Leptin in human physiology and therapeutics

Frontiers in Neuroendocrinology

Volumn 31, Issue 3, 2010, Pages 377-393

  Dardeno, Tina A ^a   Chou, Sharon H ^a   Moon, Hyun Seuk ^a   Chamberland, John P ^a   Fiorenza, Christina G ^a   Mantzoros, Christos S ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

Author keywords

Adipokines; Amenorrhea; Energy homeostasis; Insulin resistance; Leptin; Leptin deficiency; Leptin resistance; Lipoatrophy; Obesity

Indexed keywords

AGOUTI RELATED PROTEIN; GONADORELIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; JANUS KINASE 2; LEPTIN; LEPTIN RECEPTOR; LUTEINIZING HORMONE; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; NEUROPEPTIDE Y; PHOSPHATIDYLINOSITOL 3 KINASE; PROOPIOMELANOCORTIN; RECOMBINANT LEPTIN; STAT3 PROTEIN;

AMENORRHEA; BONE METABOLISM; CLINICAL TRIAL; DISEASE ASSOCIATION; DRUG INDICATION; ENERGY BALANCE; FEEDING BEHAVIOR; HORMONE DEFICIENCY; HUMAN; HYPERLEPTINEMIA; HYPOLEPTINEMIA; HYPOTHALAMUS HYPOPHYSIS GONAD SYSTEM; HYPOTHALAMUS HYPOPHYSIS THYROID SYSTEM; IMMUNE RESPONSE; LIPOATROPHY; METABOLIC REGULATION; NEUROENDOCRINOLOGY; NONHUMAN; OBESITY; PRIORITY JOURNAL; REPRODUCTION; REVIEW; SIGNAL TRANSDUCTION; WEIGHT REDUCTION; BIOLOGICAL MODEL; DEFICIENCY; ENERGY METABOLISM; HOMEOSTASIS; IMMUNE SYSTEM; METABOLIC DISEASES; METABOLISM; NEUROSECRETION; PHYSIOLOGY;

ENERGY METABOLISM; HOMEOSTASIS; HUMANS; IMMUNE SYSTEM; LEPTIN; METABOLIC DISEASES; MODELS, BIOLOGICAL; NEUROSECRETORY SYSTEMS; OBESITY; REPRODUCTION; SIGNAL TRANSDUCTION;

EID: 77955051716     PISSN: 00913022     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.yfrne.2010.06.002     Document Type: Review

References (256)

1. Abizaid A., Gao Q., et al. Thoughts for food: brain mechanisms and peripheral energy balance. Neuron 2006, 51(6):691-702.
2. Ahima R.S. Adipose tissue as an endocrine organ. Obesity (Silver Spring) 2006, 14(Suppl. 5):242S-249S.
3. Ahima R.S., Bjorbaek C., et al. Regulation of neuronal and glial proteins by leptin: implications for brain development. Endocrinology 1999, 140(6):2755-2762.
4. Ahima R.S., Prabakaran D., et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996, 382(6588):250-252.
5. Arora S., Anubhuti Role of neuropeptides in appetite regulation and obesity - a review. Neuropeptides 2006, 40(6):375-401.
6. Audi L., Mantzoros C.S., et al. Leptin in relation to resumption of menses in women with anorexia nervosa. Mol. Psychiat. 1998, 3(6):544-547.
7. Baicy K., London E.D., et al. Leptin replacement alters brain response to food cues in genetically leptin-deficient adults. Proc. Natl. Acad. Sci. USA 2007, 104(46):18276-18279.
8. Baldock P.A., Allison S., et al. Hypothalamic regulation of cortical bone mass: opposing activity of Y2 receptor and leptin pathways. J. Bone Miner. Res. 2006, 21(10):1600-1607.
9. Balthasar N., Coppari R., et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 2004, 42(6):983-991.
10. Balthasar N., Dalgaard L.T., et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 2005, 123(3):493-505.
11. Banks W.A. Leptin transport across the blood-brain barrier: implications for the cause and treatment of obesity. Curr. Pharm. Des. 2001, 7(2):125-133.
12. Banks W.A., Clever C.M., et al. Partial saturation and regional variation in the blood-to-brain transport of leptin in normal weight mice. Am. J. Physiol. Endocrinol. Metab. 2000, 278(6):E1158-E1165.
13. Banks W.A., Niehoff M.L., et al. Leptin transport across the blood-brain barrier of the Koletsky rat is not mediated by a product of the leptin receptor gene. Brain Res. 2002, 950(1-2):130-136.
14. Bates S.H., Stearns W.H., et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 2003, 421(6925):856-859.
15. Bayer L., Jacquemard C., et al. Survival of rat MCH (melanin-concentrating hormone) neurons in hypothalamus slice culture: histological, pharmacological and molecular studies. Cell Tissue Res. 1999, 297(1):23-33.
16. Berti L., Kellerer M., et al. Leptin stimulates glucose transport and glycogen synthesis in C2C12 myotubes: evidence for a P13-kinase mediated effect. Diabetologia 1997, 40(5):606-609.
17. Bjorbaek C., Elmquist J.K., et al. Expression of leptin receptor isoforms in rat brain microvessels. Endocrinology 1998, 139(8):3485-3491.
18. Bluher S., Mantzoros C.S. Leptin in humans: lessons from translational research. Am. J. Clin. Nutr. 2009, 89(3):991S-997S.
