa20 is H, R, K, hR, hK, N, Q, or is absent; Xaa21 is T, S, Hse, V, I, L, Q, N, or is absent; Xaa22 is F, L, M, V, Y, or I; Xaa23 is P or Hyp; Xaa24 is P, Hyp, R, K, hR, hK, or H; Xaa25 is T, S, Hse, V, I, L, F, or Y; Xaa26 is N, Q, D, or E; Xaa27 is T, V, S, F, I, or L; Xaa28 is G or A; Xaa29 is S, Hse, T, V, I, L, or Y; Xaa30 is E, G, K, N, D, R, hR, hK, H, or Q; Xaa31 is A, T, S, Hse, V, I, L, F, or Y; and Xaa32 is F, P; Y7Hse, S? T7 ~ d ~ Hyp; wherein X and Y are capable of creating a bond and are independently selected residues having side chains that chemically bind to each other to form an intramolecular bond such as disulfide bonds; amide bond; alkyl acids and alkylamines which can form cyclic lactams; alkylaldehydes or alkyl halides and alkylamines which can be condensed and reduced to form an alkylamine or imine bridge; or side chains which can be connected to form an alkyl or thioether alkyl, alkenyl, alkynyl, ether or thioether bond. The alkyl chains may include lower alkyl groups having from about 1 to about 6 carbon atoms. In certain embodiments, the intramolecular linkage may be a disulfide, amide, imine, amine, alkyl, and alkene bond. In certain modalities, X and Y are independently selected from Ser, Asp, Glu, Lys, Orn, or Cys. In certain modalities, X and Y are Cys and Cys. In other modalities, X and Y are Ser and Ser. In other modalities, X and Y are Asp and Lys or Lys and Asp. In yet another aspect, the LHC peptides for use in the invention comprise an amino acid sequence of the formula (IV): Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 XaalO Xaa11 Xaa12 Xaa13 Xaa14 Xaa15 Xaa16 Xaa17 Xaa18 Xaa19 Xaa20 Xaa21 Xaa22 P Xaa24 T N Xaa27 G S Xaa30 Xaa31 Xaa32 (SEQ ID NO: 65) wherein Xaa1 is A, C, D, F, I, K, S, T, or is absent; Xaa2 is CxD, S, or is absent; Xaa3 is A, D, N, or absent; Xaa4 is A, L, T, or is absent; Xaa5 is A or S; Xaa6 is T, A, S, or V; Xaa7 is C, K, or A; Xaa8 is A, V, L, or M; Xaa9 is L or T; XaalO is G, H, or Q; Xaa11 is K, R, Q, or hArg; Xaa12 is L, W, or Y; Xaa13 is A, F, N, Q, S, or T; Xaa14 is A, D, E, G, N, K, Q, or R; Xaa15 is A, D, E, F, L, S, or Y; Xaa16 is L, or F; Xaa17 is H, Q, S, or V; Xaald is K, R, hArg, u (Cit), or n (Orn); Xaa19 is F, L, S, or is absent; Xaa20 is H, Q, or is absent; Xaa21 is T, N, or absent; Xaa22 is F, L, M, V, or Y; Xaa24 is P or R; Xaa27 is T or V; Xaa30 is E, G, K, or N; Xaa31 is A or T; and Xaa32 is F, P, or Y. In yet another aspect, the LHC peptides for use in the invention comprise an amino acid sequence of the formula (V): Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 T Xaa7 Xaad Xaa9 XaalO Xaa11 L Xaa13 Xaa14 Xaa15 L Xaa17 Xaal Xaa19 Xaa20 Xaa21 Xaa22 P Xaa24 T N Xaa27 G S Xaa30 Xaa31 Xaa32, (SEQ ID NO: 66) where Xaa1 is A, C, F, I, K, S, or is absent; Xaa2 is C, D, or S; Xaa3 is A, D or N; Xaa4 is A, L or T; Xaad is A or S; Xaa7 is C or K; Xaad is A or V; Xaa9 is L or T; XaalO is G, H, or Q; Xaa11 is K, R, or hArg; Xaa13 is A, F, N, S, or T; Xaa14 is A, D, E, G, N, Q, or R; Xaa15 is A, E, F, L, S, or Y; Xaa17 is H, S, or V; Xaald is K, R, hArg, u (Cit), or n (Orn); Xaa19tes F, L70 S; Xaa20 is H or Q; Xaa21 is T or N; Xaa22 is F, L, M, V, or Y; Xaa24 is P or R; Xaa27 is T, or V; Xaa30 is E, G, K, or N; Xaa31 is A, or T; and Xaa32 is F, P, or Y. In a general aspect, the sequence of formula (IH), (IV), or (V) further comprises 1, 2, 3, 4, 5, 6, 7, d, 9, 10, 11, 12, or more modifications of substitutions, insertions, deletions, elongations and / or derivations. In certain embodiments, the sequence of formula (III), (IV) or (V) comprises a Val inserted between amino acids at positions 22 and 23. In other embodiments, the sequence of formula (III), (IV) or (V) comprises a Gln inserted between positions 22 and 23. In other embodiments, the sequence of formula (III), (IV) or (V) comprises a sequence of Gln-Thr-Tyr between positions 22 and 23. In further embodiments, the sequence of formula (III), (IV) or ( V) comprises a sequence of Leu-Gln-Thr-Tyr (SEQ ID NO: 67) between positions 22 and 23. In another general aspect, modifications of formula (III), (IV) or (V) may be at the N-terminal end. In certain embodiments, the N-terminal portion of formula (III), (IV) or (V) has an octylglycine added. In other embodiments, the N-terminal portion of formula (III) X (IV) or (V) has an added layer In yet another aspect, the LHC peptides for use in the invention comprise an amino acid sequence of the Formula (VI): Xaa1 Xaa2 Xaa3 Xaa4 Xaad Xaa6 Xaa7 Xaad Xaa9 XaalO Xaa 11 Xaa 12 Xaa 13 Xaa14 Xaa15 Xaa16 Xaa17 Xaal Xaa19 Xaa20 Xaa21 Xaa22 P Xaa24 T N Xaa27 G S Xaa30 Xaa31 Xaa32 (SEQ ID NO: 63) wherein Xaa1 is A, C, D, F, K, T, or is absent; Xaa2 is A, C, D, S, or is absent; Xaa3 is A, D, N, or absent; Xaa4 is A, L, T, or is absent; Xaad is A or S; Xaad is A, S, T, or V; Xaa7 is A, C, or K; Xaad is A, L, M, or V; Xaa9 is L or T; XaalO is G, H, or Q; Xaa11 is K, Q, or R; Xaa12 is L, W, or Y; Xaa13 is A, N, Q, S, or T; Xaa14 is A, D, E, G, K, N, Q, or R; Xaal d is A, D, E, F, L S, or Y; Xaa16 is F or L; Xaa17 is H, Q, S or V; Xaa18-es ~ K, or R; Xaa19 is F, L, S, or is absent; Xaa20 is H, K, Q, or is absent; Xaa21 is Q, T, or is absent; Xaa22 is F, L, or Y; Xaa24 is P or R; Xaa27 is T or V; Xaa30 is E, K or N; Xaa31 is A or T; and Xaa32 is F, Y, or is absent. In a general aspect, the sequence of formula (VI) further comprises 1, 2, 3, 4, d, 6, 7, 8, 9, 10, 11, 12, or more modifications of substitutions, insertions, deletions, elongations and / or derivations. In certain embodiments, the sequence of formula (III), (IV), (V) or (VI) comprises a deletion at position 24. In still another aspect, the LHC peptides to be used in the invention comprise an amino acid sequence comprising a) a loop region comprising the formula (II) Xaa1; wherein Xaa1 comprises an amino acid sequence of X Xaa2 Xaa3 Xaa4 Xaad Xaa6 Xaa7 Y (SEQ ID NO: 69) wherein, Xaa2 is any amino acid or is absent; Xaa3 is Ala, Gly, Ser, Asp or is absent; Xaa4 is Asn, Ala, Asp, Gly or is absent; Xaad ~ es-Alarteu, Thrs ~ Ser; Xaad is Ala, Ser, or Thr; and Xaa7 is Ala, Ser, Va !, Hse, (S) -2-amio-3-hydroxy-methylbutanoic acid (Ahb), (2S, 3R) -2-amino-3-hydroxy-methylpentanoic acid (Ahp), d- Thr, Thr, or a derivative thereof; X and Y are amino acids capable of creating a bond and are independently selected residues having side chains that can be chemically linked to each other to form an intramolecular bond such as a disulfide bond; an amide bond; a cyclic lactam formed by an alkyl acid and an alkylamine; an alkylamine or imine bridge formed by condensation and reduction of alkyl aldehydes or alkyl halides and alkylamines; and an alkenyl, alkenyl, alkynyl ether or thioether linkage formed by connecting side chains; b) a helical region of type I comprising the sequence XI V L Xaa10 Xaa1 I L S Q Xaa1 d L Xaa17 Xaa1 8 L Q T Xaa22 P Xaa24 T N T XI (SEQ ID NO: 70), where XaalO is Gly or Aib; Xaa11 is Lys, Arg, Orn, hArg, Cit, hLys, or Lys (for); Xaald is Glu or Phe; Xaa17 is His or Aib; Xaald is Lys, Arg, Orn, hArg, Cit, hLys, Lys (for), Lys (PEG dOOO); Xaa22 is Try or Leu; Xaa24 is Arg or Pro; and X1 is absent or comprises 1-4 additional amino acids; and c) a C-terminal tail comprising the Xaa2d sequence Xaa29 Xaa30 Xaa31 Xaa32 Xaa33 G Xaa3d Xaa36 Xaa37 Xaa38 (SEQ ID NO: 71), wherein Xaa28 is Lys, Tyr, or is absent; Xaa29 is Ser, Pro, or absent; Xaa30 is Ser, Pro, Arg, or is absent; Xaa31 is Thr, or is absent; Xaa32 is Asn or absent; Xaa33 is Val, Thr, or is absent; Xaa35 is Ser, Giu Xaa36 is Asn, Lys, or Gly; Xaa37 is Thr, Phe, or Ala; Xaa38 is Tyr, Phe, Pro, or is absent; with the proviso that when the loop region is from a calcitonin or calcitonin analogue and the Helix region a is from a calcitonin or calcitonin analog, the last position of the C-terminal tail is not Pro, Hyp, Hse or Hse derivatives. In yet another aspect, the LHC peptides for use in the invention comprise an amino acid sequence comprising a) a loop region comprising Xaa1; a) a loop region comprising the formula (II) Xaa1; wherein Xaa1 comprises an amino acid sequence of X Xaa2 Xaa3 Xaa4 Xaad Xaa6 Xaa7 Y (SEQ ID NO: 72) wherein, Xaa2 is any amino acid or is absent; Xaa3 is Ala, Gly, Ser, Asp or is absent; Xaa4 is Asn, Ala, Asp, Gly or is absent; Xaad is Ala, Leu, Thr, or Ser; Xaad is Ala, Ser, or Thr; and Xaa7 is Ala, Ser, Val, Hse, Ahb, Ahp, d-Thr, Thr, or a derivative thereof; X and Y are amino acids capable of creating a bond and are independently selected residues having side chains that can be chemically linked to each other to form an intramolecular bond such as a disulfide bond; an amide bond; a cyclic lactam formed by an alkyl acid and an alkylamine; an alkylamine or imine bridge formed by condensation and reduction of alkyl aldehydes or alkyl halides and alkylamines; and an alkenyl, alkenyl, alkynyl ether or thioether linkage, formed by chain connection laterals;; b) a helix region of type II comprising the sequence XI Xaad Xaa9 XaalO Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa Xa X KaZ X X X X X X X X X X X X X X X X X X X X X X X X X X X Xaa9 is Thr, Met or Leu; XaalO is Gln, Gly, His; Xaa12 is Leu, or Thr; Xaa13 is Ala, Thr, Asn, Phe, Tyr, Ser, or Thr; Xaa14 is Asn, Arg, Ala, Asp, Glu, Gln, Thr, or Gly; Xaald is Phe, Leu, Ser, Glu, Ala, Asp, or Tyr; Xaa16 is Leu or Asp; Xaa17 is Val, His, Ser, Phe, or Aib; Xaald is His, Arg, Lys, Orn, hArg, Cit, hLys, Lys (for), or Lys (PEGdOOO); Xaa19 is Leu, Ser or Phe; Xaa20 is Gln or His; Xaa21 is Thr or Asn; Xaa22 is Tyr, Val, Phe, Leu or Met; Xaa24 is Arg or Pro; and X1 is absent or comprises 1-4 additional amino acids; and c) a C-terminal tail comprising the sequence Xaa2d Xaa29 Xaa30 Xaa31 Xaa32 Xaa33G Xaa3d Xaa36 Xaa37 Xaa38 (SEQ ID NO: 74), where Xaa28 is Lys, Tyr, or absent; Xaa29 is Ser, Pro, or absent; Xaa30 is Ser, Pro, Arg, or is absent; Xaa31 is Thr, or is absent; Xaa32 is Asn, or is absent; Xaa33 is Val, Thr, or is absent; Xaa3d is Ser, or Glu Xaa36 is Asn, Lys, or Gly; Xaa37 is Thr, Phe, or Ala; Xaa3d is Tyr, Phe, Pro, or is absent. In yet another aspect, LHC peptides for use in the invention include: (SEQ ID NO: 7d) KCNTATCVLGKLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: 76) KCNTATCVLGRLSQELHRLQTLPRTNTGSNTY (SEQ ID NO: 77) KCNTATCVLGRLSQELHRLQTYPPTNTGSNTY (SEQ ID NO: 7d) KCNTATCVLGRLSQELHRLQTYPRTNVGSNTY (SEQ ID NO : 79) KCNTATCVLGRLSQELHRLQTLPPTNVGSNTY (SEQ ID NO: d0) KCNTATCVLGRLANFLHRLQTYPRTNTGSNTY (SEQIDNO: d1) ACNTATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: 82) KCNAATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: d3) KCNTAACVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: d4) CANLSTCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: dd) isocaproyl-STAVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: d6) CSNASTCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: d7) CSNLATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: dd) CSNLSACVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: d9) KCNTATCVLGRLSQELHKLQTYPRTNTGSNTY (SEQ ID NO: 90) KCNTATCVLGRLSQELHRLQTYPRTNTGSGTP (SEQ ID NO: 91) CSALSTCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: 92) Ac- (Agy) SNLST (Agy) VLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: 92) Ac-K (Agy) NTAT (Agy) VLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: 93) Isocaproil-STAVL (Aib) RLSQELRLQTYPRTNTGSGTP (SEQ ID NO: 94) lsocaproil-STAVLG [K (For)] LSQELH [K (For)] LQTYPRTNTG SGTP (SEQ ID NO: 9d) lsocaproil-STAVL (Aib) [K (For)] LSQEL (Aib) [K (For)] LQTYPRTNTGSNTY (SEQ ID NO: 96) lsocaproil-STAVL (Aib) [K (For)] LSQEL (Aib) [K (For)] LQTYPRTNVGSNTY (SEQ ID NO: 97) KCNTATCLLQQLQKLLQKLKQYPRTNTGSNTY (SEQ ID NO: 9d) KCNTASCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: 99) KCNTAVCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ 1D NO: 100) KCNTATCVLGRLSQELHRYPRTNTGSNTY (SEQ ID NO: 101) KCNTATCVLGK (For) LSQELHK (For) LQTYPRTNTGSNTY (SEQ ID NO: 102) KCNTA (d-Thr) CVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: 103) KCNTA (dAh) CVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: 104) Ac-ACNTATCVLGRLSQELHK (PEGdOOO) LQTYPRTNTGSNTY (SEQ ID NO: 10d) KCNTATCVLGRLSQELHRLQTLQTYPRTNTGSNTY (SEQ ID NO: 106) KCNTATCVLGRLSQELHRLQTLLQTYPRTNTGSNTY (SEQ ID NO: 107) KCNTATCVLGKLSQELHKLQTYPRTNTGSNTY (SEQ ID NO: 10d) KCNTSTCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: 109) KCNTATCATQRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: 110) KCNTATCATQRLSQELHRLQTYPRTNVGSNTY (SEQ ID N0: 111) KCNTSTCATQRLANELVRLQTYPRTNVGSNTY (SEQ ID N0: 112) KCNTA (Hse) CVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID N0: 113) KCNTA (Ahb) CVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID N0: 114) KCNTA (Ahp) CVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID N0: 11 d) KCNTAT (OP03H2) CVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID N0: 116) KCNTATCVLG (0rn) LSQELH (0m) LQTYPRTNTGSNTY (SEQ ID N0: 117) KCNTATCVLG (Cit) LSQELH (Cit) LQTYPRTNTGSNTY (SEQ ID NO: 118) KCNTATCVLG (homoK) LSQELH (homoK) LQTYPRTNTGSNTY (SEQ ID NO: 119) L-OctylglycineKCNTATCVLGRLSQELHRLQTYPRTNT GSNTY (SEQ ID NO: 120) N-3,6-dioxaoctanoyl-CNTATCVLGRLSQELHRLQTVPR TNTGSNTY (SEQ ID NO: 121 ) KCNTATCMLGRYTQDFHRLQTYPRTNTGSNTY (SEQ ID NO: 122) DSNLSTKVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: 123 KDNTATKVLGRLSQELHRLQTYPRTNTGSNTY (SEQ IDNO: 124 CNTATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ IDN0: 12d KCNTATCVLGRLSQELHRLQTYPRTNTGSNTY (9Anc) (SEQIDNO: 126 KCNTATCVLGRLSQELHRLQTYPRTNTGSNTY (L-octilglicina) (SEQ IDNO: 127 N-isocaproyl-KCNTATCVLGRLSQELHRLQTYPR TNTGSNTY (SEQ IDNO: 128 KCNTATCVLG ( homor) LSQELH (homor) LQTYPRTN TGSNTY (SEQIDNO: 129 FCNTATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQIDNO: 130 KCNTATCVLGRLSQELH (Cit) LQTYPRTNTGSNTY (SEQIDNO: 131 KCNTATCVLGRLSQELH (0m) LQTYPRTNTGSNTY (SEQIDNO: 132 ICNTATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQIDNO: 133 1-Octilglicina-CNTATCVLGRLSQELHRLQTYPRTN TGSNTY (SEQIDNO: 134 isocaproyl-CNTATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ IDNO: 13d KCNTATCVLG (Cit) LSQELHRLQTYPRTNTGSNTY (SEQIDNO: 136 KCNTATCVLGRLSQELHRLQTYPRTNTGSNTY (4ABU) (SEQIDNO: 137 isocaproyl-KCNTATCVLGRLSQELHRLQTYPRTN TGSNTY (4ABU) (SEQIDNO: 138 KCNTSTCATQRLANELVRLQTYPRTNVGSEAF (SEQIDNO: 139 KCNTATCVLGRLSQELHRLQTYPTNVGSEAF (SEQIDNO: 140 KCNTATCVLGRLSRSLHRLQTYPRTNTGSNTY (SEQIDN0: 141 KCNTATCVTHRLSQELHRLQTYPRTNTGSNTY (SEQIDNO: 142 KCNTATCVLGRLADFLHRLQTYPRTNTGSNTY (SEQ ID NO: 143 CNTATCVLGRLSQELHRLQTYPRTNTGSNT (SEQIDNO: 144 KCNTATCVLGRLSQELHRLQNFVPRTNTGSNTY (SEQ ID NO: 145 KCNTATCVLGRLSQELHRLQTYPRTNTGSETF (SEQ ID NO: 146 ACDTATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQIDNO: 147 KCNTATCVLGRLSQELHRLQTYPRTNTGSKAF (SEQ IDNO: 148 KCDTATCVTHRLAGLLSRSQTYPRTNTGSNTY (SEQ1DN0: 149 KCNTATCVLGRLADALHRLQTYPRTNTGSNTY (SEQIDNO: 1do KCNTATCVLGRLAAFLHRLQTYPRTNTGSNTY (SEQIDNO: 1d1 SCNTATCVLGRLADFLHRLQTYPRTNTGSNTY (SEQIDNO: 1d2 KCNTATCVLGRLSQELHRLQTMPRTNTGSNTY (SEQIDNO: 1d3 KCNTATCVLGRLSQELHRLQTVPRTNTGSNTY (SEQ IDNO: 1d4 KCNTATCVLGRLNEYLHRLQTYPRTNTGSNTY (SEQIDNO: 1dd SCNTATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ IDNO: 1d6 KCNTATCVLGRLTEFLHRLQTYPRTNTGSNTY (SEQ IDNO: 1D7 KCNTATCVLGRLAEFLHRLQTYPRTNTGSNTY (SEQIDNO: 1dd KCNTATCVLGRLTDYLHRLQTYPRTNTGSNTY (SEQIDNO: 159 KCNTATCVLGRLAQFLHRLQTYPRTNTGSNTY (SEQIDNO: 160 KCNTATCVLGRLADFLHRFQTFPRTNTGSNTY (SEQ ID NO: 161 KCNTATCVLGRLADFLHRFHTFPRTNTGSNTY (SEQIDNO: 162 KCNTATCVLG RLADFLHRFQTFPRTNTGSGTP (SEQ IDNO: 163 CNTATCVLGRLADFLHRLQTYPRTNTGSNTY (SEQ ID NO: 164) KCDTATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID N0: 16d) KCNTATCVLGRLFDFLHRLQTYPRTNTGSNTY (SEQ ID NO: 166) KCNTATCVLGRLAAALHRLQTYPRTNTGSNTY (SEQ ID NO: 167) TCDTATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO: 168) CSNLSTCATQRLANELVRLQTYPRTNVGSNTY (SEQ ID NO: 169) KCNTATCATQRLANELVRLQTYPRTNVGSNTY (SEQ ID NO: 170) CSNLSTCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID N0: 171) KCNTATCVLGRLSQELHRLQTYPRTNTGSNTY In yet another aspect, the LHC peptides for use in the invention include biologically active fragments of SEQ ID NOS: 7d to 171. Biologically active fragments may comprise deletions of 1 , 2, 3, 4, d, 6, 7, 8, 9, 10, 11, 12, 13, 14, 1 or more amino acids. In certain embodiments, the amino acid sequences of SEQ ID NOS: 7d to 171 comprise at least 1, 2, 3, 4, d, 6, 7, 8, 9, 10 or more modifications such as substitutions, insertions, deletions and / or derivations. In other embodiments, the amino acid sequences of SEQ ID NOS: 7d to 171 have no more than 1, 2, 3, 4, d, 6, 7, 8, 9, or 10 modifications such as substitutions, insertions, deletions and / or derivations. In still another aspect of the invention, the compounds of the invention include those having at least 7d, 80, 8d, 90, 9d, or 97% amino acid sequence identity to any of SEQ ID NOS: 7d to 171. The percent identity is determined by analysis with the AlignX® module in the NTI® vector (Invitrogen, Carlsbad CA). It is intended that each percent identity described, or reference to biologically active fragments or modifications are applied to each SEQ ID NO: individually. For example, each described modality, fragments, modification or identity percent is applicable to SEQ ID NO: 75, 76, 77, 78, 44, etc., or to any group of SEQ ID NOs. In general, amylin agonists or amylin agonist analogues are recognized as referents to compounds which, by interacting or binding directly or indirectly with one or more receptors, simulates an action of amylin. Accordingly, the compounds of the invention can act as an agonist for at least one biological effect of calitonin, amylin, CGRP, or any combination of three described herein or bind to at least one of the receptors of amylin, calcitonin or CGRP. In contrast, amylin antagonists, by interacting or binding directly or indirectly with one or more receptors, suppress an action of amylin. Such interactions or binding events include those that affect ghrelin levels. Amylin antagonists contemplated in the use of the invention include AC66 (sCT [8-32j) (SEQ ID NO: 172) and derivatives such as AC137 (Ac 30Asn, 32Tyr-sCT [d-32]) (SEQ ID NO: 173) a peptide fragment of 25 amino acids of salmon calcitonin, developed as a selective amylin receptor antagonist on CGRP receptors. Other useful antagonists include antagonists described in the U.S. Patents. Nos. D, 62d, 032 and d, dd0.9d3, which are incorporated herein by reference. Said antagonist compounds include those comprising the formula (VII): X-R1-Thr-Gln-R2-Leu-Ala-Asn-R3-Leu-Val-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-R4-Asn-Thr- Tyr-NH2 (SEQ ID NO: 174) wherein R1 is Ala or a bond; R2 is Arg, Gln, Lys, Asn or Leu; R3 is Gln, Glu, Asn, Asp or Phe; R4 is Ala or Ser; and X is hydrogen or an acetyl group. The amylin antagonists can be acetylated or non-acetylated at the N-terminus and include acid as well as amide forms for the molecule. Examples of amylin antagonists include but are not limited to acetyl-Ala Thr Gln Arg Leu Ala Asn Glu Leu Val Arg Leu Gln Thr Tyr Pro Arg Thr Asn Val Gly Ser Asn Thr Tyr (SEQ ID NO: 175), Ala Thr GlnGln Leu Ala Asn Gln Leu Val Arg Leu Gln Thr Tyr Pro Arg Thr Asn Val Gly Ser Asn Thr Tyr (SEQ ID NO: 176), Wing Thr Gln Leu Leu Wing Asn Gln Leu Val Arg Leu Gln Thr Tyr Pro Arg Thr Asn Val Gly Ser Asn Thr Tyr (SEQ ID NO: 177), Wing Thr Gln Arg Leu Ala Asn Gln Leu Val Arg Leu Gln Thr Tyr Pro Arg Thr Asn Val Gly Ser Asn Thr Tyr (SEQ ID NO: 176), Wing Thr Gln Leu Leu Wing Asn Glu Leu Val Arg Leu Gln Thr Tyr Pro Arg Thr Asn Val Gly Ser Asn Thr Tyr (SEQ ID NO: 179), Wing Thr Gln Gln Leu Wing Asn Glu Leu Val Arg Leu Gln Thr Tyr Pro Arg Thr Asn Val Gly Ser Asn Thr Tyr (SEQ ID NO: 180). Methods for testing compounds for amylin activity are known in the art. Selective determination methods illustrative and tests for testing amiline agonists or antagonists are described in the examples, particularly in example 4 hereof, and in the patents of E.U.A. Nos. 5,264,372 and 5,686,411, which are incorporated herein by reference. The activity as amylin agonists and / or analogues can be confirmed and quantified by performing several selective determination tests, including the nucleus receptor accumbens binding test, followed by the soleus muscle test, a gastric emptying test, or by the ability to induce hypocalcemia or reduce postpandial hyperglycemia in mammals. The receptor binding test, a proficiency test that measures the ability of compounds to bind specifically to membrane-bound amylin receptors, is described in the U.S. Patents. Nos. D, 264,372 and d, 636,411, the disclosures of which are incorporated herein by reference. A preferred source of the membrane preparations used in the test is the basal forebrain comprising membranes for the nucleus accumbens and surrounding regions. Compounds that are being tested compete to bind to those 1251 Bolton Hunter rat amylin receptor preparations. Competing curves, where the bound quantity (B) is plotted as a function of the logarithm of the ligand concentration, are analyzed by computer using non-linear regression analysis to a 4-parameter logistic equation (INPLOT program, GraphPad Software, San Diego, Calif.) Or the ALLFIT program of DeLean et al. (ALLFIT, Version 2.7 (NIH, Bethesda, Md. 20692)). Munson and Rodbard (1960) Anal. Biochem. 107: 220-239. Biological activity tests of agonists / amylin analogues in the soleus muscle can be performed using previously described methods (Leighton et al (1968) Nature 335: 632-636; Cooper et al. (1988) Proc. Natl. Acad. Sci. USA 85: 7763-7766), in which the activity of amylin agonist can be tested by measuring the inhibition of insulin-stimulated glycogen synthesis. In brief, an illustrative method includes strips of soleus muscle prepared from male Wistar rats fasted for 12 hours. The tendons of the muscles are ligated before joining stainless steel clips. The muscle strips are preincubated in Erlenmeyer flasks containing 3.d ml of pH buffer of Krebs-Ringer bicarbonate, 7 mM of N-2-hydroxyethyl-peperazin-N'-2-ethanesulfonic acid, pH 7.4, and dd mM of pyruvate. The flasks are sealed and gasified continuously with 02 and C02 in the ratio of 19: 1 (v / v). After preincubation of muscles in this medium for 30 minutes at 37 ° C in an oscillating water bath, the muscle strips are transferred to similar vials containing identical medium (except pyruvate) with added glucose [U-14C] (O.d μCi / ml) and insulin (100 μU / ml). The flasks are sealed and regasified for 1d initial minutes in a 1 hour incubation. At the end of the incubation period, the muscles dry and quickly freeze in liquid N2. The concentration of lactate in the incubation medium can be determined spectrophotometrically and the incorporation of glucose [U-14C] into glycogens is measured. Amylin antagonist activity is evaluated measuring the resumption of insulin-stimulated glycogen synthesis in the presence of 100 nM rat amylin and an amylin antagonist. Methods for measuring gastric emptying velocity are described, for example, in Young et al. In a phenol red method, conscious rats receive by force feeding an acolyte gel containing methylcellulose and a phenol red indicator. Twenty minutes after the forced feeding, the animals are anesthetized using halothane, the stomach is exposed and fastened in the pyloric and lower esophageal sphincters, removed and opened in an alkaline solution. The content of the stomach can be derived from the intensity of the phenol red in the alkaline solution, measured by absorbance at a wavelength of d60 nm. In a triteated glucose method, conscious rats are fed by forced feeding with glucose triteated in water. The rats are gently restrained by the tail, whose tip is anesthetized using lidocaine. The tritium in the plasma separated from the tail blood is collected at several time points and detected in a beta counter. The test compounds are normally administered approximately one minute before the forced feeding. The amylin agonist and antagonist compounds may exhibit activity in the receptor binding assay of the order of less than about 1 to dM, preferably less than about 1 nM and most preferably less than about dO pM. In the soleus muscle test, amylin agonist compounds can show CEdO values of the order of less than about 1 to 10 micromolar. In a soleus muscle test, amylin antagonists can show Cl50 values of the order of less than about 1 to 2 micromolar. In gastric emptying tests, preferred agonist compounds show ED 50 values of the order of less than 100 μg / rat. The antagonist compounds would not show the effect or show the opposite effect in the gastric emptying test. In an illustrative method of making the compounds, the compounds of the invention can be prepared using standard solid phase peptide synthesis techniques and preferably an automated or semi-automated peptide synthesizer. Typically, using such techniques, a protected N-carbamoyl amino acid and an amino acid attached to the growing peptide chain on a resin are coupled at an ambient temperature in the inert solvent such as dimethylformamide, N-methylpyrrolidinone or methylene chloride in the presence of coupling agents such as dicyclohexylcarbodiimide and 1-hydroxybenzotriazoI in the presence of a base such as diisopropylethylamine. The a-N-carbamoyl protecting group is removed from the resulting peptide-resin using a reagent such as trifluoroacetic acid or piperidine, and the coupling reaction is repeated with the next desired N-protected amino acid to be added to the peptide chain. Suitable N-protecting groups are well known in the art, with t-butyloxycarbonyl (tBoc) and fluorenylmethoxycarbonyl (Fmoc) being preferred herein. Other methods of synthesis or expression of amylin and amylin agonists and purification thereof are known to one skilled in the art. Anti-obesity agents for use in the present invention also include exendin peptide hormones and exendin agonists. Exendin native peptide hormones are known in the art, as are analogs and derivatives of functional peptides. Certain native peptides, peptide analogs and derivatives are described herein, however it is recognized that any known exendin peptides showing hormonal activity known in the art can be used in conjunction with the present invention. Exemplary exemplifying peptides include exendin-3 (His Ser Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe lie Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser ( SEQ ID NO: 181)) and exendin-4 (His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe lie Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser (SEQ ID NO: 182)). Any exendin peptide analog or derivative known in the art can be used in conjunction with the present invention. In a modality, the exendin peptide analogs and derivatives have at least one hormonal activity of a native exendin peptide. In certain embodiments, the exendin peptide analogs are agonists of a receptor to which a native exendin peptide is capable of specifically binding. Exendin compounds include exendin peptide analogs in which one or more naturally occurring amino acids are removed or replaced by other amino acids. As it is known in the technique, the exendin analogs can be amidated or they can be in the acid form. In one embodiment, an exendin analog may have one or more amino acid substitutions, deletions, inversions or additions as compared to a native or naturally occurring exendin. Therefore, exendin analogs can have an amino acid sequence having at least one or more substitutions, additions or deletions of amino acids compared to naturally occurring exendin, eg, exendin-4. In one embodiment, an exendin analog has an amino acid sequence that is about 30 or less, 2d or less, 20 or less, 1 do less, 10 or less, or less, 4 or less, 3 or less, 2 or less , or 1 or less substitutions, additions or deletions compared to a naturally occurring exendin, such as exendin-4. Illustrative exendin compounds include exendin-4 agonist analogues, including but not limited to, 14Leu, 25Phe-exendin-4 (His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Lie Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Wing Pro Pro Pro Ser (SEQ ID NO: 183), 5Ala, 14Leu, 25Phe-exendin-4 (His Gly Glu Gly Ala Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Wing Val Arg Leu Phe lie Glu Phe Leu Lys Asn Gly Gly Pro Ser Gly Wing Pro Pro Pro Ser (SEQ ID NO: 184)), and l4Leu, 22Ala, 25Phe-exendin-4 (His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Wing Val Arg Leu Wing He Glu Phe Leu Lys Asn Gly Gly Pro Be Ser Gly Wing Pro Pro Pro Ser (SEQ ID NO: 185)). Other illustrative exendin analogs include, but are not limited to, exendin-4 (1-30) (His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe lie Glu Trp Leu Lys Asn Gly Gly (SEQ ID NO: 186)), exendin-4 (1-28) amide (His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe He Glu Trp Leu Lys Asn- NH2 (SEQ ID NO: 187)), 14Leu, 25Phe exendin-4 (1-28) amide (His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe lie Glu Phe Leu Lys Asn-NH2 (SEQ ID NO: 188)), and l4Leu, 22Ala, 25Phe exendin-4 (1-28) amide (His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Ala lie Glu Phe Leu Lys Asn-NH2 (SEQ ID NO: 189)). Exemplary exemplary agonists are further described in the patent application of E.U.A. with serial No. 10/181, 102 and PCT application No. PCT / US98 / 16387, both of which claim the benefit of the patent application of E.U.A. with serial No. 60 / 056,404, filed August d, 1997, all of which are incorporated herein by reference. Illustrative exendin agonists include compounds of the formula (I), formula (II) and formula (III) of the patent application of E.U.A. with serial No. 10/181, 102 and PCT application No. PCT / US98 / 16387. Other exendin agonists are described in the patent application of E.U.A. with serial No. 09/564, 633 and PCT Application with serial number. PCT / US98 / 24210, both of which claim the benefit of the provisional application of E.U.A. No. 60 / 065,442 filed on November 14 of 1997, all of which are incorporated herein by reference. Other exendin agonists are described in the patent application of E.U.A. with serial number. 09 / 564,631 and PCT application with serial number. PCT / US98 / 24273, both of which relate the benefit of the provisional application of E.U.A. No. 60 / 066,029 filed on November 14, 1997, all of which are incorporated herein by reference. Additional exendin agonists are described in the PCT application with serial number. PCT / US97 / 14199, filed August 8, 1997, which is a continuation in part of the patent application of E.U.A. with serial number. 08 / 694,954 filed August 8, 1996, both of which are incorporated herein by reference. Other exendin agonists are described in the US patent. No 6, 956,026, which claims priority the provisional application of E.U.A. No. 60 / 034,905 filed January 7, 1997, both of which are incorporated herein by reference. Other exendin analogs and derivatives are described in US 2004/0209803 A1, filed December 19, 2003, which is incorporated herein by reference. Anti-obesity agents in the present invention also include ciliary neurotrophic factor (CNTF), CNTF-related polypeptides, modified CNTF polypeptides, CNTF agonists and CNTF analogs including but not limited to AXOKINE® (Regenerate). CNTF, CNTF-related polypeptides and compositions containing CNTF and / or CNTF-related polypeptide suitable for use in the methods of the invention are known in the art. CNTF polypeptides, related polypeptides with CNTF, modified CNTF polypeptides, CNTF agonists, analogs, derivatives, preparations, formulations, pharmaceutical compositions, dosages and routes of administration have been described above, for example in the U.S. Patents. Nos. 6,680,291 and 6,767,894, and in PCT application publications Nos. WO 94/09134, WO 98/22128, and WO 99/43813, which are incorporated herein by reference in their entirety. Anti-obesity agents in the present invention also include serotonin transport inhibitors (dHT), including but not limited to paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertraline, and imipramine. The anti-obesity agents in the present invention also include selective serotonin uptake inhibitors, including but not limited to dexfenf luramine, fluoxetine, sibutramine (e.g., MERIDIA®) and those described in the U.S.A. No. 6,366,633 and PCT patent application publications Nos. WO 01/27060 and WO 01/162341, which are hereby incorporated by reference in their entirety. Said dHT transport inhibitors and serotonin reuptake inhibitors, analogs, derivatives, preparations, formulations, pharmaceutical compositions, doses and routes of administration have been described above. Anti-obesity agents for use in the present invention also include selective serotonin agonists and selective 6-HT2C receptor agonists, including but not limited to US Pat. No. 3,914,260; and PCT application publication Nos. WO 02/36696, WO 02/48124, WO 02/10169, WO 01/66648, WO 02/44162; WO 02/61844, WO 02/40466, and WO 02/40467, which are hereby incorporated by reference in their entirety. Said selective serotonin agonists and 6-HT2C receptor agonists, compositions containing said agonists and administration routes suitable for use in the methods of the invention are known in the art. See, for example, Halford et al. (2006) Curr. Drug Targets 6: 201-213 and Weintraub e al. (1984) Arch. Intern. Med. 144: 1143-1148. Anti-obesity agents for use in the present invention also include agonists / reverse agonists of central cannabinoid receptors (the CB-1 receptors), including but not limited to rimonabant (Sanofi Synthelabo), and SR-147778 (Sanofi Synthelabo) . Antagonists / inverse agonists of CB-1, derivatives, preparations, formulations, pharmaceutical compositions, doses and routes of administration have been described above, for example, in the patents of E.U.A. Nos. 6,344,474, 6,028,084, 6,747,624, 6,696,106, 6,632,237, 4,973,687, 6,013,837, 6,081, 122, 5,112,820, 5,292,736, 5,624,941; European patent applications Nos. EP-656 354 and EP-6d8646; and PCT application publications Nos. WO 96/33159, WO 98/33765, W098 / 43636, W098 / 43635, WO 01/09120, W098 / 31227, W098 / 41619, WO96 / 37061, WO00 / 10967, WO00 / 10968 , WO97 / 29079, WO99 / 02499, WO 01/68869, and WO 02/076949, which are incorporated herein by reference in their entirety. Anti-obesity agents for use in the present invention also include melanocortins and melanocortin agonists. Melanacortins are peptides of the pro-opiomelanocortin gene, including a-melanocyte-stimulating hormone (a-MSH) and adrenocorticotropic hormone (ACTH), and five melanocortin receptors are known, MC1-5R. MC4R seems to play a role in the balance of energy and obesity. See, for example, Anderson et al. (2001) Expert Opin. Ther. Patents 11: 1683-1692, Speake ei al (2002) Expert Opin. Ther. Patents 12: 1631-1638, Bednarek et al. (2004) Expert Opin. Ther. Patents 14: 327-336. Melanocortin agonists, including but not limited to MC4R agonists and compositions containing said agonist appropriate for use in the methods of the invention are known in the art. MCR agonists, MC4R agonists, derivative preparations, formulation, pharmaceutical compositions, doses and routes of administration have been described above, for example, in the following PCT patent applications, which are incorporated herein by reference in their entirety: WO 03/007949, WO 02/0683dd, WO 02/06/387, WO 02/067869, WO 03/040117, WO 03 / 066567, WO 03/06/73, WO 03/094916, and WO 03/031410. Anti-obesity agents for use in the present invention also include sub-type 5 metabotropic glutamate receptor antagonists (mGluRd), including but not limited to compounds such as 2-methyl-6- (phenylethynyl) -pyridine (MPEP) and ( 3 - [(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine) (MTEP) and those compounds described in Anderson et al. (2003) J. Eur. J. Pharmacol. 473: 36-40; Cosford went to. (2003) Bioorg. Med. Chem. Lett. 13 (3): 3d1-4; and Anderson went to. (2002) J. Pharmacol. Exp. Ther. 303: 1044-1061.

