PREVENTION OF MUSCLE MASS LOSS WITH LEPTIN RECEPTOR LIGANDS

Abstract: This invention relates generally to methods for preserving and increasing lean body mass in a mammal in need of such treatment by administration of a therapeutically effective amount of a leptin receptor agonist.

Description: PREVENTION OF MUSCLE MASS LOSS WITH LEPTIN RECEPTOR LIGANDS BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates generally to methods for preventing the loss of lean tissue or muscle mass during catabolic states associated with improper nutrition, and methods for increasing lean tissue growth, in a mammal in need of such treatment by administration of a therapeutically effective amount of a leptin receptor agonist. 2. Description of the Related Art Anatomical recognition of organs that were proposed to release active substances were described from about 1500 - 1800. Ernest Starling and William Bayliss conceived the endocrine system in 1904 as a complex of chemical messages which coordinate the functions of different tissues. By 1930, hormones from the pituitary, gonads, thyroid, parathyroid, adrenal, and pancreas were identified and often used therapeutically to treat endocrinopathys. During the next 4 decades, new hormones were isolated from these endocrine organs and a new tissue, the hypothalamus, was proven to be a component of the endocrine system. In 1994, adipose tissue became the newest member of this endocrine tissue family. An adipocyte factor that transfers a hormonal message to the hypothalamus has been postulated for many years. Coleman (10) demonstrated in 1973 that Lepr* /Lepr^ 0 mice were resistant to such a circulating satiety factor and thus the mice were hyperphagic, diabetic, and obese. Further, Lep ab /Lep ab mice were sensitive to this satiety factor but apparently did not secrete it. At the end of 1964, a gene that encodes this protein was identified by Friedman's group (60). The 16-kD protein product of this gene was named leptin, derived from the Greek root "leptos", meaning thin (23). Administration of recombinant leptin to Lep ob /Lep ob mice replaces deficient levels and corrects their obesity (4, 23, 36). These findings suggest that adipose tissue performs important biological functions beyond storage of fat. In fact, adipose tissue functions very much like any other endocrine tissue, providing a change in circulating leptin that is perceived by the brain as a signal of lipid storage level. To fully satisfy requirements for a hormone, evidence that leptin is secreted from adipocytes (45) into blood of rodents (33) and human (11 , 33) was presented. The major target for this hormonal message appears to be the hypothalamus. Direct injection of leptin into the lateral cerebral ventricle of Lep ob /Lep ob mice generated a potent anorectic effect that could only be matched by much higher doses of the protein when it was administered subcutaneously (47). Tartaglia and colleagues (50) observed that leptin bound to choroid plexus and used techniques of expression cloning to identify the leptin receptor gene (Lepr). Others (8, 31 , 48) used genetic mapping and genomic analysis to search for a mutation in the Lepr gene. A mutation in the Lepr 13 locus results in a spliced transcript that is proposed to be incapable of signal transduction, leads to leptin resistance, and is likely the cause of severe obesity and diabetes reported in Lep^/Lepr 13 mice (8, 20, 57). The wild-type leptin receptor gene has a long intracellular domain that is thought to be crucial for intracellular signal transduction (57). This receptor closely resembles class I cytokine receptors and is only located in hypothalamus. Spliced variant isoforms of the Lepr are also located in many tissues including hypothalamus, choroid plexus, heart, lung, liver, skeletal muscle, and kidney. Functions for these variants may involve transport of leptin from blood to its target cells (2, 22). Thus, leptin fulfills Starling's definition of a hormone. It is carried from adipose where it is secreted to the hypothalamus by means of the circulatory system and the continually recurring storage and dissipation of lipid determines its production and secretion. The leptin message Development of sensitive immunoassays permit measurement of leptin during different physiological states. Studies in men and women clearly indicate that circulating leptin values are positively correlated with quantity of body fat (reviewed in (5)). Further, fasting inhibits and refeeding stimulates leptin secretion in rodents (18, 39) and human (29) suggesting that the leptin signal is one of fuel storage or energy availability. Indeed, a rapid decrease in energy stores resulting from short periods of intense exercise is associated with decreased plasma leptin levels (38, 52). Further, leptin levels are dramatically reduced following severely prolonged negative energy balance that is observed in malnutrition of patients suffering from anorexia nervosa (7, 34). Only in rare cases of leptin gene mutation reported in a strain of mice (60) and 2 related girls (35) are extremely low levels or undetectable concentrations of leptin associated with overnutrition and obesity. Thus, circulating levels of leptin function like a fuel gage, broadcasting the level of energy storage to brain and perhaps other tissues. In exceptional cases of leptin mutations, the lack of such a signal results in compensatory mechanisms to continuously replenish the lipid reserve and consequently are the etiology of severe obesity. Hypothalamus is the principal leptin target Leptin's message is perceived by hypothalamic tissue that expresses full-length in the arcuate, ventromedial, dorsomedial, and lateral hypothalamic nuclei (17). Only this full-length receptor can transduce the leptin hormonal signal to a neuronal directive (57). In the arcuate nucleus, leptin reduces the excitatory input to neuropeptide-Y (NPY) neurons and produces inhibitory postsynaptic effects (21 ) that rapidly decreases NPY release (47). Long term leptin signaling results in decreased NPY mRNA expression (42, 47). Considerable evidence supports NPY neurons of the arcuate nucleus as a major center for regulating fuel homeostasis and its associated adaptive endocrinology. These NPY neurons project to other areas of the hypothalamus that regulate feeding behavior and coordinate neuroendocrine secretion (9). Careful mapping of NPY stimulated feeding has been reported (46). Fasting and starvation are powerful stimuli while refeeding is inhibitory to these neurons and their synapses. In concert, hormones responsible for metabolic homeostasis are regulated by NPYergic transmission. Activation of NPY neurons is associated with increased insulin secretion (59), activation of the hypothalamic-pituitary-adrenal axis (55), and inhibition of the thyrotropin releasing hormone-thyroid axis (24) and the hypothalamic-growth hormone axis. In addition, both episodic basal and cyclic release of luteinizing hormone-releasing hormone (LHRH) are stimulated by NPY, rendering appropriate output from these neurons essential for fertility (27, 28). While leptin signaling in the arcuate nucleus