19. Boden G., Chen X., et al. Effect of fasting on serum leptin in normal human subjects. J. Clin. Endocrinol. Metab. 1996, 81(9):3419-3423.
20. Boden G., Duan X., et al. Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals. Diabetes 2008, 57(9):2438-2444.
21. Bouret S.G., Draper S.J., et al. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004, 304(5667):108-110.
22. Bray G.A., York D.A. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiol. Rev. 1979, 59(3):719-809.
23. Brennan A.M., Lee J.H., et al. R-metHuLeptin improves highly active antiretroviral therapy-induced lipoatrophy and the metabolic syndrome, but not through altering circulating IGF and IGF-binding protein levels: observational and interventional studies in humans. Eur. J. Endocrinol. 2009, 160(2):173-176.
24. Brennan A.M., Mantzoros C.S. Drug insight: the role of leptin in human physiology and pathophysiology - emerging clinical applications. Nat. Clin. Pract. Endocrinol. Metab. 2006, 2(6):318-327.
25. Burguera B., Couce M.E., et al. Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats. Diabetes 2000, 49(7):1219-1223.
26. Caldefie-Chezet F., Poulin A., et al. Leptin regulates functional capacities of polymorphonuclear neutrophils. Free Radic. Res. 2003, 37(8):809-814.
27. Capeau J., Magre J., et al. Diseases of adipose tissue: genetic and acquired lipodystrophies. Biochem. Soc. Trans. 2005, 33(Pt 5):1073-1077.
28. Carpenter L.R., Farruggella T.J., et al. Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor. Proc. Natl. Acad. Sci. USA 1998, 95(11):6061-6066.
29. Chan J.L., Bullen J., et al. Recombinant methionyl human leptin administration to achieve high physiologic or pharmacologic leptin levels does not alter circulating inflammatory marker levels in humans with leptin sufficiency or excess. J. Clin. Endocrinol. Metab. 2005, 90(3):1618-1624.
30. Chan J.L., Heist K., et al. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J. Clin. Invest. 2003, 111(9):1409-1421.
31. Chan J.L., Mantzoros C.S. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet 2005, 366(9479):74-85.
32. Chan J.L., Matarese G., et al. Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans. Proc. Natl. Acad. Sci. USA 2006, 103(22):8481-8486.
33. Chan J.L., Mietus J.E., et al. Short-term fasting-induced autonomic activation and changes in catecholamine levels are not mediated by changes in leptin levels in healthy humans. Clin. Endocrinol. (Oxf.) 2007, 66(1):49-57.
34. Chan J.L., Moschos S.J., et al. Recombinant methionyl human leptin administration activates signal transducer and activator of transcription 3 signaling in peripheral blood mononuclear cells in vivo and regulates soluble tumor necrosis factor-alpha receptor levels in humans with relative leptin deficiency. J. Clin. Endocrinol. Metab. 2005, 90(3):1625-1631.
35. Chan J.L., Roth J.D., et al. It takes two to tango: combined amylin/leptin agonism as a potential approach to obesity drug development. J. Invest. Med. 2009, 57(7):777-783.
36. Chehab F.F., Lim M.E., et al. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat. Genet. 1996, 12(3):318-320.
37. Cirmanova V., Bayer M., et al. The effect of leptin on bone: an evolving concept of action. Physiol. Res. 2008, 57(Suppl. 1):S143-S151.
38. Clement K., Vaisse C., et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998, 392(6674):398-401.
39. Coleman D.L. Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 1973, 9(4):294-298.
40. Collins S., Kuhn C.M., et al. Role of leptin in fat regulation. Nature 1996, 380(6576):677.
41. Considine R.V., Sinha M.K., et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New Engl. J. Med. 1996, 334(5):292-295.
42. Costa A., Poma A., et al. Stimulation of corticotrophin-releasing hormone release by the obese (ob) gene product, leptin, from hypothalamic explants. Neuroreport 1997, 8(5):1131-1134.
43. Cota D., Matter E.K., et al. The role of hypothalamic mammalian target of rapamycin complex 1 signaling in diet-induced obesity. J. Neurosci. 2008, 28(28):7202-7208.
44. Cota D., Proulx K., et al. Hypothalamic mTOR signaling regulates food intake. Science 2006, 312(5775):927-930.
45. Cowley M.A. Hypothalamic melanocortin neurons integrate signals of energy state. Eur. J. Pharmacol. 2003, 480(1-3):3-11.
46. Cowley M.A., Smart J.L., et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 2001, 411(6836):480-484.
47. Critchley H.D., Wiens S., et al. Neural systems supporting interoceptive awareness. Nat. Neurosci. 2004, 7(2):189-195.
48. Cypess A.M., Lehman S., et al. Identification and importance of brown adipose tissue in adult humans. New Engl. J. Med. 2009, 360(15):1509-1517.
49. de Roux N., Genin E., et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc. Natl. Acad. Sci. USA 2003, 100(19):10972-10976.
50. Dhillon H., Zigman J.M., et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 2006, 49(2):191-203.
51. Duan J., Choi Y.H., et al. Effects of subcutaneous leptin injections on hypothalamic gene profiles in lean and ob/ob mice. Obesity (Silver Spring) 2007, 15(11):2624-2633.
