Leptin as a modulator of neuroendocrine function in humans

Yonsei Medical Journal

Volumn 53, Issue 4, 2012, Pages 671-679

  Khan, Sami M ^a   Hamnvik, Ole Petter R ^a,b,c   Brinkoetter, Mary ^a,b   Mantzoros, Christos S ^a,b  

^a HARVARD MEDICAL SCHOOL   (United States)

^b VETERANS AFFAIRS MEDICAL CENTER   (United States)

^c BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

Amenorrhea; Leptin; Leptin deficiency

Indexed keywords

GONADORELIN; GROWTH HORMONE; INSULIN; LEPTIN; LIOTHYRONINE; LUTEINIZING HORMONE; PLACEBO; PROTIRELIN; SOMATOMEDIN C; THYROTROPIN; THYROXINE;

ABNORMALLY HIGH SUBSTRATE CONCENTRATION IN BLOOD; ANOREXIA NERVOSA; ARTICLE; CONGENITAL GENERALIZED LIPODYSTROPHY; CONGENITAL LEPTIN DEFICIENCY; DISEASE ASSOCIATION; DRUG MEGADOSE; ENERGY METABOLISM; GONADOTROPIN BLOOD LEVEL; HORMONAL REGULATION; HORMONE BLOOD LEVEL; HORMONE SUBSTITUTION; HUMAN; HYPERTRIGLYCERIDEMIA; HYPOLEPTINEMIA; HYPOTHALAMIC AMENORRHEA; HYPOTHALAMUS HYPOPHYSIS ADRENAL SYSTEM; HYPOTHALAMUS HYPOPHYSIS GONAD SYSTEM; HYPOTHALAMUS HYPOPHYSIS SYSTEM; HYPOTHALAMUS HYPOPHYSIS THYROID SYSTEM; IMPAIRED GLUCOSE TOLERANCE; LEPTIN DEFICIENCY; LIOTHYRONINE BLOOD LEVEL; LUTEINIZING HORMONE BLOOD LEVEL; NEUROENDOCRINE SYSTEM; NONHUMAN; THYROTROPIN BLOOD LEVEL; THYROXINE BLOOD LEVEL;

AMENORRHEA; ANIMALS; FEMALE; HUMANS; LEPTIN; MALE; NEUROSECRETORY SYSTEMS;

EID: 84863108775     PISSN: 05135796     EISSN: None     Source Type: Journal    
DOI: 10.3349/ymj.2012.53.4.671     Document Type: Article

References (101)