Anti-obesity agents for use in the present invention also include topiramate (TOPIMAX® (Ortho McNeil Pharmaceuticals), indicated as an anti-convulsant and an anti-convulsant, but also shown to increase weight loss. used in the present invention also include neuropeptide Y1 (NPY1) antagonists and NPYd antagonists NPY1 and NPYd antagonists are known in the art See, for example, Duhault et al. (2000) Can J Physiol. Pharm. 78: 173-186, and U.S. Patent Nos. 6,124,331, 6,214,863, and 6,340,683 The NPY1 and NPYd antagonists, derivatives, preparations, formulation, pharmaceutical compositions, doses, and routes of administration have been described above. in the present invention include: U.S. Patent No. 6,001, 836; and PCT application publication Nos. WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01 / 85173, and WO 01 / 8952d, which are incorporated herein by reference in their entirety. NPYd antagonists useful in the present invention include but are not limited to the compounds described in the U.S. Patents. Nos. 6,140,364, 6,191, 160, 6,268,837, 6,313,298, 6,337,332, 6,329,395, 6,340,683, 6,326,375, and 6,335,345; European Patents Nos. EP-01010691, and EP-01044970; and PCT Patent Publication Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00 / 69849, WO 01/09120, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0246162, WO 02/49648, and WO 01/14376. Anti-obesity agents for use in the present invention also include melanin-concentrating hormone (MCH) antagonists, including melanin-1 concentrating hormone receptor (MCH1 R) antagonists, such as T-226296 (Takeda) and receptor antagonists. of melanin concentrating hormone 2 receptor (MCH2R). MCH receptor antagonists, derivatives, preparations, formulations, pharmaceutical compositions, doses and routes of administration have been described above, for example, in the patent application publications of E.U.A. Nos. 2006/0009816, 2006/0026915, 2004/0152742, 2004/0209865; Patent application publications of Nos. WO 01/82925, WO 01/67834, WO 02/06245, WO 02/04433, and WO 02/51809; and Japanese Patent Application No. JP 13226269, which are hereby incorporated by reference in their entirety. Anti-obesity agents for use in the present invention also include opioid antagonists, including but not limited to those described in PCT Application No. WO 00/21509. Specific opioid antagonists useful in the present invention include but are not limited to nalmefene (REVEX®), 3-methoxynaltrexone naloxone, naltrexone, naloxonazine, beta-f unaltrexamine, deltal ([D-Ala2, Leu5, Cys6] -enkephalin ( DALCE), naltrindol isothiocyanate, and nor-binaltorfamine Anti-obesity agents for use in the present invention also include orexin antagonists, including but not limited to, those described in PCT patent application Nos. WO 01/96302, WO 01/68609, WO 02/51232, and WO 02/51838. Specific orexin antagonists useful in the present invention include but are not limited to SB-334867-A. Anti-obesity agents for use in the present invention also include neuropeptide Y2 agonists (NPY2), including but not limited to compounds such as PYY3-36 (e.g., Batterham et al. (2003) Nature 418: 650- 654), NPY3-36, and other Y2 agonists such as N acetyl [Leu (28,31) J NPY 24-36 (White-Smith et al. (1999) Neuropeptides 33: 526-533, TASP-V (Malis et al (1999) Br. J. Pharmacol. 126: 989-996), cyclo- (28/32) -Ac- [Lys28-Glu32] - (25-36) -pNPY (Cabrele et al. (2000) J Pept. Sci. 6: 97-122) Anti-obesity agents in the present invention also include neuropeptide Y4 (NPY4) agonists including but not limited to, compounds such as pancreatic peptide (PP) (e.g., Batterham et al (2003) J. Clin Endocrinol, Metab 88: 3989-3992) and other Y4 agonists such as 1229U91 (Raposinho et al. 2000) Neuroendocrinology 71: 2-7). NPY2 agonists and NPY4 agonists, derivatives, preparations, formulations, pharmaceutical compositions, doses, and routes of administration have been described above, for example, in the patent publication of E.U.A. No. 2002/0141985 and PCT Application Publication No. WO 2005/077094. Anti-obesity agents for use in the present invention also include inverse antagonists / agonists of histamine 3 (H3) including but not limited to those described in PCT application No. WO 02/15905, 0- [3- (1 H-imidazol-4-yl) propanol] carbamates (Kiec-Kononowicz et al (2000) Pharmazie 55: 349-355), histamine H3 receptor antagonists containing pyridine ( Lazewska et al. (2001) Pharmazie 56: 927-932), benzophenone derivatives and related compounds (Sasse et al. (2001) Arch. Pharm. (Weinheim) 334: 45-52), substituted N-phenylcarbamates (Reidemeister ei al. (2000) Pharmazie 55: 83-86), and proxyphan derivatives (Sasse et al (2000) J. Med. Chem. 43: 3335-3343). Specific H3 reverse antagonists / agonists useful in the present invention include but are not limited to thioperamide, 3- (1 H-imidazol-4-yl) propyl N- (4-pentenyl) carbamate, clobenpropit, iodophenpropit, imoproxyphan, and GT2394 (Gliatech). Anti-obesity agents for use in the present invention also include cholecystokinin (CCK) and CCK agonists. The cholecystokinin-A (CCK-A) agonists useful in the present invention include but are not limited to those described in the U.S.A. No. 5,739,106. Specific CCK-A agonists include, but are not limited to, AR-R 15849, Gl 181771, JMV-180, A-71378, A-71623 and SR146131. Anti-obesity agents for use in the present invention also include ghrelin antagonists such as those described in PCT application publication Nos. WO 01 / d7335 and WO 02/08260. Ghrelin antagonists are also known as GHS (growth hormone secretagogue receptor) antagonists. The compositions and methods of the present invention therefore comprise the use of GHS antagonists in place of ghrelin antagonists.