52. Ducy P., Amling M., et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000, 100(2):197-207.
53. Dyck D.J. Adipokines as regulators of muscle metabolism and insulin sensitivity. Appl. Physiol. Nutr. Metab. 2009, 34(3):396-402.
54. Ebihara K., Masuzaki H., et al. Long-term leptin-replacement therapy for lipoatrophic diabetes. New Engl. J. Med. 2004, 351(6):615-616.
55. Elmquist J.K., Bjorbaek C., et al. Distributions of leptin receptor mRNA isoforms in the rat brain. J. Comp. Neurol. 1998, 395(4):535-547.
56. Ernst M.B., Wunderlich C.M., et al. Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity. J. Neurosci. 2009, 29(37):11582-11593.
57. Farooqi I.S. Monogenic human obesity. Front. Horm. Res. 2008, 36:1-11.
58. Farooqi I.S., Bullmore E., et al. Leptin regulates striatal regions and human eating behavior. Science 2007, 317(5843):1355.
59. Farooqi I.S., Jebb S.A., et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. New Engl. J. Med. 1999, 341(12):879-884.
60. Farooqi I.S., Keogh J.M., et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. New Engl. J. Med. 2003, 348(12):1085-1095.
61. Farooqi I.S., Matarese G., et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Invest. 2002, 110(8):1093-1103.
62. Farooqi I.S., O'Rahilly S. Monogenic human obesity syndromes. Recent Prog. Horm. Res. 2004, 59:409-424.
63. Farooqi I.S., O'Rahilly S. Monogenic obesity in humans. Annu. Rev. Med. 2005, 56:443-458.
64. Farooqi I.S., Wangensteen T., et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. New Engl. J. Med. 2007, 356(3):237-247.
65. Farooqi S. Insights from the genetics of severe childhood obesity. Horm. Res. 2007, 68(Suppl. 5):5-7.
66. Fei H., Okano H.J., et al. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc. Natl. Acad. Sci. USA 1997, 94(13):7001-7005.
67. Figlewicz D.P., Evans S.B., et al. Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat. Brain Res. 2003, 964(1):107-115.
68. Finn P.D., Cunningham M.J., et al. The stimulatory effect of leptin on the neuroendocrine reproductive axis of the monkey. Endocrinology 1998, 139(11):4652-4662.
69. Flier J.S., Harris M., et al. Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring. J. Clin. Invest. 2000, 105(7):859-861.
70. Fogteloo A.J., Pijl H., et al. Effects of recombinant human leptin treatment as an adjunct of moderate energy restriction on body weight, resting energy expenditure and energy intake in obese humans. Diabetes Nutr. Metab. 2003, 16(2):109-114.
71. Gao J., Tian J., et al. Leptin induces functional activation of cyclooxygenase-2 through JAK2/STAT3, MAPK/ERK, and PI3K/AKT pathways in human endometrial cancer cells. Cancer Sci. 2009, 100(3):389-395.
72. Gao Q., Horvath T.L. Cross-talk between estrogen and leptin signaling in the hypothalamus. Am. J. Physiol. Endocrinol. Metab. 2008, 294(5):E817-E826.
73. Gao Q., Horvath T.L. Neuronal control of energy homeostasis. FEBS Lett. 2008, 582(1):132-141.
74. Gao Q., Wolfgang M.J., et al. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proc. Natl. Acad. Sci. USA 2004, 101(13):4661-4666.
75. Garris D.R., Burkemper K.M., et al. Influences of diabetes (db/db), obese (ob/ob) and dystrophic (dy/dy) genotype mutations on hind limb bone maturation: a morphometric, radiological and cytochemical indices analysis. Diabetes Obes. Metab. 2007, 9(3):311-322.
76. Gat-Yablonski G., Phillip M. Leptin and regulation of linear growth. Curr. Opin. Clin. Nutr. Metab. Care 2008, 11(3):303-308.
77. Gavrila A., Hsu W., et al. Improvement in highly active antiretroviral therapy-induced metabolic syndrome by treatment with pioglitazone but not with fenofibrate: a 2×2 factorial, randomized, double-blinded, placebo-controlled trial. Clin. Infect. Dis. 2005, 40(5):745-749.
78. Gavrilova O., Marcus-Samuels B., et al. Leptin and diabetes in lipoatrophic mice. Nature 2000, 403(6772):850. (discussion 850-851).
79. Gibson W.T., Farooqi I.S., et al. Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J. Clin. Endocrinol. Metab. 2004, 89(10):4821-4826.
80. Gong L., Yao F., et al. Signal transducer and activator of transcription-3 is required in hypothalamic agouti-related protein/neuropeptide Y neurons for normal energy homeostasis. Endocrinology 2008, 149(7):3346-3354.
81. Gordeladze J.O., Drevon C.A., et al. Leptin stimulates human osteoblastic cell proliferation, de novo collagen synthesis, and mineralization: impact on differentiation markers, apoptosis, and osteoclastic signaling. J. Cell. Biochem. 2002, 85(4):825-836.
82. Gottsch M.L., Cunningham M.J., et al. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 2004, 145(9):4073-4077.
83. Grill H.J., Schwartz M.W., et al. Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Endocrinology 2002, 143(1):239-246.
84. Grinspoon S., Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. New Engl. J. Med. 2005, 352(1):48-62.
85. Hakansson M.L., Brown H., et al. Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J. Neurosci. 1998, 18(1):559-572.