1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425-32.
2. Moschos S, Chan JL, Mantzoros CS. Leptin and reproduction: a review. Fertil Steril 2002;77:433-44.
3. Blüher S, Mantzoros CS. Leptin in humans: lessons from translational research. Am J Clin Nutr 2009;89:991S-7S.
4. Hamnvik OP, Liu X, Petrou M, Gong H, Chamberland JP, Kim EH, et al. Soluble leptin receptor and leptin are associated with baseline adiposity and metabolic risk factors, and predict adiposity, metabolic syndrome, and glucose levels at 2-year follow-up: the Cyprus Metabolism Prospective Cohort Study. Metabolism 2011;60:987-93.
5. Matarese G, Mantzoros C, La Cava A. Leptin and adipocytokines: bridging the gap between immunity and atherosclerosis. Curr Pharm Des 2007;13:3676-80.
6. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996;382:250-2.
7. Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest 2003;111:1409-21.
8. Chan JL, Matarese G, Shetty GK, Raciti P, Kelesidis I, Aufiero D, et al. Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans. Proc Natl Acad Sci U S A 2006;103:8481-6.
9. Luque RM, Huang ZH, Shah B, Mazzone T, Kineman RD. Effects of leptin replacement on hypothalamic-pituitary growth hormone axis function and circulating ghrelin levels in ob/ob mice. Am J Physiol Endocrinol Metab 2007;292:E891-9.
10. Costa A, Poma A, Martignoni E, Nappi G, Ur E, Grossman A. Stimulation of corticotrophin-releasing hormone release by the obese (ob) gene product, leptin, from hypothalamic explants. Neuroreport 1997;8:1131-4.
11. Licinio J, Mantzoros C, Negrão AB, Cizza G, Wong ML, Bongiorno PB, et al. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat Med 1997;3:575-9.
12. Boden G, Chen X, Mozzoli M, Ryan I. Effect of fasting on serum leptin in normal human subjects. J Clin Endocrinol Metab 1996;81:3419-23.
13. Denver RJ, Bonett RM, Boorse GC. Evolution of leptin structure and function. Neuroendocrinology 2011;94:21-38.
14. Trayhurn P, Duncan JS, Hoggard N, Rayner DV. Regulation of leptin production: a dominant role for the sympathetic nervous system? Proc Nutr Soc 1998;57:413-9.
15. Matarese G, Moschos S, Mantzoros CS. Leptin in immunology. J Immunol 2005;174:3137-42.
16. Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord 2002;26:1407-33.
17. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334:292-5.
18. Yannakoulia M, Yiannakouris N, Blüher S, Matalas AL, Klimis-Zacas D, Mantzoros CS. Body fat mass and macronutrient intake in relation to circulating soluble leptin receptor, free leptin index, adiponectin, and resistin concentrations in healthy humans. J Clin Endocrinol Metab 2003;88:1730-6.
19. Mantzoros CS, Flier JS. Editorial: leptin as a therapeutic agent--trials and tribulations. J Clin Endocrinol Metab 2000;85:4000-2.
20. Mantzoros CS. Role of leptin in reproduction. Ann N Y Acad Sci 2000;900:174-83.
21. Kelesidis T, Kelesidis I, Chou S, Mantzoros CS. Narrative review: the role of leptin in human physiology: emerging clinical applications. Ann Intern Med 2010;152:93-100.
22. Mullington JM, Chan JL, Van Dongen HP, Szuba MP, Samaras J, Price NJ, et al. Sleep loss reduces diurnal rhythm amplitude of leptin in healthy men. J Neuroendocrinol 2003;15:851-4.
23. Scheer FA, Hilton MF, Mantzoros CS, Shea SA. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A 2009;106:4453-8.
24. Mantzoros CS, Liolios AD, Tritos NA, Kaklamani VG, Doulgerakis DE, Griveas I, et al. Circulating insulin concentrations, smoking, and alcohol intake are important independent predictors of leptin in young healthy men. Obes Res 1998;6:179-86.
25. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996;84:491-5.
26. Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998;392:398-401.
27. Mantzoros CS, Moschos SJ. Leptin: in search of role(s) in human physiology and pathophysiology. Clin Endocrinol (Oxf) 1998;49:551-67.
28. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83:1263-71.
29. Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R, et al. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci U S A 1997; 94:7001-5.
30. Baumann H, Morella KK, White DW, Dembski M, Bailon PS, Kim H, et al. The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proc Natl Acad Sci U S A 1996;93:8374-8.
31. Maffei M, Fei H, Lee GH, Dani C, Leroy P, Zhang Y, et al. Increased expression in adipocytes of ob RNA in mice with lesions of the hypothalamus and with mutations at the db locus. Proc Natl Acad Sci U S A 1995;92:6957-60.
32. Papathanassoglou E, El-Haschimi K, Li XC, Matarese G, Strom T, Mantzoros C. 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;176:7745-52.
33. Moon HS, Chamberland JP, Diakopoulos KN, Fiorenza CG, Ziemke F, Schneider B, et al. Leptin and amylin act in an additive manner to activate overlapping signaling pathways in peripheral tissues: in vitro and ex vivo studies in humans. Diabetes Care 2011;34:132-8.
34. Moon HS, Matarese G, Brennan AM, Chamberland JP, Liu X, Fiorenza CG, et al. Efficacy of metreleptin in obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance. Diabetes 2011;60:1647-56.