Dosage / formulation The anti-obesity agents and weight-inducing agents (referred to herein as the "compositions") can be administered alone or in combination with pharmaceutically acceptable carriers or excipients, either in single or multiple doses. These pharmaceutical compounds can be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those described in Remington's Pharmaceutical Sciences by E. W. Martin. See also Wang ei al. (1986) J. of Parenteral Set and Tech., Technical Report No. 10, Supp. 42: 2S. In general, the compounds can be formulated into a stable and safe pharmaceutical composition for administration to a patient. The pharmaceutical formulations contemplated for use in the methods of the invention may comprise about 0.01 to 1.0% (w / v), in certain cases 0.05 to 1.0%, of the compound, about 0.02 to 0.5% (w / v) of a pH of acetate, phosphate, citrate or glutamate allowing a pH of the final composition of about 3.0 to about 7.0; about 1.0 to 10% (w / v) of a carbohydrate or polyhydric alcohol toner and, optionally, about 0.006 to 1.0% (w / v) of a preserved selected from the group consisting of m-cresol, benzyl alcohol, methyl, ethyl, propyl and butyl parabens and phenol. Said conservative is generally included if the formulated peptide is to be included in a multipurpose product. In a particular embodiment of the present invention, a pharmaceutical formulation of the present invention may contain a range of concentrations of the compound, e.g., between about 0.01% to about 98% w / w, or between about 1 to about 98% p / p, or preferably between 80% and 90% w / w, or preferably between about 0.01% to about 60% w / w, or most preferably between about 10% to about 26% w / w in this embodiment. A sufficient amount of water for injection can be used to obtain the desired concentration of solution. Additional toning agents such as sodium chloride, as well as other known excipients, may also be present if desired. In some cases, said excipients are useful in maintaining the overall tonicity of the compound. An excipient can be included in the currently described formulations at various concentrations. For example, an excipient may be included in the concentration range of from about 0.02% to about 20% w / w, preferably between about 0.02% and 0.6% w / w, about 0.02% to about 10% w / w, or about 1% at approximately 20% p / p. In addition, similar to the present formulations themselves, an excipient may be included in solid (including powder), liquid, semisolid or gel form. The pharmaceutical formulations can be composed of various forms, e.g., solid, liquid, semi-solid or liquid. The term "solid", as used herein, encompasses all normal uses of this term, including, for example, powders and lyophilized formulations. The currently described formulations can be lyophilized. The terms "pH regulation", "buffer solution" and "pH regulated solution", when used with reference to ion-hydrogen concentration or pH, refer to the ability of a system, particularly an aqueous solution, to withstand a change in pH when adding acid or alkali, or when diluted with a solvent. Characteristics of solutions regulated in their pH, which undergo small changes of pH when adding acid or base, is the presence of either a weak acid or a weak acid salt, or a weak base and a weak base salt. A system of the first example is acetic acid and sodium acetate. The change in pH is light as long as the amount of hydronium or hydroxyl ion added does not exceed the capacity of the pH regulator system to neutralize it. As described herein, a variety of liquid carriers are suitable for use in peptide anti-obesity agent formulations, for example, water or a mixture / suspension of aqueous / organic solvent. The stability of a peptide formulation for use in the present invention is increased by maintaining the pH of the formulation in the range of about 3.0 to about 7.0 when in liquid form. In certain embodiments, the pH of the formulation is maintained in the range of about 3.5 to 5.0, or about 3.5 to 6.6, in some embodiments from about 3.7 to 4.3, or about 3.8 to 4.2. In some embodiments, the pH may be about 4.0. Although not intended to be bound by this theory, it is currently understood that where the pH of the pharmaceutical formulation exceeds d.d, the chemical degradation of the peptide can be accelerated in such a way that the shelf life is less than about two years. In certain embodiments, the pH regulator with the anti-obesity agents is an acetate pH regulator (preferably at a final formulation concentration of about 1 -da about 60 mM), phosphate pH regulator (preferably at a final formulation concentration). about 1 -5 to about 30 mM) or glutamate pH regulator (preferably at a final formulation concentration of about 1-5 to about 60 mM). In some embodiments, the pH regulator is acetate (preferably at a final formulation concentration of about d to about 30 mM) ..}. A stabilizer can be included in anti-obesity agent formulations but, and importantly, is not necessarily necessary. However, if a stabilizer useful in the practice of the present invention is included it is a carbohydrate or a polyhydric alcohol. A suitable stabilizer useful in the practice of the present invention is about 1.0 to 10% (w / v) of a carbohydrate or polyhydric alcohol.