86. Halaas J.L., Gajiwala K.S., et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995, 269(5223):543-546.
87. Hamrick M.W. Leptin and bone: a consensus emerging?. BoneKEy-Osteovision 2007, 4(3):99-107.
88. Hamrick M.W., Della-Fera M.A., et al. Leptin treatment induces loss of bone marrow adipocytes and increases bone formation in leptin-deficient ob/ob mice. J. Bone Miner. Res. 2005, 20(6):994-1001.
89. Hamrick M.W., Della Fera M.A., et al. Injections of leptin into rat ventromedial hypothalamus increase adipocyte apoptosis in peripheral fat and in bone marrow. Cell Tissue Res. 2007, 327(1):133-141.
90. Harris R.B., Zhou J., et al. A leptin dose-response study in obese (ob/ob) and lean (+/?) mice. Endocrinology 1998, 139(1):8-19.
91. Harvey J., McKay N.G., et al. Essential role of phosphoinositide 3-kinase in leptin-induced K(ATP) channel activation in the rat CRI-G1 insulinoma cell line. J. Biol. Chem. 2000, 275(7):4660-4669.
92. Heiman M.L., Ahima R.S., et al. Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress. Endocrinology 1997, 138(9):3859-3863.
93. Heymsfield S.B., Greenberg A.S., et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999, 282(16):1568-1575.
94. Hileman S.M., Pierroz D.D., et al. Characterization of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity. Endocrinology 2002, 143(3):775-783.
95. Hill J.W., Elmquist J.K., et al. Hypothalamic pathways linking energy balance and reproduction. Am. J. Physiol. Endocrinol. Metab. 2008, 294(5):E827-E832.
96. Holloway W.R., Collier F.M., et al. Leptin inhibits osteoclast generation. J. Bone Miner. Res. 2002, 17(2):200-209.
97. Hommel J.D., Trinko R., et al. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 2006, 51(6):801-810.
98. Hosoi T., Kawagishi T., et al. Brain stem is a direct target for leptin's action in the central nervous system. Endocrinology 2002, 143(9):3498-3504.
99. Howard J.K., Cave B.J., et al. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat. Med. 2004, 10(7):734-738.
100. Howard J.K., Lord G.M., et al. Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J. Clin. Invest. 1999, 104(8):1051-1059.
101. Hsu A., Aronoff D.M., et al. Leptin improves pulmonary bacterial clearance and survival in ob/ob mice during pneumococcal pneumonia. Clin. Exp. Immunol. 2007, 150(2):332-339.
102. Hukshorn C.J., Saris W.H., et al. Weekly subcutaneous pegylated recombinant native human leptin (PEG-OB) administration in obese men. J. Clin. Endocrinol. Metab. 2000, 85(11):4003-4009.
103. Hummel K.P., Dickie M.M., et al. Diabetes, a new mutation in the mouse. Science 1966, 153(740):1127-1128.
104. Ingalls A.M., Dickie M.M., et al. Obese, a new mutation in the house mouse. J. Hered. 1950, 41(12):317-318.
105. Irwig M.S., Fraley G.S., et al. Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 2004, 80(4):264-272.
106. Jackson R.S., Creemers J.W., et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat. Genet. 1997, 16(3):303-306.
107. Jacobson D.L., Knox T., et al. Prevalence of, evolution of, and risk factors for fat atrophy and fat deposition in a cohort of HIV-infected men and women. Clin. Infect. Dis. 2005, 40(12):1837-1845.
108. Javor E.D., Cochran E.K., et al. Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes 2005, 54(7):1994-2002.
109. Javor E.D., Ghany M.G., et al. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology 2005, 41(4):753-760.
110. Jimerson D.C., Mantzoros C., et al. Decreased serum leptin in bulimia nervosa. J. Clin. Endocrinol. Metab. 2000, 85(12):4511-4514.
111. Jurimae J., Jurimae T., et al. The influence of ghrelin, adiponectin, and leptin on bone mineral density in healthy postmenopausal women. J. Bone Miner. Metab. 2008, 26(6):618-623.
112. Kiess W., Petzold S., et al. Adipocytes and adipose tissue. Best Pract. Res. Clin. Endocrinol. Metab. 2008, 22(1):135-153.
113. Kim J.K., Gavrilova O., et al. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J. Biol. Chem. 2000, 275(12):8456-8460.
114. Kim M.S., Pak Y.K., et al. Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis. Nat. Neurosci. 2006, 9(7):901-906.
115. Kim M.S., Small C.J., et al. The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin. J. Clin. Invest. 2000, 105(7):1005-1011.
116. Kim Y.B., Uotani S., et al. In vivo administration of leptin activates signal transduction directly in insulin-sensitive tissues: overlapping but distinct pathways from insulin. Endocrinology 2000, 141(7):2328-2339.
117. H.R. Kissileff, Thornton J.C., et al., Maintenance of reduced body weight in humans is associated with leptin-reversible changes in appetite-related ratings, in: Society for Neuroscience Annual Meeting, San Diego, CA, USA, 2007.
118. Krude H., Biebermann H., et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat. Genet. 1998, 19(2):155-157.
119. Lee G.H., Proenca R., et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996, 379(6566):632-635.
120. Lee J.H., Chan J.L., et al. Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy. J. Clin. Endocrinol. Metab. 2006, 91(7):2605-2611.