is inhibitory, neurons in the ventromedial, dorsomedial, and ventral premammillary hypothalamic nuclei appear to be activated by leptin (16, 53). These neurons may release satiety neuropeptides such as cholecystokinin and cortiocotropin-releasing hormone (CRH) that are also important hypothalamic components of the sympathetic nervous system (19, 40) that participate in regulation of body temperature, resting energy expenditure gastrointestinal motility, and insulin secretion. The hypothalamus is an important central processing center that integrates neuroendocrine circuits and it depends on leptin afferent information to extend some or all neuroendocrine feedback loops, especially those that are dependent and differentially regulated by fuel reserve level. The hypothalamic-pituitary-adrenal-adipose axis (HPAAA) Much endocrinology has been learned by studying the consequences following disconnection or surgical removal of an endocrine gland. Although adipose tissue ablation is not practical, leptin was discovered because of the obese phenotype resulting from mutations in the leptin gene (60). These leptin deficient mice are characterized by high expression of hypothalamic NPY (58) as well as increased levels of feeding, plasma corticosterone and plasma insulin suggesting that leptin is inhibitory to NPY neurons (discussed above) as well as the HPAA. CRH neurons comprise much of the complex hypothalamic paraventricular nucleus (PVN) that is divided into neurons that project to the median eminence (30, 56) and neurons that give rise to descending efferent autonomic transmission (41 ). Interestingly, induction of Fos protein after acute intravenous leptin administration was detected in only these latter autonomic regions of the PVN (16). Fos immunoactivity was not noticeably altered in the medial subneurons that contain CRH, project to the median eminence, and participate in regulation of the HPAA. Further, we have recently demonstrated that leptin inhibits hypoglycemia mediated CRH release in vitro and stress stimulated HPAA in vivo (26). Hypoglycemia and restraint were techniques used to stimulate the PVN hypophysiotropic CRH neurons. Some studies have failed to appreciate the different subdivisions of the PVN and as a consequence have measured expression of CRH MRNA in the entire anatomical complex. Expression of this transcript in the PVN of Lep o /Lep ob mice, that should be most sensitive to the adipocyte hormone, is not altered by leptin treatment (42) but the same group has reported that administration of leptin to Long-Evans rats increases CRH message levels in this complex nucleus (43). In addition, unstimulated hypothalamic slices (37) or hypothalamic explants (13) appear to release CRH after exposure to leptin. Collectively, these data support that leptin negatively feeds back at the hypothalamic level to inhibit HPAA. Leptin also stimulates the CRH - sympathetic neuronal network that is distinct from the HPAA. Experimental designs that measure cumulative changes in CRH release or MRNA expression in the basal state likely reflect stimulation of the latter. Decreased CRH release or MRNA expression by the medial subneurons of the PVN can best be observed under conditions of HPAA activation such as in Lep ob /Lep ob mice during feeding or during stress. The etiology of obesity observed in Lep ob / Lep ob mice involves failure to produce mature leptin (60) and replacement of leptin by exogenous administration to Lep ob /Lep ob mice corrects the hypercorticism (47). Rapid frequent blood sampling of 6 healthy men permitted the measurement of leptin, ACTH and cortisol for 24 h (32). These data clearly demonstrate that plasma leptin concentrations are inversely correlated to both plasma ACTH and plasma cortisol levels, supporting an inhibitory role for leptin on the HPAA. Prolonged fasting, that activates the HPAA, is accompanied by decreased endogenous leptin secretion. The activated HPAA during fasting, however, is attenuated by administration of exogenous leptin (1 ). In addition, elevated plasma ACTH and corticosterone levels resulting from restraint stress are blocked by administration of exogenous leptin (26). Leptin actions at the pituitary level of the HPAA are unclear. Full length leptin receptor mRNA has been detected in the adenohypophysis of mice (37) and sheep (15). Mouse pituitary slices in perifusion release ACTH (1.5 - 2 fold) acutely when incubated with leptin (37). We also found a slight (1.4 - fold) stimulation of ACTH release from rat primary cultured pituitary cells when incubated with leptin (26). In contrast, we observed almost a 9- fold increase in CRH mediated secretion of ACTH that was not altered by the co-administration of leptin. Because leptin appears to inhibit the HPAA, we do not think that leptin significantly alters secretion of ACTH by corticotropes. Although there is no demonstration of leptin receptors in the adrenal gland, leptin has been reported to inhibit cortisol release from primary cultured bovine adrenal cortex cells (3). Cortisol, however, stimulates leptin secretion (14, 45, 54) and this finding permits insertion of leptin in feedback regulation of the HPAA (Fig. 1 ). Physiological states of low fuel supply such as fasting are characterized by low circulating leptin levels. In turn, plasma ACTH and glucocorticoid levels are stimulated by increased CRH release into the median eminence. Whether decreased leptin levels release inhibition of CRH release directly or indirectly by releasing inhibition of NPY stimulated CRH release (51 , 55) is not known. Finally, elevated glucocorticoid stimulates leptin secretion to complete this negative feedback axis. It must be remembered that corticosterone has also been demonstrated to stimulate hypothalamic NPY levels (12). Therefore, in the rare cases of leptin deficiency, the hypothalamic-pituitary-adrenal axis is intact with negative feedback exerted by glucocorticoid at both the hypothalamus and pituitary, but nevertheless remains activated. These elevated glucocorticoid levels result in over- expression of NPY and thus obesity that is corrected by leptin replacement. The hypothalamic-αrowth hormone-adipose axis Growth hormone (GH) levels are suppressed in leptin deficient male Lep ob /Lep ob mice (44). Moreover, exogenous leptin administration rescues fasting-induced depression of GH secretion in normal rats (6) that is associated with decreased secretion of endogenous leptin. Thus, it appears that leptin is stimulatory to the hypothalamic-GH axis. Secretion of GH is regulated by complex interaction of neural and hormonal feedback systems that result in a striking pulsatile pattern. Extensive evidence indicates that this episodic pattern of GH release is produced by interchange between at least two hypothalamic hormones; a GH releasing hormone (GHRH) and an inhibitory hormone, somatostatin (SRIF) (25, 49). Such inhibition may be direct or it may be a consequence of leptin inhibition of NPY release (47) because NPY neurons stimulate release of SRIF (63). A major outcome of GH stimulation is to induce production of insulinlike growth factor-l (IGF-1 ), and anabolic