The polyhydric alcohols and carbohydrates share the same characteristics in their base structures, that is, -CHOH-CHOH-, which is responsible for stabilizing the proteins. Polyhydric alcohols include compounds such as sorbitol, mannitol, glycerol, and polyethylene glycols (PEGs). These compounds are straight chain molecules. Carbohydrates such as mannose, ribose, sucrose, fructose, trehalose, maltose, inositol, and lactose, on the other hand, are cyclic molecules that may contain a keto or aldehyde group. These two classes of compounds have been shown to be effective in stabilizing protein against denaturation caused by elevated temperature and by freeze-thawing or freeze-drying processes. Suitable carbohydrates include: galactose, arabinose, lactose or any other carbohydrate that does not have an adverse effect on a diabetic patient, ie, the carbohydrate is not metabolized to form unacceptably large concentrations of glucose in the blood. Said carbohydrates are well known in the art as suitable for diabetics. Sucrose and fructose are suitable for use with the compound in non-diabetic applications (e.g., treating obesity). In certain embodiments, if a stabilizer is included, the compound is stabilized with a polyhydric alcohol such as sorbitol, mannitol, inositol, glycerol, xylitol, and polypropylene glycol / ethylene glycol copolymer, as well as various polyethylene glycols (PEG) of molecular weight (200, 400, 1460, 3360, 4000, 6000, and 8000). Mannitol is the preferred polyhydric alcohol in some embodiments. Another useful feature of freeze-dried formulations of the present invention is the maintenance of the tonicity of the lyophilized formulations described herein with the same formulation component which serves to maintain its stability. In some embodiments, mannitol is the preferred polyhydric alcohol used for this purpose. The United States Pharmacopeia (USP) states that antimicrobial agents at bacteriostatic or fungistatic concentrations should be added to preparations contained in multi-dose containers. They must be present in adequate concentration at the time of use to prevent the multiplication of microorganisms inadvertently introduced into the preparation while extracting a portion of the contents with a hypodermic needle and syringe or using other invasive means for delivery, such as pen injectors . Antimicrobial agents should be evaluated to ensure compatibility with all other components of the formula, and their activity should be evaluated in the total formula to ensure that a particular agent that is effective in one formulation is not ineffective in another. It is not uncommon to find that a particular antimicrobial agent is effective in one formulation but not effective in another formulation. A preservative, in the common pharmaceutical sense, is a substance that prevents or inhibits microbial growth and can be added to pharmaceutical formulations for this purpose to avoid consequent rotting of the formulation by microorganisms. Although the amount of conservative is not large, it can nevertheless affect the overall stability of the peptide. Although the preservative for use in the pharmaceutical compositions can vary from 0.005 to 1.0% (w / v), in some embodiments the range for each preservative, alone or in combination with others, is: benzyl alcohol (0.1-1.0%), or m-cresol (0.1-0.6%), or phenol (0.1-0.8%) or combination of methyl (0.05-0.25%) and ethyl or propyl or butyl (0.005% -0.03%) parabens. Parabens are alkyl esters of para-hydroxybenzoic acid. A detailed description of each preservative is set forth in Martin's Remington's Pharmaceutical Sciences. Pramlintide, 25,28,29 Pro-human amylin, does not have a tendency to adsorb onto the glass in a glass container when it is in the liquid form, therefore, a surfactant is not required to further stabilize the pharmaceutical formulation. However, with respect to compounds that do not have such a tendency when in liquid form, a surfactant agent must be used in its formulation. These formulations can then be lyophilized. Surfactants frequently cause protein denaturation, both hydrophobic disturbance and salt bridging. The relatively low concentrations of the surfactant can exert a potent denaturing activity, due to the strong interactions between portions of surfactant and sites reactive on the proteins. However, the use of criteria for this interaction can stabilize proteins against interfacial or surface denaturation. The surfactants that they could additionally stabilize the peptide may optionally be present in a range of about 0.001 to 0.3% (w / v) of the total formulation and include polysorbate 80 (ie, polyoxyethylene (20) sorbitan monooleate), CHAPS® (ie, 3 - [(3-colamidopropyl) dimethylammonium] -3-propansulfonate, Brij® (e.g., Brij 35, which is (polyoxyethylene (23) lauryl ether), poloxamer, or other nonionic surfactant. It is desirable to add sodium chloride or other salt to adjust the tonicity of the pharmaceutical formulation, depending on the selected toner, however, this is optional and depends on the particular formulation selected Parenteral formulations may preferably be isotonic or substantially isotonic. for parenteral products it is water, water of adequate quality for parenteral administration can be prepared either by distillation or by reverse osmosis. Ion is the preferred aqueous vehicle for use in pharmaceutical formulations. It is possible that other ingredients may be present in the pharmaceutical formulations. Such additional ingredients may include, e.g., wetting agents, emulsifiers, oils, antioxidants, body-forming agents, tonicity modifiers, chelating agents, metal ions, oleaginous vehicles, proteins (e.g., human serum albumin, gelatin or proteins) and a zwitterion (e.g., an amino acid such as betaine, taurine, arginine, glycine, lysine and histidine). In addition, polymer solutions or polymer blends provide the opportunity for release controlled peptide. Such additional ingredients, of course, should not adversely affect the overall stability of the pharmaceutical formulation of the present invention. Containers are also an integral part of the formulation of an injection and can be considered a component, so there is no container that is totally inert, or in some way does not affect the liquid it contains, particularly if the liquid is aqueous. Therefore, the selection of a container for a particular injection should be based on a consideration of the composition of the container, as well as the solution, and the treatment of which it will be subject. The adsorption of the peptide from the glass surface of the bottle can also be minimized, if necessary, by the use of a borosilicate glass, for example, type I boron silicate glass of Wheaton T # 33 ( type 1-33 of Wheaton) or its equivalent (Wheaton Glass Co.). Other suppliers of similar borosilicate glass jars and acceptable cartridges for manufacturing include Kimbel Glass Co., West Co., Bünder Glas GmbH and Forma Vitrum. The biological and chemical properties of the compound can be stabilized by formulation and lyophilization in a Wheaton type 1-33 boron silicate serum bottle at a final concentration of 0.1 mg / ml and 10 mg / ml of the compound in the presence of 5% mannitol, and 0.02% Tween 80. For the formulations to be given by injection, in order to allow the introduction of a needle from a hypodermic syringe into a multi-dose vial and to provide resealing as soon as the needle is Withdrawal, the open end of each bottle is preferably sealed with a rubber stopper closure held in place by an aluminum band. Glass bottle stoppers, such as West 4416/50, 4416/50 (Teflon face) and 4406/40, Abbott 5139 or any equivalent stopper can be used as the closure for pharmaceutical injection. For formulations comprising peptide anti-obesity agents, these stoppers are compatible with the peptide as well as the other components of the formulation. The inventors have also discovered that these plugs pass the plug integrity test when tested using patient use patterns, e.g., the plug can withstand at least about 100 injections. Alternatively, the peptide can be lyophilized in flasks, syringes or cartridges for subsequent reconstitution. The liquid formulations of the present invention can be filled in one or two chamber cartridges, or in one or two chamber syringes. Each of the components of the pharmaceutical formulation described above is known in the art and is described in Pharmaceutical Dosage Forms: Parenteral Medications, Vol. 1, 2nd ed., Avis et al. Ed., Mercel Dekker, New York, N.Y. 1992, which is incorporated herein by reference in its entirety. The manufacturing process for the above liquid formulations generally involves the steps of combination, sterile filtration and filling. The combination procedure involves the dissolution of ingredients in a specific order (conservative followed by stabilizer / tonicity agents, pH regulator and peptide) or dissolving at the same time. Alternative formulations, e.g., non-parenteral, may not require sterilization. However, if sterilization is desired or necessary, any suitable sterilization procedure can be used in the development of the peptide pharmaceutical formulation of the present invention. Typical sterilization procedures include filtration, steam (moist heat), dry heat, gases (eg, ethylene oxide, formaldehyde, chlorine dioxide, propylene oxide, beta-propiolactone, ozone, chloropicrin, acid methyl bromide). peracetic and similar), exposure to a source of radiation and aseptic handling. Filtration is the preferred method of sterilization for liquid formulations of the present invention. Sterile filtration involves filtration through 0.46 μm and 0.22 μm (1 or 2) that can be connected in series. After the filtration, the solution is filled in appropriate jars or containers. In one embodiment, the anti-obesity agents are peripherally administered to the subjects. In some embodiments, the liquid pharmaceutical formulations of the present invention are designed for parenteral administration. Suitable routes of administration include intramuscular, intravenous, subcutaneous, intradermal, intra-articular, intrathecal, and the like. In some embodiments, the subcutaneous route of administration is preferred. In certain embodiments, delivery by the mucosa is also preferred. These pathways include but are not limited to oral, nasal, sublingual, pulmonary and buccal which may include administration of the peptide in liquid, semisolid or solid form. For formulations comprising peptide anti-obesity agents, administration by these routes requires substantially more peptide to obtain the desired biological effects due to reduced biosavailability as compared to parenteral delivery. In addition, parenteral controlled release delivery can be achieved by forming polymeric microcapsules, matrices, solutions, implants and devices and administering them parenterally or by surgical means. Examples of controlled release formulations are described in the patents of E.U.A. Nos. 6,368,630, 6,379,704, and 6,766,627, which are incorporated herein by reference. These dosage forms may have a lower biosavailability due to the entrapment of some of the peptide in the polymer matrix or device. See, e.g., US patents. Nos. 6,379,704, 6,379,703, and 6,296,842. The compounds may be provided in a dosage unit form containing an amount of compound with or without insulin or glucose (or a glucose source) which will be effective in single or multiple doses to control the effects of ghrelin. Therapeutically effective amounts of the compounds for the treatment of diseases or disorders associated with ghrelin are those sufficient to treat, prevent or mitigate the physiological effects of undesired ghrelin levels. As will be recognized by experts in the field, an effective amount of anti-obesity agents will vary by many factors including the age and weight of the patient, the physical condition of the patient, the condition to be treated and other factors. An effective amount of the anti-obesity agents will also vary with the particular combination administered. As described herein, administration of the agents in combination may allow a reduced amount of any of the agents administered to be an effective amount. However, typical doses may contain from a lower limit of about 1 μg, 5 μg, 10 μg, 60 μg to 100 μg to an upper limit of about 100 μg, 600 μg, 1 mg, 5 mg, 10 mg, 60 mg or 100 mg of the pharmaceutical compound per day. Other dose ranges such as 0.1 μg to 1 mg of the compound per dose are also contemplated. Doses per day can be delivered in discrete unit doses, provided it is continuously in a 24-hour period or any of that 24 hours. The number of doses per day can be from 1 to approximately 4 per day, although it could be more. The continuous supply can be in the form of continuous infusions. Illustrative infusion rates and rates include from O.OOd nmol / kg to approximately 20 nmol / kg per discrete dose or from approximately 0.01 / pmol / kg / min to approximately 10 pmol / kg / min in a continuous infusion. These doses and infusions can be delivered by intravenous administration (i.v.) or subcutaneous administration (s.c.). The total illustrative dose / supply of the given pharmaceutical composition intravenously may be from about 2 μg to about 8 mg per day, while the total dose / supply of the composition Pharmaceutically given subcutaneously can be from about 6 μg to about 6 mg per day. Leptin and leptin derivatives can be administered, for example, at a daily dose of about 0.01 mg / kg to about 20 mg / kg, in some cases, from about 0.01 mg / kg to about 0.3 mg / kg. The administration can be by injection of a single dose or in divided doses. Sibutramine can be administered, for example, at a daily dose of about 0.01 mg / kg to about 10 mg / kg, in some cases from about 0.01 mg / kg to about 1 mg / kg in a single dose or in divided doses 2 a 3 times per day, or in the form of sustained release. In some cases, sibutramine can be administered as the only daily dose of d mg, 10 mg, 1d mg, 20 mg or 30 mg orally. Rimonabant can be administered, for example, at a daily dose of about 0.01 mg / kg to about 8 mg / kg, in some cases from about 0.3 mg / kg to about 3 mg / kg of body weight in a single dose or in doses divided 2 to 3 times per day or in a sustained release form. The following examples are provided to illustrate, but limit, the invention.