121. Legradi G., Emerson C.H., et al. Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus. Endocrinology 1997, 138(6):2569-2576.
122. Lehman M.N., Coolen L.M., et al. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology 2010, 151(8).
123. Leinninger G.M., Jo Y.H., et al. Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell Metab. 2009, 10(2):89-98.
124. Leinninger G.M., Myers M.G. LRb signals act within a distributed network of leptin-responsive neurones to mediate leptin action. Acta Physiol. (Oxf.) 2008, 192(1):49-59.
125. Lejeune M.P., Hukshorn C.J., et al. Effect of dietary restraint during and following pegylated recombinant leptin (PEG-OB) treatment of overweight men. Int. J. Obes. Relat. Metab. Disord. 2003, 27(12):1494-1499.
126. Leshan R.L., Bjornholm M., et al. Leptin receptor signaling and action in the central nervous system. Obesity (Silver Spring) 2006, 14(Suppl. 5):208S-212S.
127. Levin B.E., Dunn-Meynell A.A., et al. Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004, 286(1):R143-R150.
128. Licinio J., Caglayan S., et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc. Natl. Acad. Sci. USA 2004, 101(13):4531-4536.
129. Licinio J., Mantzoros C., et al. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat. Med. 1997, 3(5):575-579.
130. Lim C.T., Kola B., et al. AMPK as a mediator of hormonal signalling. J. Mol. Endocrinol. 2009, 44(2):87-97.
131. Loffreda S., Yang S.Q., et al. Leptin regulates proinflammatory immune responses. FASEB J. 1998, 12(1):57-65.
132. Logothetis N.K. The neural basis of the blood-oxygen-level-dependent functional magnetic resonance imaging signal. Philos. Trans. Royal Soc. Lond. B Biol. Sci. 2002, 357(1424):1003-1037.
133. Lord G.M., Matarese G., et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998, 394(6696):897-901.
134. Lorentzon R., Alehagen U., et al. Osteopenia in mice with genetic diabetes. Diabetes Res. Clin. Pract. 1986, 2(3):157-163.
135. Mancuso P., Gottschalk A., et al. Leptin-deficient mice exhibit impaired host defense in Gram-negative pneumonia. J. Immunol. 2002, 168(8):4018-4024.
136. Mantzoros C., Flier J.S., et al. Cerebrospinal fluid leptin in anorexia nervosa: correlation with nutritional status and potential role in resistance to weight gain. J. Clin. Endocrinol. Metab. 1997, 82(6):1845-1851.
137. Mantzoros C.S. The role of leptin in human obesity and disease: a review of current evidence. Ann. Intern. Med. 1999, 130(8):671-680.
138. Mantzoros C.S. Whither recombinant human leptin treatment for HIV-associated lipoatrophy and the metabolic syndrome?. J. Clin. Endocrinol. Metab. 2009, 94(4):1089-1091.
139. Mantzoros C.S. W(h)ither metreleptin for lipodystrophy and the metabolic syndrome?. Endocr. Pract. 2010, 1:18.
140. Mantzoros C.S., Ozata M., et al. Synchronicity of frequently sampled thyrotropin (TSH) and leptin concentrations in healthy adults and leptin-deficient subjects: evidence for possible partial TSH regulation by leptin in humans. J. Clin. Endocrinol. Metab. 2001, 86(7):3284-3291.
141. Mantzoros C.S., Qu D., et al. Activation of beta(3) adrenergic receptors suppresses leptin expression and mediates a leptin-independent inhibition of food intake in mice. Diabetes 1996, 45(7):909-914.
142. Marchetti P., Bugliani M., et al. The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia 2007, 50(12):2486-2494.
143. Margetic S., Gazzola C., et al. Leptin: a review of its peripheral actions and interactions. Int. J. Obes. Relat. Metab. Disord. 2002, 26(11):1407-1433.
144. Maroni P., Bendinelli P., et al. Early intracellular events induced by in vivo leptin treatment in mouse skeletal muscle. Mol. Cell. Endocrinol. 2003, 201(1-2):109-121.
145. Matarese G., Moschos S., et al. Leptin in immunology. J. Immunol. 2005, 174(6):3137-3142.
146. Matochik J.A., London E.D., et al. Effect of leptin replacement on brain structure in genetically leptin-deficient adults. J. Clin. Endocrinol. Metab. 2005, 90(5):2851-2854.
147. Mayer J., Bates M.W., et al. Hereditary diabetes in genetically obese mice. Science 1951, 113(2948):746-747.
148. McMurtry V., Simeone A.M., et al. Leptin utilizes Jun N-terminal kinases to stimulate the invasion of MCF-7 breast cancer cells. Clin. Exp. Metast. 2009, 26(3):197-204.
149. Miller K.K., Parulekar M.S., et al. Decreased leptin levels in normal weight women with hypothalamic amenorrhea: the effects of body composition and nutritional intake. J. Clin. Endocrinol. Metab. 1998, 83(7):2309-2312.
150. Minokoshi Y., Alquier T., et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 2004, 428(6982):569-574.
151. Minokoshi Y., Kim Y.B., et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002, 415(6869):339-343.
152. Moitra J., Mason M.M., et al. Life without white fat: a transgenic mouse. Genes Dev. 1998, 12(20):3168-3181.
153. Montague C.T., Prins J.B., et al. Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution. Diabetes 1997, 46(3):342-347.