actions of GH may be mediated through IGF-I (68). It is still debatable if GH-mediated production of IGF-I has local autocrine and paracrine physiology or whether the peptide is secreted into the circulation and functions as a hormone. In fact, significant local stimulation of IGF-I may leak into the general circulation to function as a hormone. Although IGF-I is produced by most organs, the liver is the major source of the circulating peptide (64). Circulating IGF-I feeds back to inhibit GH release at both the pituitary (69) and hypothalamus (61 ,75) to complete this neuroendocrine feedback loop. IGF-l also appears to inhibit leptin gene expression by rat adipose tissue (62,74). Such decreased circulating leptin would release its inhibition of SRIF release and therefore augment IGF-I inhibition of GH secretion. These data indicate that the hypothalamic-GH-IGF-l axis should be extended to include leptin (Fig. 2). Indeed, GH-deficient adults present depressed circulating IGF-l levels and elevated plasma leptin concentrations that are corrected by GH replacement therapy (67,66). Recent clinical observations and experimental animal data clearly indicate that regulation of this neuroendocrine axis is substantially impacted by nutrition (71 ). Fasting and disorders of nutritional deprivation and malnutrition in human are associated with elevated serum GH and depressed IGF-I concentrations (62). The magnitude of IGF-I reduction relates to the severity of nutritional insult, and IGF-I levels increase with nutritional rehabilitation (71 ). Therefore, changes in circulating IGF-I levels are positively correlated with changes in blood leptin levels and in concert supply a signal of fuel reserve. GH secretion is impaired in obese Zucker rats. Since this obese genotype is relatively insensitive to leptin (see above), it follows that SRIF release from hypothalamus of obese Zucker rats is increased (73). Such leptin- resistant increases in SRIF secretion result in decreased plasma GH (65). Further, the decreased GH stimulation of IGF-I may be countered by nutritional stimulation of IGF-1. Thus, IGF-I levels do not change during overnutrition (73). In a similar manner, most phenotypes of human obesity are associated with reduced GH levels and either decreased or normal IGF-I levels (71 ). Adipose tissue to sends a message of fuel supply to the hypothalamus by secreting the hormone leptin to achieve circulating concentrations that reflect energy stores. While this afferent directive results in an appropriate efferent feeding behavior, it also modulates relevant neuroendocrine axes. We suggest that the glucocorticoid and GH axes be extended to include leptin feedback. Recent studies by Ahima and colleagues (1 ) also imply that leptin feedback be included in regulation of the thyroid and reproduction axes. During states of scarce fuel supply, leptin levels fall yielding a signal for energy replenishment such as increased feeding and augmented glucocorticoid secretion. In addition, conservation of existent energy reserve for maintenance of basal physiological processes would prohibit energy used for growth and reproduction until the energy level is replenished and thus these axes would be inhibited until the adequate fuel level is replenished as signaled by elevation of circulating leptin levels. SUMMARY OF THE INVENTION A major object of the present invention is to provide a method of preventing the loss of lean tissue mass associated with improper nutrition or fasting. Leptin used as an adjunct in weight loss programs would not only aid the weight loss itself but would prevent the associated loss of muscle. The use of leptin and leptin receptor ligands may also result in an increase in lean tissue mass, which represents an opportunity for therapy during catabolic states such as cachexia resulting from illnesses such as anorexia and malnutrition. Methods of increasing lean tissue growth would also be useful in the fields of veterinary science and animal husbandry in benefitting the health and quality of livestock. This invention, therefore, discloses the utility of leptin, leptin mimetics, or novel leptin analogs in preventing the loss of or increasing lean tissue mass in either obese or lean subjects. In addition, leptin, leptin mimetics, or novel leptin analogs may be used to increase lean body mass. With the foregoing and other objects, advantages and features of the invention that will become hereinafter apparent, the nature of the invention may be more clearly understood by reference to the following detailed description of the preferred embodiments of the invention and to the appended claims. DET AILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION For purposes of the present invention, as disclosed and claimed herein, the following terms and abbreviations are defined as follows: Lean tissue or body mass -- muscle, not adipose tissue. Base pair (bp) -- refers to DNA or RNA. The abbreviations A,C,G, and T correspond to the δ'-monophosphate forms of the nucleotides (deoxy)adenine, (deoxy)cytidine, (deoxy)guanine, and (deoxy)thymine, respectively, when they occur in DNA molecules. The abbreviations U,C,G, and T correspond to the 5'-monophosphate forms of the nucleosides uracil, cytidine, guanine, and thymine, respectively when they occur in RNA molecules. In double stranded DNA, base pair may refer to a partnership of A with T or C with G. In a DNA/RNA heteroduplex, base pair may refer to a partnership of T with U or C with G. Chelating Peptide - An amino acid sequence capable of complexing with a multivalent metal ion. DNA - Deoxyribonucleic acid. EDTA - an abbreviation for ethylenediamine tetraacetic acid. ED50 - an abbreviation for half-maximal value. FAB-MS -- an abbreviation for fast atom bombardment mass spectrometry. Hypothalamic-Pituitary-Adrenal-Adipose Axis (HPAAA): A physiological regulatory system wherein each of the named elements (the hypothalamus, the pituitary gland, the adrenal glands, and adipose tissue) release chemicals that regulate the activity of the others. For example, CRH released by the hypothalamus stimulates pituitary secretion of ACTH, that in turn stimulates adrenal secretion of glucocorticoids, which in turn modulates adipose tissue leptin release, that finally acts back on the hypothalamus. Immunoreactive Protein(s) - a term used to collectively describe antibodies, fragments of antibodies capable of binding antigens of a similar nature as the parent antibody molecule from which they are derived, and single chain polypeptide binding molecules as described in PCT Application No. PCT/US 87/02208, International Publication No. WO 88/01649. mRNA -- messenger RNA. MWCO -- an abbreviation for molecular weight cut-off. Modulating -- stimulation, potentiation, or inhibition of the activity of a receptor or system. Plasmid -- an extrachromosomal self-replicating genetic element. PMSF -- an abbreviation for phenylmethylsulfonyl fluoride. Reading frame - the nucleotide sequence from which translation occurs "read" in triplets by the translational apparatus of tRNA, ribosomes and associated factors, each triplet corresponding to a particular