35. Cioffi JA, Shafer AW, Zupancic TJ, Smith-Gbur J, Mikhail A, Platika D, et al. Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction. Nat Med 1996;2: 585-9.
36. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996;379:632-5.
37. Peelman F, Couturier C, Dam J, Zabeau L, Tavernier J, Jockers R. Techniques: new pharmacological perspectives for the leptin receptor. Trends Pharmacol Sci 2006;27:218-25.
38. Sun Q, Cornelis MC, Kraft P, Qi L, van Dam RM, Girman CJ, et al. Genome-wide association study identifies polymorphisms in LEPR as determinants of plasma soluble leptin receptor levels. Hum Mol Genet 2010;19:1846-55.
39. Sinha MK, Ohannesian JP, Heiman ML, Kriauciunas A, Stephens TW, Magosin S, et al. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J Clin Invest 1996;97:1344-7.
40. Shea SA, Hilton MF, Orlova C, Ayers RT, Mantzoros CS. Independent circadian and sleep/wake regulation of adipokines and glucose in humans. J Clin Endocrinol Metab 2005;90:2537-44.
41. Rosenbaum M, Nicolson M, Hirsch J, Heymsfield SB, Gallagher D, Chu F, et al. Effects of gender, body composition, and menopause on plasma concentrations of leptin. J Clin Endocrinol Metab 1996;81:3424-7.
42. Saad MF, Damani S, Gingerich RL, Riad-Gabriel MG, Khan A, Boyadjian R, et al. Sexual dimorphism in plasma leptin concentration. J Clin Endocrinol Metab 1997;82:579-84.
43. Roemmich JN, Clark PA, Berr SS, Mai V, Mantzoros CS, Flier JS, et al. Gender differences in leptin levels during puberty are related to the subcutaneous fat depot and sex steroids. Am J Physiol 1998;275(3 Pt 1):E543-51.
44. Lin KC. Increase of leptin levels following exogenous administration of estrogen in women with normal menstruation. Kaohsiung J Med Sci 2000;16:13-9.
45. Shimizu H, Shimomura Y, Nakanishi Y, Futawatari T, Ohtani K, Sato N, et al. Estrogen increases in vivo leptin production in rats and human subjects. J Endocrinol 1997;154:285-92.
46. Asimakopoulos B, Milousis A, Gioka T, Kabouromiti G, Gianisslis G, Troussa A, et al. Serum pattern of circulating adipokines throughout the physiological menstrual cycle. Endocr J 2009;56:425-33.
47. Montague CT, Prins JB, Sanders L, Digby JE, O'Rahilly S. Depot-and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution. Diabetes 1997;46:342-7.
48. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999;341: 879-84.
49. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 2002;110:1093-103.
50. Paz-Filho G, Delibasi T, Erol HK, Wong ML, Licinio J. Congenital leptin deficiency and thyroid function. Thyroid Res 2009;2:11.
51. Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest 2005;115:3579-86.
52. Chan JL, Mietus JE, Raciti PM, Goldberger AL, Mantzoros CS. 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;66:49-57.
53. Mantzoros C, Flier JS, Lesem MD, Brewerton TD, Jimerson DC. Cerebrospinal fluid leptin in anorexia nervosa: correlation with nutritional status and potential role in resistance to weight gain. J Clin Endocrinol Metab 1997;82:1845-51.
54. Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004;351:987-97.
55. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998;18:213-5.
56. Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O'Kirwan F, et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci U S A 2004;101: 4531-6.
57. Mantzoros CS, Flier JS, Rogol AD. A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty. J Clin Endocrinol Metab 1997;82:1066-70.
58. Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS. Leptin accelerates the onset of puberty in normal female mice. J Clin Invest 1997;99:391-5.
59. Chen R, Mick GJ, Xu R, Zheng D, Fan Y, Lin X, et al. Effect of central antileptin antibody on the onset of female rat puberty. Int J Pediatr Endocrinol 2009;2009:194807.
60. Chehab FF, Lim ME, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet 1996;12:318-20.
61. Yu WH, Kimura M, Walczewska A, Karanth S, McCann SM. Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci U S A 1997;94:1023-8.
62. Chan JL, Wong SL, Mantzoros CS. Pharmacokinetics of subcutaneous recombinant methionyl human leptin administration in healthy subjects in the fed and fasting states: regulation by gender and adiposity. Clin Pharmacokinet 2008;47:753-64.
63. Quennell JH, Mulligan AC, Tups A, Liu X, Phipps SJ, Kemp CJ, et al. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology 2009;150:2805-12.
64. Hill JW, Elmquist JK, Elias CF. Hypothalamic pathways linking energy balance and reproduction. Am J Physiol Endocrinol Metab 2008;294:E827-32.
65. Dardeno TA, Chou SH, Moon HS, Chamberland JP, Fiorenza CG, Mantzoros CS. Leptin in human physiology and therapeutics. Front Neuroendocrinol 2010;31:377-93.
66. Lehman MN, Coolen LM, Goodman RL. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology 2010;151:3479-89.
67. Smith JT, Acohido BV, Clifton DK, Steiner RA. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol 2006;18:298-303.
68. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 2001;276:34631-6.
69. Matsuzaki T, Iwasa T, Kinouchi R, Yoshida S, Murakami M, Gereltsetseg G, et al. Fasting reduces the kiss1 mRNA levels in the caudal hypothalamus of gonadally intact adult female rats. Endocr J 2011;58:1003-12.