154. Moran S.A., Patten N., et al. Changes in body composition in patients with severe lipodystrophy after leptin replacement therapy. Metabolism 2004, 53(4):513-519.
155. Mori H., Hanada R., et al. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat. Med. 2004, 10(7):739-743.
156. Morris D.L., Rui L. Recent advances in understanding leptin signaling and leptin resistance. Am. J. Physiol. Endocrinol. Metab. 2009, 297(6):E1247-E1259.
157. Morrison C.D. Leptin signaling in brain: a link between nutrition and cognition?. Biochim. Biophys. Acta 2009, 1792(5):401-408.
158. Morton G.J., Blevins J.E., et al. Leptin action in the forebrain regulates the hindbrain response to satiety signals. J. Clin. Invest. 2005, 115(3):703-710.
159. Mulligan K., Khatami H., et al. The effects of recombinant human leptin on visceral fat, dyslipidemia, and insulin resistance in patients with human immunodeficiency virus-associated lipoatrophy and hypoleptinemia. J. Clin. Endocrinol. Metab. 2009, 94(4):1137-1144.
160. Munzberg H., Jobst E.E., et al. Appropriate inhibition of orexigenic hypothalamic arcuate nucleus neurons independently of leptin receptor/STAT3 signaling. J. Neurosci. 2007, 27(1):69-74.
161. Musso C., Cochran E., et al. The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism 2005, 54(2):255-263.
162. Myers M.G., Cowley M.A., et al. Mechanisms of leptin action and leptin resistance. Annu. Rev. Physiol. 2008, 70:537-556.
163. Myers M.G. Leptin receptor signaling and the regulation of mammalian physiology. Recent Prog. Horm. Res. 2004, 59:287-304.
164. Nagy G.S., Tsiodras S., et al. Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin. Clin. Infect. Dis. 2003, 36(6):795-802.
165. Nattiv A., Loucks A.B., et al. American college of sports medicine position stand. The female athlete triad. Med. Sci. Sports Exerc. 2007, 39(10):1867-1882.
166. Nishiyama A., Yagi M., et al. Two Japanese infants with congenital generalized lipodystrophy due to BSCL2 mutations. Pediatr. Int. 2009, 51(6):775-779.
167. Niswender K.D., Morrison C.D., et al. Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 2003, 52(2):227-231.
168. Niswender K.D., Morton G.J., et al. Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature 2001, 413(6858):794-795.
169. Ogunwobi O.O., Beales I.L. The anti-apoptotic and growth stimulatory actions of leptin in human colon cancer cells involves activation of JNK mitogen activated protein kinase, JAK2 and PI3 kinase/Akt. Int. J. Colorectal Dis. 2007, 22(4):401-409.
170. Ollmann M.M., Wilson B.D., et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997, 278(5335):135-138.
171. Oral E.A., Ruiz E., et al. Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J. Clin. Endocrinol. Metab. 2002, 87(7):3110-3117.
172. Oral E.A., Simha V., et al. Leptin-replacement therapy for lipodystrophy. New Engl. J. Med. 2002, 346(8):570-578.
173. Oswal A., Yeo G. Leptin and the control of body weight: a review of its diverse central targets, signaling mechanisms, and role in the pathogenesis of obesity. Obesity (Silver Spring) 2009, 18(2):221-229.
174. Ozata M., Ozdemir I.C., et al. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J. Clin. Endocrinol. Metab. 1999, 84(10):3686-3695.
175. Ozcan L., Ergin A.S., et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 2009, 9(1):35-51.
176. Ozcan U., Cao Q., et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004, 306(5695):457-461.
177. Papathanassoglou E., El-Haschimi K., et al. Leptin receptor expression and signaling in lymphocytes: kinetics during lymphocyte activation, role in lymphocyte survival, and response to high fat diet in mice. J. Immunol. 2006, 176(12):7745-7752.
178. Pardini V.C., Victoria I.M., et al. Leptin levels, beta-cell function, and insulin sensitivity in families with congenital and acquired generalized lipoatropic diabetes. J. Clin. Endocrinol. Metab. 1998, 83(2):503-508.
179. Paz-Filho G., Delibasi T., et al. Congenital leptin deficiency and thyroid function. Thyroid Res. 2009, 2(1):11.
180. Paz G.J., Babikian T., et al. Leptin replacement improves cognitive development. PLoS One 2008, 3(8):7.
181. Petersen K.F., Oral E.A., et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J. Clin. Invest. 2002, 109(10):1345-1350.
182. Pierroz D.D., Ziotopoulou M., et al. Effects of acute and chronic administration of the melanocortin agonist MTII in mice with diet-induced obesity. Diabetes 2002, 51(5):1337-1345.
183. Pinto S., Roseberry A.G., et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 2004, 304(5667):110-115.
184. Plum L., Ma X., et al. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J Clin Invest 2006, 116(7):1886-1901.
185. Pombo M., Pombo C.M., et al. Hormonal control of growth hormone secretion. Horm. Res. 2001, 55(Suppl. 1):11-16.
186. Qu D., Ludwig D.S., et al. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 1996, 380(6571):243-247.
187. Quennell J.H., Mulligan A.C., et al. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology 2009, 150(6):2805-2812.