amino acid. Because each triplet is distinct and of the same length, the coding sequence must be a multiple of three. A base pair insertion or deletion (termed a frameshift mutation) may result in two different proteins being coded for by the same DNA segment. To insure against this, the triplet codons corresponding to the desired polypeptide must be aligned in multiples of three from the initiation codon, i.e. the correct "reading frame" must be maintained. In the creation of fusion proteins containing a chelating peptide, the reading frame of the DNA sequence encoding the structural protein must be maintained in the DNA sequence encoding the chelating peptide. Receptor agonist - any compound that binds to a receptor and triggers the action of the receptor (usually an intracellular signalling event or, in the case of receptors that form transmembrane channel, the opening or closing of the channel). Receptor antagonist - any compound that binds to a receptor and blocks the action of the receptor (usually by out-competing the endogenous agonist for binding sites on the receptor). Receptor ligand -- any compound that binds to a receptor. The preferred receptor ligands of the present invention include leptin, leptin mimetics and leptin analogs. Chemically modified leptin, particularly mono- and poly- pegylated leptin may also be used. The structure and advantages of such modified compounds are known in the art, as evidenced by European patent applications EP 0741187 and EP 0822199, herein incorporated by reference. Recombinant DNA Cloning Vector - any autonomously replicating agent including, but not limited to, plasmids and phages, comprising a DNA molecule to which one or more additional DNA segments can or have been added. Recombinant DNA Expression Vector -- any recombinant DNA cloning vector in which a promoter has been incorporated. Replicon -- A DNA sequence that controls and allows for autonomous replication of a plasmid or other vector. RNA - ribonucleic acid. RP-HPLC - an abbreviation for reversed-phase high performance liquid chromatography. Transcription - the process whereby information contained in a nucleotide sequence of DNA is transferred to a complementary RNA sequence. Translation - the process whereby the genetic information of messenger RNA is used to specify and direct the synthesis of a polypeptide chain. Tris -- an abbreviation for tris-(hydroxymethyl)aminomethane. Treating - describes the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a leptin receptor ligand of the present invention to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition, or disorder. Treating obesity, for example, includes the inhibition of food intake, the inhibition of weight gain, and inducing weight loss in patients in need thereof. Vector - a replicon used for the transformation of cells in gene manipulation bearing polynucleotide sequences corresponding to appropriate protein molecules which, when combined with appropriate control sequences, confer specific properties on the host cell to be transformed. Plasmids, viruses, and bacteriophage are suitable vectors, since they are replicons in their own right. Artificial vectors are constructed by cutting and joining DNA molecules from different sources using restriction enzymes and ligases. vectors include Recombinant DNA cloning vectors and Recombinant DNA expression vectors. X-gal - an abbreviation for 5-bromo-4-chloro-3-idolyl beta-D- galactoside. Leptin receptor agonists may be used to preserve or increase lean body or tissue mass. The inventors have found that administration of leptin receptor ligands, in particular leptin receptor agonists, effectively may be used to prevent against the loss of lean tissue mass associated with improper nutrition. Specifically, it has been found that administration of leptin to either normal rats fed a low fat diet or rats fed a diet rich in fat for 2- 4 weeks results in the loss of significant quantities of adipose tissue but the preservation of lean tissue mass. Leptin administration initially resulted in anorexia during the first two weeks of treatment. However, decreased food consumption waned with further treatment and the animals resumed eating similar quantities of food as did the ad libitum control rats. Never-the-less, leptin treatment continued to result in fat loss and defend against lean tissue loss. It is predicted that prolonged administration of leptin or OB protein to a leptin-sufficient animal or human would not produce starvation and would actually prevent lean tissue (muscle) loss during catabolic states such as cachexia, anorexia and malnutrition. Indeed, since such patients are usually hospitalized with intravenous therapy, leptin or leptin receptor agonist administration would preferably be facilitated intravenously. Alternatively, such treatment could be facilitated in conjunction with parenteral nutrition or dietary therapy assuming the patient is able to eat. The phrases "receptor ligands", "receptor agonists", and "receptor antagonists" used herein are understood to refer to pharmacologically active compounds, and to salts thereof. Preferred leptin receptor agonists for use in the present invention include endogenous leptin (i.e., endogenous OB protein - the protein produced from the obesity gene following transcription and translation and deletion of introns, translation to a protein and processing to the mature protein with secretory signal peptide removed, e.g., from the N-terminal valine-proline to the C-terminal cysteine of the mature protein). The mouse OB protein and human OB protein are published in Zhang et al., Nature 372:425-432 (1994). The rat OB protein is published in Murakami et al., Biochem. Biophys. Res. Com. 209:944-952 (1995). The porcine and bovine OB genes and proteins are disclosed in EP 0 743 321 , the contents of which are incorporated by reference. Various primate OB genes and proteins are disclosed in U.S. Application Serial No.08/710,483, the contents of which are incorporated by reference. Also preferred for use in the present invention are leptin analogs, preferably leptin analogs having one or more amino acid substitution, more preferably less than five and most preferably less than three substitutions. Particularly preferred leptin analogs for use in the present invention include proteins disclosed by Basinski et al., in WO 96/23515 and WO 96/23517 (the contents of which are incorporated by reference), of the Formula (I): SEQ ID NO: 1 1 5 10 15 Val Pro He Gi n Lys Val Gi n Asp Asp Thr Lys Thr Leu He Lys 20 25 30 Thr He Val Thr Arg He Asn Asp He Ser His Thr Xaa Ser Val 35 40 45 Ser Ser Lys Gin Lys Val Thr Gly Leu Asp Phe He Pro Gly Leu 50 55 60 His Pro He Leu Thr Leu Ser Lys Met Asp Gin Thr Leu Ala Val 65 70 75 Tyr Gin Gin He Leu Thr Ser Met Pro Ser Arg Asn Val He Gin 80 85 90 H e Ser Asn Asp Leu Gl u Asn Leu Arg Asp Leu Leu His Val Leu 95 100 105 Al a Phe Ser Lys Ser Cys His Leu Pro Trp Ala Ser Gly Leu Glu 110 115 120 Thr Leu Asp Ser Leu Gly Gly Val Leu Gl u Al a Ser Gly Tyr Ser 125 130 135 Thr Glu Val Val Ala Leu Ser Arg Leu Gin Gly Ser Leu Gin Asp 140 145 Met Leu Trp Gi n Leu Asp Leu Ser Pro Gly Cys or