EXAMPLES EXAMPLE 1 Diet-induced obesity (DIO) in the Sprague-Dawley rat is a valuable model for the study of obesity and regulation of energy homeostasis. These rats were developed from a line of rats (Crl: CD® (SD) BR) that were subject to becoming obese with a diet relatively high in fat and energy. See, for example, Levin (1994) Am. J. Physiol. 267: R527-R53d, Levin et al. (1997) Am. J. Physiol. 273: R72d-R730. Male DIO rats were obtained from Charles River Laboratories, Inc. (Wilmington, MA). The rats were housed individually in shoe box type cages at 22 ° C in a 12/12 hour light-dark cycle. Rats were maintained ad libitum to a moderately high fat diet (32% kilocalories of fat; Research Diets D1226B) for 6-7 weeks before drug treatment. At the end of the fattening period (prior to drug administration) the animals typically achieved an average body weight of approximately 600 g. The DIO animals were divided into four treatment groups. Subcutaneous osmotic minibombs (DURECT Corp., Cupertino, CA) designed to deliver vehicle, leptin (600 μg / kg / day), amylin (100 μg / kg / day) or leptin (500 μg / kg / day) were implanted in each group. ) + amine (100 μg / kg / day) for a period of 14 days. As described here, amylin acts on structures in the posterior brain involved in modulation of food intake and / or body weight and leptin acts on structures in the hypothalamus involved in the modulation of food intake and / or body weight. Food intake and body weight were recorded daily. Body composition was measured before and after drug treatment using NMR (Echo Medical Systems, Houston, TX). Indirect calorimetry was used to measure changes in energy expenditure on days 4, 5 and 6 of drug treatment (Oxymax, Columbus Instruments, Columbus, OH). All data are represented as mean ± SEM. Analysis of variance (ANOVA) and post-hoc tests were used to test group difference. A value of P < 0.05 was considered significant. Statistical analysis and graphing were performed using PRISM® 4 for Windows (GraphPad Software, Inc., San Diego, CA). In some early studies, SYSTAT® for Windows (Systat Software, Inc., Point Richmond CA) was used for analysis. Figures 1 and 2 show the effects of amylin and leptin on cumulative feed intake and total changes in body weight after 14 days of drug administration. Of particular interest is that (1) leptin, the agent acting in the forebrain, was ineffective as such in this model of obesity (with no effect on food intake or body weight), and (2) rats treated with the combination of amylin and leptin consumed significantly less food and lost significantly more weight relative to the rats treated with either vehicle or amylin or leptin alone (p <0.0d, different letters indicate that the groups differed significantly from one another).