188. Rahmouni K., Haynes W.G., et al. Intracellular mechanisms involved in leptin regulation of sympathetic outflow. Hypertension 2003, 41(3 Pt 2):763-767.
189. Rahmouni K., Sigmund C.D., et al. Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin. Diabetes 2009, 58(3):536-542.
190. Ravussin E., Smith S.R., et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring) 2009, 17(9):1736-1743.
191. Rios M., Fan G., et al. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol. Endocrinol. 2001, 15(10):1748-1757.
192. Roemmich J.N., Clark P.A., et al. Relationship of leptin to bone mineralization in children and adolescents. J. Clin. Endocrinol. Metab. 2003, 88(2):599-604.
193. Rogge G., Jones D., et al. CART peptides: regulators of body weight, reward and other functions. Nat. Rev. Neurosci. 2008, 9(10):747-758.
194. Rosenbaum M., Goldsmith R., et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J. Clin. Invest. 2005, 115(12):3579-3586.
195. Rosenbaum M., Nicolson M., et al. Effects of gender, body composition, and menopause on plasma concentrations of leptin. J. Clin. Endocrinol. Metab. 1996, 81(9):3424-3427.
196. Rosenbaum M., Sy M., et al. Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli. J. Clin. Invest. 2008, 118(7):2583-2591.
197. Roth J.D., Roland B.L., et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc. Natl. Acad. Sci. USA 2008, 105(20):7257-7262.
198. Saad M.F., Damani S., et al. Sexual dimorphism in plasma leptin concentration. J. Clin. Endocrinol. Metab. 1997, 82(2):579-584.
199. Sahu A. Leptin decreases food intake induced by melanin-concentrating hormone (MCH), galanin (GAL) and neuropeptide Y (NPY) in the rat. Endocrinology 1998, 139(11):4739-4742.
200. Sakurai T., Amemiya A., et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998, 92(5). (1 page following 696).
201. Sanchez V.C., Goldstein J., et al. Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone. J. Clin. Invest. 2004, 114(3):357-369.
202. Sato S., Hanada R., et al. Central control of bone remodeling by neuromedin U. Nat. Med. 2007, 13(10):1234-1240.
203. Scarpace P.J., Matheny M., et al. Leptin increases uncoupling protein expression and energy expenditure. Am. J. Physiol. 1997, 273(1 Pt 1):E226-E230.
204. Schwartz M.W., Baskin D.G., et al. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 1996, 45(4):531-535.
205. Segal-Lieberman G., Bradley R.L., et al. Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype. Proc. Natl. Acad. Sci. USA 2003, 100(17):10085-10090.
206. Seminara S.B., Messager S., et al. The GPR54 gene as a regulator of puberty. New Engl. J. Med. 2003, 349(17):1614-1627.
207. S. Severin, C. Ghevaert, et al., The mitogen-activated protein kinase signalling pathways: role in megakaryocyte differentiation. J. Thromb. Haemost., 2009.
208. Shahab M., Mastronardi C., et al. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc. Natl. Acad. Sci. USA 2005, 102(6):2129-2134.
209. Sharma N.K., Das S.K., et al. Endoplasmic reticulum stress markers are associated with obesity in nondiabetic subjects. J. Clin. Endocrinol. Metab. 2008, 93(11):4532-4541.
210. Sharma V., Mustafa S., et al. Stimulation of cardiac fatty acid oxidation by leptin is mediated by a nitric oxide-p38 MAPK-dependent mechanism. Eur. J. Pharmacol. 2009, 617(1-3):113-117.
211. Shimada M., Tritos N.A., et al. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 1998, 396(6712):670-674.
212. Shimomura I., Hammer R.E., et al. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999, 401(6748):73-76.
213. Sinha M.K., Ohannesian J.P., et al. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J. Clin. Invest. 1996, 97(5):1344-1347.
214. Smith J.T., Acohido B.V., et al. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J. Neuroendocrinol. 2006, 18(4):298-303.
215. Smith P.M., Ferguson A.V. Neurophysiology of hunger and satiety. Dev. Disabil. Res. Rev. 2008, 14(2):96-104.
216. Stanley B.G., Leibowitz S.F. Neuropeptide Y: stimulation of feeding and drinking by injection into the paraventricular nucleus. Life Sci. 1984, 35(26):2635-2642.
217. Ste Marie L., Miura G.I., et al. A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc. Natl. Acad. Sci. USA 2000, 97(22):12339-12344.
218. Steinberg G.R., McAinch A.J., et al. The suppressor of cytokine signaling 3 inhibits leptin activation of AMP-kinase in cultured skeletal muscle of obese humans. J. Clin. Endocrinol. Metab. 2006, 91(9):3592-3597.
219. Steinberg G.R., Rush J.W., et al. AMPK expression and phosphorylation are increased in rodent muscle after chronic leptin treatment. Am. J. Physiol. Endocrinol. Metab. 2003, 284(3):E648-E654.
220. Steppan C.M., Crawford D.T., et al. Leptin is a potent stimulator of bone growth in ob/ob mice. Regul. Pept. 2000, 92(1-3):73-78.
221. Steppan C.M., Swick A.G. A role for leptin in brain development. Biochem. Biophys. Res. Commun. 1999, 256(3):600-602.
222. Sternson S.M., Shepherd G.M., et al. Topographic mapping of VMH→arcuate nucleus microcircuits and their reorganization by fasting. Nat. Neurosci. 2005, 8(10):1356-1363.