pharmaceutically acceptable salts thereof, wherein: Xaa at position 28 is Gin or absent; said protein having at least one of the following substitutions: Gin at position 4 is replaced with Glu; Gin at position 7 is replaced with Glu; Asn at position 22 is replaced with Gin or Asp; Thr at position 27 is replaced with Ala; Xaa at position 28 is replaced with Glu; Gin at position 34 is replaced with Glu; Met at position 54 is replaced with methionine sulfoxide, Leu, lie, Val, Ala, or Gly; Gin at position 56 is replaced with Glu; Gin at position 62 is replaced with Glu; Gin at position 63 is replaced with Glu; Met at position 68 is replaced with methionine sulfoxide, Leu, He, Val, Ala, or Gly; Asn at position 72 is replaced with Gin, Glu, or Asp; Gin at position 75 is replaced with Glu; Ser at position 77 is replaced with Ala; Asn at position 78 is replaced with Gin or Asp; Asn at position 82 is replaced with Gin or Asp; His at position 97 is replaced with Gin, Asn, Ala, Gly, Ser, or Pro; Trp at position 100 is replaced with Ala, Glu, Asp, Asn, Met, He, Phe, Tyr, Ser, Thr, Gly, Gin, Val, or Leu; Ala at position 101 is replaced with Ser, Asn, Gly, His, Pro, Thr, or Val; Ser at position 102 is replaced with Arg; Gly at position 103 is replaced with Ala; Glu at position 105 is replaced with Gin; Thr at position 106 is replaced with Lys or Ser; Leu at position 107 is replaced with Pro; Asp at position 108 is replaced with Glu; Gly at position 111 is replaced with Asp; Gly at position 118 is replaced with Leu; Gln at position 130 is replaced with Glu; Gin at position 134 is replaced with Glu; Met at position 136 is replaced with methionine sulfoxide, Leu, He, Val, Ala, or Gly; Trp at position 138 is replaced with Ala, Glu, Asp, Asn, Met, lie, Phe, Tyr, Ser, Thr, Gly, Gin, Val, or Leu; or Gin at position 139 is replaced with Glu. In addition, N-terminally-extended and C-terminally-extended leptins and leptin analogs may also be used in the present invention. Addition of one or a few amino acids to the leptin receptor ligands of the present invention will not appreciably affect the binding of the protein to the leptin receptor. In particular, "met-Leptin," a leptin with a single methionine added to the N-terminus of the protein, as commonly occurs in some recombinant expression systems, is useful in the present invention. Leptin receptor ligands for use in the present invention may also optionally be substituted with a functional group. Any art-recognized functional group which does not eliminate or significantly reduce the compound's ability to bind to leptin receptors are contemplated, including, but not limited to, ester, amide, acid, amine, alcohol, ether, thioether, etc. Solvates, e.g., hydrates of the compounds useful in the methods of the present invention, are also included within the scope of the present invention. Methods of solvation to produce such solvates are generally known in the art. Pharmaceutical salts of the leptin receptor agonists and antagonists suitable for administration by a variety of routes are known in the art and need not be described herein in detail. Examples of pharmaceutically acceptable salts of the leptin receptor ligands and derivatives thereof according to the invention, include base salts, e.g., derived from an appropriate base. Pharmaceutically acceptable salts of an acid group or an amino group include, but are not limited to, salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isothionic, and lactobionic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-tolylsulfonic acids, and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Pharmaceutically- acceptable salts of a compound with a hydroxy group include, but are not limited to, the anion of the compound in combination with a suitable cation such as Na + . In a further embodiment of the present invention comprises a method for preventing the loss of lean body mass associated with improper nutrition by administration of antibodies to the endogenous leptin receptor which act as leptin receptor agonists to a mammal in need of such treatment. Such antibodies may be monoclonal or polyclonal antibodies to the leptin receptor, so long as their affect is to act as a leptin receptor agonist. Both polyclonal and monoclonal antibodies are obtainable by immunization of an animal with purified leptin receptor or fragments thereof, or purified fusion proteins of leptin receptor, or cells expressing the leptin receptor. The methods of obtaining both types of antibodies are well known in the art with excellent protocols for antibody production being found in Harlow et al. (1988) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 726 pp. Polyclonal sera are relatively easily prepared by injection of a suitable laboratory animal with an effective amount of purified leptin receptor agonists, or parts thereof, collecting serum from the animal, and isolating specific sera by any of the known immunoadsorbent techniques. Monoclonal antibodies are particularly useful because they can be produced in large quantities and with a high degree of homogeneity. Hybridoma cell lines which produce monoclonal antibodies are prepared by fusing an immortal cell line with lymphocytes sensitized against the immunogenic preparation using techniques which are well-known to those who are skilled in the art. (See, for example, Douillard, I.Y. and Hoffman, T., "Basic Facts About Hybridomas", in Compendium of Immunology, Vol. II, L. Schwartz (Ed.) (1981); Kohler, G. and Milstein, C, Nature 256: 495-497 (1975) and European Journal of Immunology 6: 511 -519 (1976); Harlow et al.; Koprowski, et al., U.S. Patent 4,172,124; Koprowski et al., U.S. Patent 4,196,265 and Wands, U.S. Patent 4,271 ,145, the teachings of which are herein incorporated by reference. A still further part of this invention is a pharmaceutical composition of matter for administering to a mammal for the prevention or increase in lean body mass that comprises at least one of the leptin receptor agonists described above, mixtures thereof, and/or pharmaceutical salts thereof, and a pharmaceutically-acceptable carrier therefor. Such compositions are prepared in accordance with accepted pharmaceutical procedures, for example, as described in Remington's Pharmaceutical Sciences, seventeenth edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, PA (1985). For therapeutic use in a method of preventing the loss of lean body mass associated with improper nutrition, a leptin receptor agonist or its salt can be conveniently administered in the form of a pharmaceutical composition containing one or more leptin receptor agonists or salts thereof and a pharmaceutically acceptable carrier therefor. Suitable carriers are well known in the art and vary with the desired form and mode of administration of the pharmaceutical composition. For example, they may include diluents or excipients such as fillers, binders, wetting agents, disintegrators, surface-active agents, lubricants, and the like. Typically, the carrier may be a solid, liquid, or vaporizable carrier, or combinations thereof. In one preferred embodiment, the composition is a therapeutic composition and the carrier is a pharmaceutically acceptable carrier. The leptin receptor ligands for use in the present invention, or salts thereof, may be formulated together with the carrier into any desired unit dosage form. Typical unit dosage forms include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories; injectable solutions and suspensions are particularly preferred. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients in the formulation and not injurious to the patient. The carrier must be biologically acceptable and inert, i.e., it must permit the cell to conduct its metabolic reactions so that the leptin receptor ligands suitable for use in the method of the present invention may effect their prophylactic or therapeutic activity. Formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal) administration, with topical ointment formulations, and formulations appropriate for oral administration, being preferred. For example, to prepare formulations suitable for injection, solutions and suspensions are sterilized and are preferably isotonic to blood. In making injectable preparations, carriers which are commonly used in this field can also be used, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitate esters. In these instances, adequate amounts of isotonicity adjusters such as sodium chloride, glucose or glycerin can be added to make the preparations isotonic. The aqueous sterile injection solutions may further contain anti-oxidants, buffers, bacteriostats, and like additions acceptable for parenteral formulations. The formulations may conveniently be presented in unit dosage form and may be prepared by any method known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which may encompass one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. Various unit dose and multidose containers, e.g., sealed ampules and vials, may be used, as is well known in the art. In addition to the ingredients particularly mentioned above, the formulations of this invention may also include other agents conventional in the art for this type of pharmaceutical formulation. The leptin receptor ligands suitable for use in the present invention may be present in the composition in an broad proportion to the carrier. For instance, the leptin receptor ligands may be present in the amount of 0.01 to 99.9 wt%, and more preferably in about 0.1 to 99 wt%. Still more preferably, the leptin receptor ligand may be present in an amount of about 1 to 70 wt% of the composition depending on the patient and the amount of muscle loss. The dosage of the leptin receptor agonists, pharmaceutically acceptable salts thereof, or mixtures thereof administered to a patient according to the present invention will vary depending on several factors, including, but not limited to, the age, weight, and species of the patient, the general health of the patient, the severity of the symptoms, whether the composition is being administered alone or in combination with other therapeutic agents, the incidence of side effects and the like. In general, a dose suitable for application in preventing loss of lean body mass associated with improper nutrition is about 0.001 to 100 mg/kg body weight/dose, preferably about 0.01 to 60 mg/kg body weight/dose, and still more preferably about 0.1 to 40 mg/kg body weight/dose per day. The desired dose may be administered as 1 to 6 or more subdoses administered at appropriate intervals throughout the day. The leptin receptor ligands may be administered repeatedly over a period of months or years, or it may be slowly and constantly infused to the patient. Higher and lower doses may also be administered. The daily dose may be adjusted taking into account, for example, the above-identified variety of parameters. Typically, the present compositions may be administered in an amount of about 0.001 to 100 mg/kg body weight/day. However, other amounts may also be administered. To achieve good plasma concentrations, leptin receptor ligands suitable for use in the present invention may be administered, for instance, by intravenous injection of an approximate 0.1 to 1% solution of the active ingredient, optionally in saline, or orally administered as a bolus. The active ingredient may be administered for therapy by any suitable routes, including topical, oral, rectal, nasal, vaginal and parenteral (including intraperitoneal, subcutaneous, intramuscular, intravenous, intradermal, and transdermal) routes. It will be appreciated that the preferred route will vary with the condition and age of the patient, the nature of the disorder and the chosen active ingredient including other therapeutic agents. Preferred is the oral route. Also preferred is the topical route. However, other routes may also be utilized depending on the conditions of the patient and how long- lasting the treatment is. While it is possible for the active ingredient to be administered alone, it is preferably present as a pharmaceutical formulation. The formulations of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents. The above method may be practiced by administration of leptin receptor ligands by themselves or in a combination with other active ingredients, including therapeutic agents in a pharmaceutical composition. Other therapeutic agents suitable for use herein are any compatible drugs that are effective by the same or other mechanisms for the intended purpose, or drugs that are complementary to those of the present agents. These include agents that are effective for preventing loss of lean body mass and/or associated conditions in humans. The compounds utilized in combination therapy may be administered simultaneously, in either separate or combined formulations, or at different times than the present compounds, e.g., sequentially, such that a combined effect is achieved. The amounts and regime of administration will be adjusted by the practitioner, by preferably initially lowering their standard doses and then titrating the results obtained. The therapeutic method of the invention may be used in conjunction with other therapies as determined by the practitioner. While the invention has been described and illustrated herein by references to various specific material, procedures and examples, it is understood that the invention is not restricted to the particular material, combinations of material, and procedures selected for that purpose. Numerous variations of such details can be implied and will be appreciated by those skilled in the art. References 1. Ahima, R. S., et al. 1996. Role of leptin in the neuroendocrine response to fasting. Nature. 382:250- 252. 2. Banks, W. A., et al. 1996. Leptin enters the brain by a saturable system independent of insulin. Peptides. 17:305 - 311. 3. Bomstein, S. R., et al. 1997. Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland. Diabetes. 46:12351238. 4. Campfield, L. A., et al. 1995. Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks. Science. 269:546-549. 5. Caro, J. F., et al. 1996. Leptin: the tale of an obesity gene. Diabetes. 45:1455 - 1462. 6. Carro, E., et al. 1997. Regulation of in vivo growth hormone secretion by leptin. Endocrinology. 