Similar effects were observed in body composition. Figure 3 illustrates changes in body fat produced by the treatments and Figure 4 illustrates changes in body protein produced by the treatments. Fat loss in animals treated with the combination of amylin + leptin was significantly greater than in animals treated with either single agent or vehicle (p <0.05). These changes in body fat were not accompanied by significant decrease in lean tissue (p> 0.0d; figure 4). Figure 5 illustrates changes in energy expenditure during the dark cycle of the treatment groups. Although the drug-induced reduction (or diet) in food intake and body weight is often accompanied by a slow metabolic rate (heat, kcal / h / kg), the rats treated with the combination of leptin and amylin had a significantly higher metabolic rate during the dark cycle in relation to the other groups (p <; 0.06). Therefore, the posterior brain and anterior brain feeding centers targeted with the combination of amylin + leptin resulted in a significant and sustained reduction in food intake, body weight and body fat while increasing the metabolic rate. In addition, reductions in body weight and body fat were not achieved by a reduction in lean tissue mass.

EXAMPLE 2 Another series of experiments were performed to wait additionally the synergistic effects of the combination of amylin and leptin on changes in body weight and body composition. Inbred DIO rats (Levin) were obtained from Charles Rivers Labs for these studies. These rats were developed by Barry Levin from a line of Crl: CD® (SD) BR rats that are subject to becoming obese with a diet relatively high in fat and energy. They were individually housed in shoe box type cages at 22 ° C in a 12/12 hour light-dark cycle. Rats were maintained ad libitum with a moderately high fat diet (32% of fat kcal; Research Diets D1226B) for approximately 6 weeks prior to drug treatment and throughout the experiment with the exception of paired feeding controls (PF ). The PF rats were restricted to the intake of the group treated with amylin. Prior to drug administration, the rats typically had achieved an average body weight of 500 g. The animals were divided into counterbalanced treatment groups for body weight and subcutaneous osmotic minipumps were implanted (Durect Corp., Cupertino, CA). Two minipumps containing drug or the appropriate vehicle were implanted into each rat. Rat amylin (AC0128; Lot # 2S) was dissolved in 50% DMSO in sterile water and murine leptin (Peprotech, catalog # 450-31) was dissolved in sterile water. The pumps were designed to deliver vehicle, amylin at 100 μg / kg / day or murine leptin at 500 μg / kg / day for a period of 14 days. Osmotic minipumps were implanted to each group subcutaneous (DURECT Corp., Cupertino, CA) designed to deliver vehicle, ieptin (500 μg / kg / day), amylin (100 μg / kg / day) or leptin (500 μg / kg / day) + amylin (100 μg / day) kg / day) during a period of 14 days. Body weight and food intake were recorded daily. Body composition was measured before and after drug treatment using NMR (Echo Medical Systems, Houston, TX). For body composition measurements, the rats were placed briefly (~ 1 min) in a well ventilated plexiglass tube which was then inserted into a specialized NMR machine for rodent. The rats were scrutinized before the pumping implantation and the final day of the experiment. This allowed the calculation of changes in real grams of fat and dry lean tissue (eg, grams of body fat after treatment-grams of body fat in the baseline = change in grams of body fat) and changes in percent of body composition for fat and dry lean tissue (eg,% body fat after treatment -% body fat in the baseline = change in% body fat). The graph in Figure 6A illustrates corrected changes per vehicle in body weight percent of the treatment groups during the two weeks of treatment. In this experiment, administration of leptin resulted in a 2% overall decrease in body weight and the administration of amylin resulted in an overall decrease of 6% in body weight. Notably, the decrease in percent body weight in response to administration of a combination of amylin and leptin was of about 12%, an effect greater than the combined effect of single agents administered alone. Therefore, amylin and leptin act synergistically to reduce body weight. Figure 6B and 6C illustrate changes in body fat and changes in body protein, respectively, produced after the two weeks of treatment. Again, the reduction in body fat as a result of the combination of agents is more than the combined reduction in body fat as a result of the individual agents. These changes in body fat were not accompanied by reductions in body protein but rather by a gain in protein percent. These results support a metabolic effect of the combination of agents as well as a weight-reducing effect. It is known that amylin has an anorectic effect on a receptor. In order to examine the effect of amylin + leptin in the context of an annectic amylin effect, a paired feeding experiment was carried out. DIO rats and drug treatment groups were established as described above. DIO rats in the vehicle treatment groups, amylin and amylin + leptin had access ad libitum to food, while intake in the paired feed leptin treatment was restricted to the amount consumed by the group treated with amylin. Body weight was recorded daily during the two weeks of treatment. As shown in Figure 7, the amylin treatment group and the paired-feeding leptin treatment group both had approximately a 6% decrease in body weight in relation to vehicle control. This result is consistent with the previous result of leptin that had little or no effect on body weight in DIO animals. The combination of amylin + leptin results in a decrease of approximately 12% in body weight in relation to vehicle control. Therefore, the paired feeding experiment demonstrates that the combination of amylin + leptin reduces body weight above and above that conferred by caloric restriction.

EXAMPLE 3 As described here, leptin levels in the serum in most obese humans are high, and a state of leptin resistance is thought to exist for these individuals. Plasma leptin levels and leptin resistance were examined in normal Harlan Sprague-Dawley rats (HSD) and in rats subjected to DIO. Rats subject to normal DIO and HSD were divided into three treatment groups. Two groups were implanted subcutaneous osmotic minipumps (DURECT Corp., Cupertino, CA) designed to deliver vehicle or amylin (100 μg / kg / day) and the third group was fed in pairs to the amount consumed by the group treated with amiline for a period of 14 days. Leptin levels in the serum were determined by immunoassays using a commercial kit (Lineo Research, Inc., St. Charles, MO). As shown in Figures 8A-8B, the level of leptin in serum in animals subject to IOD is approximately three times higher than in normal HSD animals. Therefore, the rats subject to DIO are hyper-leptinémicas. Both amylin treatment and caloric restriction to the amount of food eaten by animals treated with amylin significantly reduced leptin levels in plasma in both DIO and normal subjects. Slender, normal HSD rats were divided into two treatment groups. Subcutaneous osmotic minipumps (DURECT Corp., Cupertino, CA) designed to deliver either vehicle or leptin (500 μg / kg / day) for a period of 14 days and body weight were recorded each week were implanted into each group. As shown in Figure 9, the ineffective dose of leptin (500 mg / kg / day) in animals subject to IOD induced a significant and sustained reduction in body weight in normal HSD rats. The animals subject to DIO described here appear to be resistant to the weight-reducing effect of leptin.