223. Strobel A., Issad T., et al. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat. Genet. 1998, 18(3):213-215.
224. Takeda S., Elefteriou F., et al. Leptin regulates bone formation via the sympathetic nervous system. Cell 2002, 111(3):305-317.
225. Tartaglia L.A. The leptin receptor. J. Biol. Chem. 1997, 272(10):6093-6096.
226. Thomas T., Gori F., et al. Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology 1999, 140(4):1630-1638.
227. Thompson E.L., Patterson M., et al. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J. Neuroendocrinol. 2004, 16(10):850-858.
228. Tritos N.A., Mantzoros C.S. Leptin: its role in obesity and beyond. Diabetologia 1997, 40(12):1371-1379.
229. Tu H., Kastin A.J., et al. Soluble receptor inhibits leptin transport. J. Cell. Physiol. 2008, 214(2):301-305.
230. Tung Y.C., Ma M., et al. Novel leptin-regulated genes revealed by transcriptional profiling of the hypothalamic paraventricular nucleus. J. Neurosci. 2008, 28(47):12419-12426.
231. Turek V.F., Trevaskis J.L., et al. Mechanisms of amylin/leptin synergy in rodent models. Endocrinology 2010, 151(1):143-152.
232. Udagawa J., Hashimoto R., et al. The role of leptin in the development of the cortical neuron in mouse embryos. Brain Res. 2006, 1120(1):74-82.
233. Uehara Y., Shimizu H., et al. Hypothalamic corticotropin-releasing hormone is a mediator of the anorexigenic effect of leptin. Diabetes 1998, 47(6):890-893.
234. Valassi E., Scacchi M., et al. Neuroendocrine control of food intake. Nutr. Metab. Cardiovasc. Dis. 2008, 18(2):158-168.
235. van der Kroon P.H., Boldewijn H., et al. Congenital hypothyroidism in latent obese (ob/ob) mice. Int. J. Obes. 1982, 6(1):83-90.
236. van Marken Lichtenbelt W.D., Vanhommerig J.W., et al. Cold-activated brown adipose tissue in healthy men. New Engl. J. Med. 2009, 360(15):1500-1508.
237. Vila R., Adan C., et al. Plasma leptin turnover rates in lean and obese Zucker rats. Endocrinology 1998, 139(11):4466-4469.
238. Virtanen K.A., Lidell M.E., et al. Functional brown adipose tissue in healthy adults. New Engl. J. Med. 2009, 360(15):1518-1525.
239. Wang J.H., Wang F., et al. Leptin regulated calcium channels of neuropeptide Y and proopiomelanocortin neurons by activation of different signal pathways. Neuroscience 2008, 156(1):89-98.
240. Wang R., Swick A.G. Identification and characterization of a leptin-responsive neuroblastoma cell line. Biochem. Biophys. Res. Commun. 2009, 379(4):835-839.
241. Wang Y., Kuropatwinski K.K., et al. Leptin receptor action in hepatic cells. J. Biol. Chem. 1997, 272(26):16216-16223.
242. Warren M.P. Clinical review 77: evaluation of secondary amenorrhea. J. Clin. Endocrinol. Metab. 1996, 81(2):437-442.
243. Welt C.K., Chan J.L., et al. Recombinant human leptin in women with hypothalamic amenorrhea. New Engl. J. Med. 2004, 351(10):987-997.
244. White D.W., Tartaglia L.A. Leptin and OB-R: body weight regulation by a cytokine receptor. Cytokine Growth Factor Rev. 1996, 7(4):303-309.
245. Williams D.L., Baskin D.G., et al. Leptin regulation of the anorexic response to glucagon-like peptide-1 receptor stimulation. Diabetes 2006, 55(12):3387-3393.
246. Won J.C., Jang P.G., et al. Central administration of an endoplasmic reticulum stress inducer inhibits the anorexigenic effects of leptin and insulin. Obesity (Silver Spring) 2009, 17(10):1861-1865.
247. Wren A.M., Small C.J., et al. Hypothalamic actions of neuromedin U. Endocrinology 2002, 143(11):4227-4234.
248. Xu A.W., Ste-Marie L., et al. Inactivation of signal transducer and activator of transcription 3 in proopiomelanocortin (Pomc) neurons causes decreased pomc expression, mild obesity, and defects in compensatory refeeding. Endocrinology 2007, 148(1):72-80.
249. Xu B., Goulding E.H., et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat. Neurosci. 2003, 6(7):736-742.
250. Yadav V.K., Oury F., et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 2009, 138(5):976-989.
251. Yamanaka A., Beuckmann C.T., et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 2003, 38(5):701-713.
252. Yamauchi T., Kamon J., et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med. 2001, 7(8):941-946.
253. Yu W.H., Kimura M., et al. Role of leptin in hypothalamic-pituitary function. Proc. Natl. Acad. Sci. USA 1997, 94(3):1023-1028.
254. Yue T.L., Gu J.L., et al. Extracellular signal-regulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy. J. Biol. Chem. 2000, 275(48):37895-37901.
255. Zhang F., Basinski M.B., et al. Crystal structure of the obese protein leptin-E100. Nature 1997, 387(6629):206-209.
256. Zhang Y., Proenca R., et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994, 372(6505):425-432.