138:2203 - 2206. 7. Casanueva, F. F., et al. 1997. Serum immunoreactive leptin concentrations in patients with anorexia nervosa before and after partial weight recovery. Biochem. Mol. Med. 60:116 - 120. 8. Chen, H., et al. 1996. Evidence that the diabetes gene encodes the leptin receptor-, identification of a mutation in the leptin receptor gene in db/db mice. Cell. 84:491-495. 9. Chronwall, B., et al. 1985. The anatomy of neuropeptide-Y-containing neurons in the rat brain. Neuroscience. 15:1159 1181. 10. Coleman, D. L. 1973. Effects of parabiosis of obese with diabetes and normal mice. Diabetologia. 9:294 - 298. 11. Considine, R. V., et al. 1996. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 334:292 - 295. 12. Corder, R., et al. 1988. Dexamethasone treatment increases neuropeptide Y levels in rat hypothalamic neurons. Life Sci. 43:1879 - 1886. 13. Costa, A., et al. 1997. Stimulation of corticotrophin-releasing hormone release by the obese (ob) gene product, leptin, from hypothalamic explants. Neuro Report. 8:1131 - 1134. 14. DeVos, P., et al. 1995. Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake. J Biol. Chem. 270:15958-15961. 15. Dyer, C. J., et al. 1997. Leptin receptor MRNA is expressed in ewe anterior pituitary and adipose tissues and is differentially expressed in hypothalamic regions of well-fed and feed-restricted ewes. Dom. An. Endocrinol. 14:119 - 128. 16. Elmquist, J., et al. 1997. Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology. 138:839 - 842. 17. Fei, H., et al. 1997. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl. Acad. Sci. USA. 94. 18. Frederich, R. C, et al. 1995. Expression of ob MRNA and its encoded protein in rodents: impact of nutrition and obesity. J. Clin. Invest. 96:1658- 1663. 19. Fulwiler, C. E., and C. B. Saper. 1985. Cholecystokinin-immunoreactive innervation of the ventromedial hypothalamus in the rat: possible substrate for autonomic regulation of feeding. Neurosci. Lett 53:289 - 296. 20. Ghilaedi, N., 1996. Defective STAT signaling by the leptin receptor in diabetic mice. Proc. Natl. Acad. Aci. USA. 93:6231-6235. 21. Glaum, S. R., 1996. Leptin, the Obese gene product, rapidly modulates synaptic transmission in the hypothalamus. Mol. Pharmacol. 50:230 - 235. 22. Golden, P. L., et al. 1997. Human blood-brain barrier leptin receptor. J. Clin. Invest. 99:14-18. 23. Halaas, J. L., et al. 1995. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 269:543-546. 24. Harfstrand, A., et al. 1987. Further studies on the effects of central administration of neuropeptide Y on enuroenedocrine function in the male rat: relationship to hypothalamic catecholamines. Regul. Pept. 17:167 - 179. 25. Hartman, M. L., et ak, 1993. Normal control of growth hormone secretion. Horm. Res. 40:37 - 47. 26. Heiman, M. L., et al. 1997. Leptin inhibition of the hypothalamic- pituitary adrenal axis in response to stress. Endocrinology. 138:3859 - 3863. 27. Kalra, S. P. 1993. Mandatory neuropeptide-steroid signaling for the preovulatory luteinizing hormone-releasing hormone discharge. Endocrine Rev. 14-.507 - 538. 28. Kaira, S. P., and P. S. Kaira. 1996. Nutritional infertility-, the role of the interconnected hypothalamic neuropeptide Y-galanin-opiod network. Front Neuroendocrinol. 17-.371 401. 29. Kolaczynski, J. W., et al. 1996. Responses of leptin to short-term fasting and refeeding in humans. Diabetes. 45:1511-1515. 30. Lechan, R. M., Nestler, J. L., Jacobson, S., and Reichlin, S. (1980). The hypothalamic tuberoinfundibular system of the rat as demonstrated by horseradish peroxidase (HRP) microiontophoresis. Brain Res. 195:13-27. 31. Lee, G.-H., et al. 1996. Abnormal splicing of the leptin receptor in diabetic mice. Nature. 379-.632 - 635. 32. Licinio, J., et al. 1997. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nature Med. 3:575 - 579. 33. Maffei, M., et al. 1995. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Med. 1 :1155 - 1161. 34. Mantzoros, C, et al. 1997. Cerebrospinal fluid leptin in anorexia nervosa: correlation with nutritional status and potential role in resistance to weight gain. J. Clin. Endocrinol. Metab. 82:1845 - 1851. 35. Montague, C. T., et al. 1997. Congenitial leptin deficiency is associated with severe early-onset obesity in humans. Nature. 387:903 - 908. 36. Pelleymounter, M. A., et al. 1995. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 269:540-543. 37. Raber, J., et al. 1997. Corticotropin-releasing factor and adrenocorticotropic hormone as potential central mediators of OB effects. J. Biol. Chem. 272:15057 - 15060. 38. Racette, S. B., et al. 1997. Leptin production during moderate-intensity aerobic exercise. J. Clin. Endocrinol. Metab. 82:2275-2277. 39. Saladin, R., et al. 1995. Transient increase in obese gene expression after food intake or insulin administration. Nature. 377:527-529. 40. Saper, C. B., et al. 1976. Direct hypothalamo-autonomic connections. Brain Res. 117:305 - 312. 41. Sawchenko, P. E., and L. W. Swanson. 1982. Immunohistochemical identification of neurons in the paraventricular nucleus of the hypothalamus that project to the medulla or the spinal cord in the rat. J. Comp. Neurol. 205:260-272. 42. Schwartz, M. W., et al. 1996. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes. 45:531 - 535. 43. Schwartz, M. W., et al. 1996. Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98:1101 - 1106. 44. Sinha, Y. N., et al. 1975. Prolactin and growth hormone secretion in chemically induced and genetically obese mice. Endocrinology. 97:1386 1393. 45. Slieker, L. J., 1996. Regulation of expression of ob MRNA and protein by glucocorticoids and CAMP. J. Biol. Chem. 271 :5301 - 5304. 46. Stanley, B. G., et al. 1993. The perifornical area: the major focus of (a) patchily distributed hypothalamic neuropeptide Y-sensitive feeding system(s). Brain Res. 604-.304 - 317. 47. Stephens, T. W., et al. 1995. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature. 377-.530 - 532. 48. Streamson, J., et al. 1996. Phenotypes of mouse deiabetes and rat fatty due to mutations in the OB (leptin) receptor. Science. 271 :994 - 996. 49. Tannenbaum, G. S. 1993. Genesis of episodic growth hormone secretion. J. Pediatr. Endocrinol. 6:273 - 282. 50. Tartaglia, L. A., et al. 1995. Identification and expression cloning of a leptin receptor, OB-R. Cell. 83.-1263 - 1271. 51. Tsagarakis, S., et al. 1989. Neuropeptide-Y stimulates CRF-41 release from rat hypothalami in vitro. Brain Res. 502:167 - 170. 52. Tuominen, J. A., et al. 1997. Serum leptin concentration and fuel homeostasis in healthy man. Eur. J. Clin. Invest. 27:206-211. 53. van Dijk, G., et al. 1996. Central infusion of leptin and glp-1(7-36) amide differentially stimulate c-fos-like immunoreactivity in the rat brain. Am. J. Physiol. 40:RI096 - R1100. 54. Wabitsch, M., et al. 1996. Insulin and cortisol promote leptin production in cultured human fat cells. Diabetes. 45:1435 - 1438. 55. Wahlestedt, C, et al. 1987. Neuropeptide Y (NPY) in the area of the hypothalamic paraventricular nucleus activates the pituitary-adrenocortical axis in the rat. Brain Res. 417:33 - 38. 56. Weigand, S. J., and J. L. Price. 