EXAMPLE 4 To demonstrate the effects of the combination of amylin and a serotonergic / noradrenergic reuptake inhibitor on changes in body weight and body composition, male DIO rats were fattened and divided into four treatment groups, as described in example 2.

The rat amylin was dissolved in 60% DMSO in sterile water and sibutramine was dissolved in sterile water. Subcutaneous osmotic minipumps designed to deliver vehicle, sibutramine (3 mg / kg / day) or amylin (100 μg / kg / day) were implanted for each group over a period of 14 days. Body weight and food intake were recorded daily. Body composition was measured before and after drug treatment using NMR (Echo Medical Systems, Houston, TX). For body composition measurements, the rats were placed briefly. (~ 1 min) in a well ventilated plexiglass tube that was then inserted into a specialized NMR machine for rodents. The rats were scrutinized before the implantation of the pump and the final day of the experiment. This allowed the calculation of changes in real grams of fat and dry lean tissue (eg, grams of body fat after treatment - grams of body fat in the baseline = change in grams of body fat) and changes in% of body fat. body composition for rat and dry lean tissue (eg,% body fat after treatment -% body fat in the baseline = change in% body fat). The graph in Figure 10A illustrates corrected changes per vehicle in body weight percent of the treatment groups during the two weeks of treatment. Administration of sibutramine alone and administration of amylin alone resulted in approximately a 6% decrease in body weight. The percent decrease in body weight in response to the administration of a combination of amylin and Sibutramine was approximately 12%. Figures 10B and 10C illustrate changes in body fat and changes in body protein, respectively, produced after the two weeks of treatment. The loss of fat mass was evident with the treatment of amylin alone or sibutramine alone, and a synegistic effect was obtained when both amylin and sibutramine were administered in combination (Figure 10B). The administration of amylin alone resulted in an increase in lean mass (protein). Lean mass (protein) was relatively invariant when sibutramine was administered alone or in combination with amylin (Figure 10C). These results support a metabolic effect of the combination of agents as well as a weight-reducing effect. The combination of amylin and catecholaminergic agonist, phentermine, was also tested for effects on changes in body weight and body composition. Phentermine is classically referred to as a catecholaminergic agonist since it currently has NA / d-HT receptors. Male DIO rats were fattened and divided into four treatment groups as described above. Subcutaneous osmotic minipumps were implanted to each group and / or an oral feed was inserted by forced feeding, designed to supply vehicle, phentermine (10 mg / kg / day), amylin (100 μg / kg / day) or phentermine (10 mg / kg / day) + amine (100 μg / kg / day) for a period of 14 days. The minipumps contained either vehicle (50% DMSO in water) or amylin while forced feeding administered either sterile water or phentermine. Body weight is recorded daily and body composition was measured before and after drug treatment using NMR. The graph in Figure 11A shows changes corrected per vehicle in percent body weight of the treatment groups during the two weeks of treatment. The administration of phenethyl ester alone resulted in approximately a 5% decrease in body weight and the administration of amylin alone resulted in approximately a 7% decrease in body weight. The percent decrease in body weight in response to administration of a combination of amylin and phentermine was approximately 12%. Figures 11 B and 11 C illustrate changes in body fat and changes in body protein, respectively, produced after two weeks of treatment. A moderate amount of fat mass loss was evident with the treatment of phentermine alone and a greater amount of fat mass loss was evident with the treatment of amylin alone. When amylin and phentermine were administered in combination, a synergistic effect was obtained (Figure 11B). Lean mass (protein) did not change or tended to be lost when phentermine alone was administered. Administration of amylin alone retained lean mass (protein) and the combination of amylin and phentermine tended to have the largest increase in lean mass (protein), even though the animals suffered approximately 12% loss in body weight (Figure 11 C). ). These results support a metabolic effect of the combination of agents as well as a weight-reducing effect.

EXAMPLE 5 To demonstrate the effects of the combination of amylin and a CB-1 antagonist on changes in body weight and body composition, inbred DIO rats (Levin) were obtained from Charles Rivers Labs. These rats were developed by Barry Levin from a line of Crl: CD® (SD) BR rats that are subject to becoming obese with a diet relatively high in fat and energy. They were individually housed in shoe box type cages at 22 ° C in a 12/12 hour light-dark cycle. The rats were maintained ad libitum with a moderately high fat diet (32% of fat kcal; Research Diets D1226B) for approximately 6 weeks before drug treatment and throughout the experiment. Prior to drug administration, the rats typically had achieved an average body weight of 500 g. The rats were used to forced oral feeding for 1 week before treatment. Rimonabant was administered at a dose interval of (0.1, 0.3, 1.0, 3.0, 10 mg / kg / day) by forced oral feeding. Amylin (dissolved in 50% DMSO in sterile water) or vehicle was administered by minipump (100 μg / kg / day). Rimonabant was always supplied immediately before turning off the light. Food intake and body weight were measured at 1 and 2 weeks after treatment. Body composition was measured before and after drug treatment using NMR (Echo Medical Systems, Houston, TX). For body composition measurements, rats are placed briefly (~ 1 min) in a well ventilated plexiglass tube which was then inserted into a specialized NMR machine for rodent. The rats were scrutinized before the pumping implantation and the final day of the experiment. This allowed the calculation of changes in real grams of fat and dry lean tissue (eg, grams of body fat after treatment-grams of body fat in the baseline = change in grams of body fat) and changes in percent of body composition for fat and dry lean tissue (eg,% body fat after treatment -% body fat in the baseline = change in% body fat). The graph in Figure 12A illustrates corrected changes per vehicle in body weight percent of the treatment groups during the two weeks of treatment. The administration of Rimonabant alone resulted in approximately a 4% decrease in body weight and the administration of amylin alone resulted in approximately a 6% decrease in body weight. The percent decrease in body weight in response to the administration of a combination of amylin and rimonabant was approximately 11%. Figures 12B and 12C illustrate changes in body fat and changes in body protein, respectively, produced after the two weeks of treatment. The loss of fat mass was evident with the treatment of either amylin alone or rimonabant alone, and a synergistic effect was obtained when both amiline and rimonabant were administered in combination (Figure 12B). The administration of amylin alone, rimonabant alone, and amylin + rimonabant in combination gave resulted in a relatively equivalent increase in lean mass (protein) (Figure 12C). These results support a metabolic effect of the combination of agents as well as a weight-reducing effect. In another test, the CB-1 antagonist rimonanbant (AC163720) was administered in combination with amylin. The rats subject to IOD were maintained ad libitum with a moderately high fat diet (32% of fat kcal; Research Diets D1226B) for 6 weeks before drug treatment. At the end of the fattening period they typically had an average body weight of 600 g. The rats were then divided into treatment groups and a subcutaneous mini-pump (Durect Corp) was implanted and forced oral feeding was inserted. The minipump contained either vehicle (60% DMSO in water) or amylin (100 μg / kg / day) while forced oral feeding administered either sterile water or a dose range of rimonabant (AC 163720) (0.1, 0.3, 1.0, 3.0, 10.0 mg / kg / day). The change in body weight after 2 weeks is illustrated in Figure 13 and two of these combinations (enclosed in a circle) are highlighted in Figures 14A and 14B in more detail.

EXAMPLE 6 To demonstrate the effects of the combination of amylin and an exendin analog, 14Leu-exendin-4: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe He Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Pro Pro Pro Ser Wing (SEQ ID NO: 190), on changes in body weight and body composition, male DIO rats were fattened and divided into four treatment groups as described above. Prior to drug administration, the rats typically had achieved an average body weight of 500 g. Exendin-4 analogue was administered by minipump at a range (0.3, 1, 3, 10, 30 μg / kg / day). Amylin (dissolved in 50% DMSO in sterile water) or vehicle was administered by minipump (100 μg / kg / day). Body weight and food intake were recorded daily. Body composition was measured before and after drug treatment using NMR (Echo Medical Systems, Houston, TX). For body composition measurements, the rats were placed briefly (~ 1 min) in a well ventilated plexiglass tube which was then inserted into a specialized rodent NMR machine. The rats were scrutinized before the implantation of the pump and the final day of the experiment. This allowed the calculation of changes in real grams of fat and dry lean tissue (v.gr., grams of body fat after treatment - grams of body fat in the baseline = change in grams of body fat) and changes in% body composition for rat and dry lean tissue (eg,% body fat after treatment -% body fat in the baseline = change in% body fat). The graph in Figure 1 shows changes corrected per vehicle in percent body weight of the treatment groups during the two weeks of treatment. Administration of exendin-4 analog alone and the administration of amylin alone resulted in each one approximately a decrease of 6% in body weight. The percent decrease in body weight in response to administration of a combination of amylin and exendin-4 analog was about 12%. Figures 16B and 15C illustrate changes in body fat and changes in body protein, respectively, produced after the two weeks of treatment. The loss of fat mass was evident with the exendin-4 analog treatment alone. The administration of amylin alone and amylin + analog of exendin-4 in combination resulted in a relatively equivalent decrease in fat mass (Figure 16B). The administration of amylin alone, exendin-4 analog alone, and amylin + AC3174 in combination resulted in a relatively equivalent increase in lean mass (protein) (Figure 1dC). These results support a metabolic effect of the combination of agents as well as a weight-reducing effect.

EXAMPLE 7 To demonstrate the effects of the combination of amylin and PYY agonists on changes in body weight and body composition, male DIO rats were fattened and divided into four treatment groups as described above. Osmotic subcutaneous minipumps were implanted to each group, designed to supply vehicle, PYY (3-36) (1000 μg / kg / day), amylin (100 μg / kg / day) or PYY (3-36) (1000 μg / kg / day) + amylin (100 μg / kg / day) during a period of 14 days. PYY (3-36) was administered by minipump at a dose interval (100, 200, 400, 800, 1000 μg / kg / day). Amylin 100 μg / kg / day (dissolved in 50% DMSO in sterile water), PYY (3-36) (dissolved in 50% DMSO in sterile water) or vehicle was administered by mini-pump. Food intake and body weight were recorded daily. Body composition was measured before and after drug treatment using NMR (Echo Medical Systems, Houston, TX). For body composition measurements, the rats were placed briefly (~ 1 min) in a well ventilated plexiglass tube which was then inserted into a specialized rodent NMR machine. The rats were scrutinized before the implantation of the pump and the final day of the experiment. This allowed the calculation of changes in real grams of fat and dry lean tissue (eg, grams of body fat after treatment - grams of body fat in the baseline = change in grams of body fat) and changes in% of body fat. body composition for rat and dry lean tissue (eg,% body fat after treatment -% body fat in the baseline = change in% body fat). The graph in Figure 16A shows corrected changes per vehicle in percent body weight of the treatment groups during the two weeks of treatment. The administration of PYY (3-36) only resulted in approximately a 9% decrease in body weight and the administration of amylin alone resulted in approximately 7% decrease in body weight. The percent decrease in body weight in response to the administration of a combination of amylin and PYY (3-36) was approximately 15%. Figures 16B and 16C illustrate changes in body fat and changes in body protein, respectively, produced after the two weeks of treatment. The increase in loss of amount of fat mass was evident with the treatment of PYY (3-36) alone, amylin alone, and amylin + PYY (3-36) in combination (Figure 16B). The administration of amylin alone and amylin + PYY (3-36) in combination resulted in an increase in lean mass (protein) (Figure 16C). These results support a metabolic effect of the combination of agents as well as a weight-reducing effect. Although the foregoing description describes the present invention, with examples provided for purposes of illustration, it will be understood that the practice of the present invention encompasses all customary variations, adaptations or modifications as being within the scope of the claimed invention. Therefore, the descriptions and examples should not be considered as limiting the scope of the invention, which is delineated by the appended claims.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of at least two different anti-obesity agents, wherein at least one anti-obesity agent acts on the structures of the forebrain involved in the modulation of food intake or body weight and at least one anti-obesity agent. obesity that acts on the structures of the posterior brain involved in the modulation of food intake or body weight; wherein when an anti-obesity agent is a PYY (3-36), an analogue of PYY (3-36), or a PYY agonist (3-36), then another anti-obesity agent is not an amylin, an amylin agonist, an amylin analog, a CCK, a CCK analog, or a CCK agonist; and wherein when an anti-obesity agent is an exendin, an exendin derivative or an exendin agonist, then another anti-obesity agent is not an amylin, an amylin agonist, an amylin analog, in the manufacture of a medicament. useful for treating obesity in a subject, wherein the medicament is adapted to be peripherally administrable.