70. Castellano JM, Bentsen AH, Sánchez-Garrido MA, Ruiz-Pino F, Romero M, Garcia-Galiano D, et al. Early metabolic programming of puberty onset: impact of changes in postnatal feeding and rearing conditions on the timing of puberty and development of the hypothalamic kisspeptin system. Endocrinology 2011;152: 3396-408.
71. Irwig MS, Fraley GS, Smith JT, Acohido BV, Popa SM, Cunningham MJ, et al. Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 2004;80:264-72.
72. Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, Crowley WF, et al. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 2004;145: 4073-7.
73. Thompson EL, Patterson M, Murphy KG, Smith KL, Dhillo WS, Todd JF, et al. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol 2004;16:850-8.
74. Louis GW, Greenwald-Yarnell M, Phillips R, Coolen LM, Lehman MN, Myers MG Jr. Molecular mapping of the neural pathways linking leptin to the neuroendocrine reproductive axis. Endocrinology 2011;152:2302-10.
75. Donato J Jr, Cravo RM, Frazão R, Gautron L, Scott MM, Lachey J, et al. Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J Clin Invest 2011;121:355-68.
76. Mantzoros CS, Ozata M, Negrao AB, Suchard MA, Ziotopoulou M, Caglayan S, 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: 3284-91.
77. van der Kroon PH, Boldewijn H, Langeveld-Soeter N. Congenital hypothyroidism in latent obese (ob/ob) mice. Int J Obes 1982; 6:83-90.
78. Légrádi G, Emerson CH, Ahima RS, Flier JS, Lechan RM. Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus. Endocrinology 1997;138:2569-76.
79. Kim MS, Small CJ, Stanley SA, Morgan DG, Seal LJ, Kong WM, et al. The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin. J Clin Invest 2000;105:1005-11.
80. Sanchez VC, Goldstein J, Stuart RC, Hovanesian V, Huo L, Munzberg H, et al. Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone. J Clin Invest 2004;114:357-69.
81. Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, et al. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 2011;301:E567-84.
82. Shetty GK, Matarese G, Magkos F, Moon HS, Liu X, Brennan AM, et al. Leptin administration to overweight and obese subjects for 6 months increases free leptin concentrations but does not alter circulating hormones of the thyroid and IGF axes during weight loss induced by a mild hypocaloric diet. Eur J Endocrinol 2011;165:249-54.
83. Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 2007; 356:237-47.
84. Chan JL, Williams CJ, Raciti P, Blakeman J, Kelesidis T, Kelesidis I, et al. Leptin does not mediate short-term fasting-induced changes in growth hormone pulsatility but increases IGF-I in leptin deficiency states. J Clin Endocrinol Metab 2008;93:2819-27.
85. Pralong FP, Roduit R, Waeber G, Castillo E, Mosimann F, Thorens B, et al. Leptin inhibits directly glucocorticoid secretion by normal human and rat adrenal gland. Endocrinology 1998;139: 4264-8.
86. Heiman ML, Ahima RS, Craft LS, Schoner B, Stephens TW, Flier JS. Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress. Endocrinology 1997;138:3859-63.
87. Sienkiewicz E, Magkos F, Aronis KN, Brinkoetter M, Chamberland JP, Chou S, et al. Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism 2011;60:1211-21.
88. Blüher S, Shah S, Mantzoros CS. Leptin deficiency: clinical implications and opportunities for therapeutic interventions. J Investig Med 2009;57:784-8.
89. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903-8.
90. Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet 2005; 366:74-85.
91. Miller KK, Parulekar MS, Schoenfeld E, Anderson E, Hubbard J, Klibanski A, 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; 83:2309-12.
92. Chou SH, Chamberland JP, Liu X, Matarese G, Gao C, Stefanakis R, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A 2011;108:6585-90.
93. Arimura C, Nozaki T, Takakura S, Kawai K, Takii M, Sudo N, et al. Predictors of menstrual resumption by patients with anorexia nervosa. Eat Weight Disord 2010;15:e226-33.
94. Fiorenza CG, Chou SH, Mantzoros CS. Lipodystrophy: pathophysiology and advances in treatment. Nat Rev Endocrinol 2011;7:137-50.
95. Pardini VC, Victória IM, Rocha SM, Andrade DG, Rocha AM, Pieroni FB, et al. Leptin levels, beta-cell function, and insulin sensitivity in families with congenital and acquired generalized lipoatropic diabetes. J Clin Endocrinol Metab 1998;83:503-8.
96. Nagy GS, Tsiodras S, Martin LD, Avihingsanon A, Gavrila A, Hsu WC, et al. Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin. Clin Infect Dis 2003;36:795-802.
97. Musso C, Cochran E, Javor E, Young J, Depaoli AM, Gorden P. 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;54:255-63.
98. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002;346:570-8.
99. Chong AY, Lupsa BC, Cochran EK, Gorden P. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia 2010;53:27-35.
100. Mantzoros CS. W(h)ither metreleptin for lipodystrophy and the metabolic syndrome? Endocr Pract 2010:1-18.
101. Mantzoros CS. Whither recombinant human leptin treatment for HIV-associated lipoatrophy and the metabolic syndrome? J Clin Endocrinol Metab 2009;94:1089-91.