1980. The cells of the afferent fibers to the median eminence in the rat. J. Comp. Neurol. 192:1-19. 57. White, D. W., et al. 1997. Leptin receptor (OB-R) signaling. J. Biol. Chem. 272:4065-4071. 58. Wilding, J. P. H., et al. (1993). Increased neuropeptide Y messenger ribonucleic acid (MRNA) and decreased neurotensin MRNA in the hypothalamus of the obese (ob/ob) mouse. Endocrinology. 132:1939 - 1944. 59. Zarjevski, N., Cusin, I., Vettor, R., Rohner-Jeanrenaud, F. and Jeanrenaud, B. (1993). Chronic intracerebroventricular neuropeptide- Y administration to normal rats mimics hormonal and metabolic changes of obesity. Endocrinology 133:1753 -1758. 60. Zhang, Y., et al. 1994. Positional cloning of the mouse obese gene and its human homologue. Nature 372:425 - 431. 61. Berelowitz, M., Szabo, M., Frohman, L.A., Firestone, S., and Chu, L. (1981), Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary. Science 212, 1279- 1281. 62. Bόni-Schnetzler, M., Gosteli-Peter, M.A., Moritz, W., Froesch, E.R., and Zapf, J. (1996). Reduced ob mRNA in hypophysectomised rats is not restored by growth hormone (GH), but further suppressed by exogenously administered insulin-like growth factor (IGF) I. Biochem. Biophys. Res. Commun. 225, 296-301. 62. Cahill, G.F., Herrera, M.G., Morgan, A.P., Soeldner J.S., Steinke, J., Levy, P.L., Reichard, G.A., and Kipnis, D.M. (1966). Hormone-fuel interrelationships during fasting. J. Clin. Invest. 45, 1751-1767. 63. Chan, Y.Y., Steiner, R.A., and Clifton, D.K. (1996). Regulation of hypothalamic Neuropeptide- Y neurons by growth hormone in the rat. Endocrinology 137, 1319-1325. 64. D'Ercole, A.J., Stiles, A.D., and Underwood, L.E. (1984). Tissue concentrations of somatomedin-C: Further evidence for multiple sites of synthesis and paracrine or autocrine mechanisms of action. Proc. Natl. Acad. Sci. USA 81 , 935-939. 65. Finkelstein, J.A., Jervois, P., Menadue, M., and Willoughby, J.O. (1986). Growth hormone and prolactin secretion in generaly obese Zucker rats. Endocrinology 118, 1233-1236. 66. Fisker, S., Vahl, N., Hansen, T.B., Jergensen, J.O.L., Hagen, C, Orskov, H., and Christiansen, J.S. (1997). Serum leptin is increased in growth hormone-deficient adults: relationship to body composition and effects of placebo-controlled growth hormone therapy for 1 year. Metabolism 46, 812-817. 67. Florkowski, CM., Collier, G.R., Zimmet, P.Z., Livesey, J.H., Espiner, E.A., and Donald, R.A. (1996). Low-dose growth hormone replacement lowers plasma leptin and fat stores without affecting body mass index in adults with growth hormone deficiency. Clin. Endocrinol. 45, 769-773. 68. Froesch, E.R., Schmid, C, Schwander, J., and Zapf, J. (1985). Actions of insulin-like growth factor activity. Ann. Rev. Physiol. 47, 443-467. 69. Goodyear, C.G., DeStephano, L., Guyda, H.J., and Posner, B.I. (1984). Effects of insulin-like growth factors on adult male rat pituitary function in tissue culture. Endocrinology, 115, 1568-1576. 70. Ho, K.Y., Veldhuis, J.D., Johnson, M.L., Furlanetto, R., Evans, W.S., Alberti, K.G.M.M., and Thorner, M.O. (1988). Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. J. Clin. Invest. 81 , 968-975. 71. Ketelslegers, J.M., Maiter, D., Maes, M., Underwood, L.E., and Thissen, J.P. (1995). Nutritional regulation of insulin-like growth factor-l. Metabolism 44, 50-57. 72. Leidy, J., J.W., Romano, T.M., and Millard, W.J. (1993). Developmental and sex-related changes of the growth hormone axis in lean and obese Zucker rats. Neuroendocrinology 57, 213-223. 73. Reul, B.A., Ongemba, L.N., Pottier, A.M., Henquin, J.C., and Brichard, S.M. (1997). Insulin and insulin-like growth factor 1 antagonize the stimulation of ob gene expression by dexamethasone in cultured rat adipose tissue. Biochemical Journal 324, 605-610. 74. Tannenbaum, G.S., Guyda, H.J., and posner, B.I., (1983). Insulin-like growth factors: a role in growth hormone negative feedback and body weight regulation via brain. Sc ience 220, 77-79.

Claims: WHAT IS CLAIMED IS: 1. A method of preventing the loss of lean tissue mass associated with improper nutrition comprising administering to a mammal in need of such treatment a leptin receptor ligand in an amount effective to prevent loss of lean tissue mass. 2. The method of claim 1 , wherein said leptin receptor ligand is a leptin receptor agonist. 3. The method of claim 2, wherein said leptin receptor agonist is human leptin. 4. The method of claim 2, wherein said leptin receptor agonist has the amino acid sequence of SEQ ID NO: 1. 5. The method of claim 1 , wherein the leptin receptor ligand is administered in an amount of about 0.001 to 100 mg/kg body weight/dose. 6. The method of claim 1 , wherein the leptin receptor ligand is administered orally, intravenously, subcutaneously, topically, transdermally, intramuscularly, or intraperitoneally. 7. The method of claim 6, wherein the leptin receptor ligand is administered orally. 8. The method of claim 6, wherein the leptin receptor ligand is administered intravenously. 9. The method of claim 1 , wherein the leptin receptor ligand is administered in the form of a pharmaceutical composition of matter which further comprises a pharmaceutically-acceptable carrier. 10. A method of increasing lean tissue mass comprising administering to a mammal in need of such treatment a leptin receptor ligand in an amount effective to prevent loss of lean tissue mass. 11. The method of claim 10, wherein said leptin receptor ligand is a leptin receptor agonist. 12. The method of claim 11 , wherein said leptin receptor agonist is human leptin. 13. The method of claim 11 , wherein said leptin receptor agonist has the amino acid sequence of SEQ ID NO: 1. 14. The method of claim 10, wherein the leptin receptor ligand is administered in an amount of about 0.001 to 100 mg/kg body weight/dose. 15. The method of claim 10, wherein the leptin receptor ligand is administered orally, intravenously, subcutaneously, topically, transdermally, intramuscularly, or intraperitoneally. 16. The method of claim 15, wherein the leptin receptor ligand is administered orally. 17. The method of claim 15, wherein the leptin receptor ligand is administered intravenously. 18. The method of claim 10, wherein the leptin receptor ligand is administered in the form of a pharmaceutical composition of matter which further comprises a pharmaceutically-acceptable carrier. 19. A pharmaceutical composition of matter for preserving or increasing lean tissue mass, comprising a leptin receptor ligand and a pharmaceutically acceptable carrier therefor. 20. The composition of claim 19, wherein said leptin receptor ligand is a leptin receptor agonist. 21. The composition of claim 20, wherein said leptin receptor agonist is human leptin. 22. The composition of claim 21 , wherein said leptin receptor agonist has the amino acid sequence of SEQ ID NO: 1.

Inventors: CARO JOSE F, HEIMAN MARK L, TINSLEY FRANK C, CARO, JOSE, F., HEIMAN, MARK, L., TINSLEY, FRANK, C.
Applicants: CARO JOSE F, HEIMAN MARK L, LILLY CO ELI, TINSLEY FRANK C, CARO, JOSE, F., ELI LILLY AND COMPANY, HEIMAN, MARK, L., TINSLEY, FRANK, C.
Application year: 1999
Main classification: A61K38
IPC codes: A61K38, A61P3