2. The use as claimed in claim 1, wherein at least one of the anti-obesity agents is selected from the group consisting of an NPY1 receptor antagonist, an NPYd receptor antagonist, a receptor agonist. of NPY2, an NPY4 receptor agonist, a leptin, a leptin derivative, a leptin agonist, a CNTF, a CNTF agonist / modulator, a CNTF derivative, an MCH1 R antagonist, an MCH2R antagonist, a melanocortin 4 agonist, an MC4 receptor agonist, a cannabinoid receptor antagonist / reverse agonist (CB-1) , a ghrelin antagonist, a dHT2c agonist, a serotonin reuptake inhibitor, a serotonin transport inhibitor, an exendin, an exendin derivative, an exendin agonist, a GLP-1, a GLP-1 analog, a GLP-1 agonist, a DPP-IV inhibitor, an opioid antagonist, an orexin antagonist, a metabotropic glutamate receptor antagonist of subtype d, an antagonist / inverse agonist of histamine 3, topiramate, a CCK, a CCK analog, a CCK agonist, an amylin, an amylin analog and an amylin agonist.

3. The use as claimed in claim 2, wherein at least one anti-obesity agent is phentermine, rimonabant, sibutramine or pramlintide.

4. The use of at least two anti-obesity agents, wherein the first anti-obesity agent is selected from the group consisting of an NPY1 receptor antagonist, an NPYd receptor antagonist, an NPY2 receptor agonist. , a NPY4 receptor agonist, a leptin, a leptin derivative, a leptin agonist, a CNTF, an CNTF agonist / modulator, a CNTF derivative, an MCH1R antagonist, an MCH2R antagonist, an agonist of melanocortin 4, an MC4 receptor agonist, a cannabinoid receptor antagonist / inverse agonist (CB-1), a ghrelin antagonist, a dHT2c agonist, a serotonin reuptake inhibitor, a serotonin transport inhibitor, an exendin, an exendin derivative, an exendin agonist, a GLP-1, a GLP-1 analog, a GLP-1 agonist, a DPP-inhibitor IV, an opioid antagonist, an orexin antagonist, a metabotropic glutamate receptor antagonist of subtype d, an inverse antagonist / agonist of histamine 3, topiramate, wherein the second anti-obesity agent is selected from the group consisting of CCK , a CCK analog, a CCK agonist, an amylin, an amylin analog and an amylin agonist, wherein when the first anti-obesity agent is not a PYY (3-36), an analog of PYY (3- 36), or a PYY agonist (3-36), and wherein when the first anti-obesity agent is an exendin, an exendin derivative or an exendin agonist, then the second anti-obesity agent is not an amylin, an amylin agonist, an analog of amylin, in the manufacture of a drug useful for trafficking Obesity in a subject, wherein the medicament is adapted to be peripherally administrable. d.- The use as claimed in any of claims 1-4, wherein the subject reduces body weight by at least 10%. 6. The use as claimed in any of claims 1-5, wherein the subject reduces body fat mass. 7. The use of at least two different anti-obesity agents, wherein at least one anti-obesity agent acts on the structures of the forebrain involved in the modulation of food intake or body weight and at least one agent anti-obesity that acts on the posterior brain structures involved in the modulation of food intake or body weight; wherein when an anti-obesity agent is a PYY (3-36), an analogue of PYY (3-36), or a PYY agonist (3-36), then another anti-obesity agent is not an amylin, an amylin agonist, an amylin analog, a CCK, a CCK analog, or a CCK agonist; wherein when an anti-obesity agent is an exendin, an exendin derivative or an exendin agonist, then another anti-obesity agent is not an amylin, an amylin agonist, an amylin analog, in the manufacture of a useful medicament. for reducing the availability of nutrients in a subject, wherein the drug is adapted to be peripherally administrable. 8. The use as claimed in claim 7, wherein at least one of the anti-obesity agents is selected from the group consisting of an NPY1 receptor antagonist, an NPYd receptor antagonist, a receptor agonist. of NPY2, a NPY4 receptor agonist, a leptin, a leptin derivative, a leptin agonist, a CNTF, an CNTF agonist / modulator, a CNTF derivative, an MCH1 R antagonist, an MCH2R antagonist, a melanocortin agonist 4, an MC4 receptor agonist, a cannabinoid receptor antagonist / reverse agonist (CB-1), a ghrelin antagonist, a dHT2c agonist, a serotonin reuptake inhibitor, a serotonin transport inhibitor , an exendin, an exendin derivative, an exendin agonist, a GLP-1, a GLP-1 analogue, a GLP-1 agonist, a DPP-inhibitor IV, an opioid antagonist, an orexin antagonist, a metabotropic glutamate receptor antagonist of subtype 5, an inverse antagonist / agonist of histamine 3, topiramate, a CCK, a CCK analogue, a CCK agonist, an amylin, an amylin analog, and an amylin agonist. 9. The use as claimed in claim 8, wherein at least one anti-obesity agent is phentermine, rimonabant, sibutramine or pramlintide. 10. The use as claimed in claim 8, wherein an anti-obesity agent is an amylin, an amylin analog or an amylin agonist and another anti-obesity agent is a leptin, a leptin derivative or an agonist of leptin. 11. The use of at least two anti-obesity agents, wherein the first anti-obesity agent is selected from the group consisting of an NPY1 receptor antagonist, an NPYd receptor antagonist, an NPY2 receptor agonist. , a NPY4 receptor agonist, a leptin, a leptin derivative, a leptin agonist, a CNTF, an CNTF agonist / modulator, a CNTF derivative, an MCH1R antagonist, an MCH2R antagonist, an agonist of melanocortin 4, an MC4 receptor agonist, a cannabinoid receptor antagonist / reverse agonist (CB-1), a ghrelin antagonist, a 6HT2c agonist, a serotonin reuptake inhibitor, a serotonin transport inhibitor, a exendin, an exendin derivative, an exendin agonist, a GLP-1, a GLP-1 analog, a GLP-1 agonist, a DPP-inhibitor IV, an opioid antagonist, an orexin antagonist, a metabotropic glutamate receptor antagonist of subtype 5, an inverse antagonist / histamine agonist 3, topiramate, wherein the second anti-obesity agent is selected from the group consisting of CCK , a CCK analogue, a CCK agonist, an amylin, an amylin analogue, and an amylin agonist, wherein when the first anti-obesity agent is not a PYY (3-36), an analog of PYY (3 -36), or a PYY agonist (3-36), and wherein when the first anti-obesity agent is an exendin, an exendin derivative or an exendin agonist, then the second anti-obesity agent is not an amylin , an amylin agonist, an amylin analog, in the manufacture of a medicament useful for reducing the availability of nutrients in a subject, wherein the medicament is adapted to be peripherally administrable. 12. The use as claimed in any of claims 7-11, where the reduction in the availability of nutrients is indicated in the subject by loss of body weight, by loss of fat mass, or by loss of ectopic fat. 13. The use as claimed in any of claims 7-12, wherein the subject has at least one condition selected from the group consisting of obesity, a disorder related to obesity, a disease related to obesity, a condition related to obesity, diabetes, insulin resistance syndrome, lipodystrophy, nonalcoholic steatohepatitis, a cardiovascular disease, polycystic ovary syndrome and metabolic syndrome. 14. The use of at least two different anti-obesity agents, wherein at least one anti-obesity agent acts on the structures of the forebrain involved in the modulation of food intake or body weight and at least one agent anti-obesity that acts on the structures of the posterior brain involved in the modulation of food intake or body weight; wherein when an anti-obesity agent is a PYY (3-36) an analog of PYY (3-36), or a PYY agonist (3-36), then the other anti-obesity agent is not an amylin, an agonist of amylin, an amylin analogue, a CCK, a CCK analogue, or a CCK agonist, wherein when an anti-obesity agent is an exendin, an exendin derivative or an exendin agonist, then another anti-obesity agent does not is an amylin, an amylin agonist, an amylin analogue, in the manufacture of a medicament useful for reducing body weight in a subject by at least 10%, wherein the medicament is adapted to be peripherally administrable. 1

5. The use as claimed in claim 14, wherein at least one of the anti-obesity agents is selected from the group consisting of an NPY1 receptor antagonist, an NPYd receptor antagonist, a receptor agonist. of NPY2, a NPY4 receptor agonist, a leptin, a leptin derivative, a leptin agonist, a CNTF, an CNTF agonist / modulator, a CNTF derivative, an MCH1 R antagonist, an MCH2R antagonist, a melanocortin agonist 4, a MC4 receptor agonist, a cannabinoid receptor antagonist / inverse agonist (CB-1), a ghrelin antagonist, a dHT2c agonist, a serotonin reuptake inhibitor, a serotonin transport inhibitor, an exendin, a derivative of exendin, an exendin agonist, a GLP-1, a GLP-1 analogue, a GLP-1 agonist, a DPP-IV inhibitor, an opioid antagonist, an orexin antagonist, a glutamate receptor antagonist metabotropic subtype d, an inverse antagonist / agonist of histamine 3, topiramate, a CCK, a CCK analogue, a CCK agonist, an amylin, an amylin analogue, and an amylin agonist. 1

6. The use as claimed in claim 16, wherein at least one anti-obesity agent is phentermine, rimonabant, sibutramine or pramlintide. 1

7. The use as claimed in claim 16, wherein an anti-obesity agent is an amylin, an amylin analog or an amylin agonist and another anti-obesity agent is a leptin, a leptin derivative or an agonist of leptin. 1

8. The use of at least two anti-obesity agents, wherein the first anti-obesity agent is selected from the group consisting of an NPY1 receptor antagonist, an NPYd receptor antagonist, an NPY2 receptor agonist. , a NPY4 receptor agonist, a leptin, a leptin derivative, a leptin agonist, a CNTF, an CNTF agonist / modulator, a CNTF derivative, an MCH1R antagonist, an MCH2R antagonist, an agonist of melanocortin 4, a MC4 receptor agonist, a cannabinoid receptor antagonist / inverse agonist (CB-1), a ghrelin antagonist, a dHT2c agonist, a serotonin reuptake inhibitor, a serotonin transport inhibitor, an exendin, a derivative of exendin, an exendin agonist, a GLP-1, a GLP-1 analog, a GLP-1 agonist, a DPP-IV inhibitor, an opioid antagonist, an orexin antagonist, a glutamate receptor antagonist metabotropic of subtype 5, an inverse antagonist / agonist of histamine 3, topiramate, wherein the second anti-obesity agent is selected from the group consisting of a CCK, a CCK analog, a CCK agonist, an amylin, an analogue amylin, and an amylin agonist, wherein when the first anti-obesity agent is not a PYY (3-36), an analog of PYY (3-36), or a PYY agonist (3-36), wherein when the first anti-obesity agent is an exendin, an exendin derivative or an exendin agonist, then the second anti-obesity agent is not an amylin, an amylin agonist, an amylin analog, in the manufacture of a medicament useful for reducing body weight in a subject by at least 10%, wherein the medicament is adapted to be peripherally administrable. 1

9. The use of at least one leptin, a leptin derivative or a leptin agonist and at least one of an amylin, an amylin agonist or an amylin analogue, in the manufacture of a medicament useful for reducing body weight in a subject by at least 10%.