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Physiology of leptin

Author
Christos Mantzoros, MD, DSc
Section Editor
F Xavier Pi-Sunyer, MD, MPH
Deputy Editor
Kathryn A Martin, MD

INTRODUCTION

Leptin is a product of the ob gene, which is expressed primarily in adipocytes. Leptin acts on leptin receptors (LEPRs), which are widely distributed and account for its pleiotropic effects on energy homeostasis and neuroendocrine, reproductive, and immune function [1]. Leptin is produced primarily in fat cells but also in other organs such as the placenta [2].

The physiology of leptin [3,4] and a review of disorders associated with leptin deficiency are reviewed here. The pathogenesis of obesity and lipodystrophy are reviewed separately. (See "Genetic contribution and pathophysiology of obesity" and "Lipodystrophic syndromes".)

ACTION OF LEPTIN

In humans, the leptin gene is located on chromosome 7q32 and consists of three exons and two introns that span 20 kilobases (kb) of DNA. The mouse and human ob genes have 84 percent homology. The gene codes for a secreted protein of 167 amino acids. Leptin is a member of the cytokine family, and its receptor (LEPR) has similarities to the gp130 group of cytokine receptors.

There are at least six isoforms of LEPR (LEPR-a to -f) [5], and all the isoforms are encoded by LEPR gene. The short isoform of the receptor, which is present in several tissues, serves to transport leptin into the brain. There is also a circulating form of the LEPR (LEPR-e) that binds leptin, functions as a leptin-binding protein, and may modulate its action [6].

The LEPR-b receptor is the "longest form," and in most of the cases, mutations in this isoform cause severe obesity. This form of the receptor is located in several organs but, most importantly, areas of the brain, including hypothalamic and other brainstem nuclei. A number of pathogenic mutations have been reported in both the LEP and LEPR [7], which can lead to obesity. LEPR-b is also expressed in cells of the immune system and regulates immune function, most importantly, Type 1/Type 2 T helper (Th1/Th2) cells balance. It is also expressed in the hypothalamic-pituitary-gonadal axis, where it contributes to the regulation of reproductive function.

                
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Literature review current through: Oct 2017. | This topic last updated: May 09, 2017.
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References
Top
  1. Procaccini C, Jirillo E, Matarese G. Leptin as an immunomodulator. Mol Aspects Med 2012; 33:35.
  2. Gambino YP, Maymó JL, Pérez-Pérez A, et al. 17Beta-estradiol enhances leptin expression in human placental cells through genomic and nongenomic actions. Biol Reprod 2010; 83:42.
  3. Paz-Filho G, Mastronardi CA, Licinio J. Leptin treatment: facts and expectations. Metabolism 2015; 64:146.
  4. Park HK, Ahima RS. Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism 2015; 64:24.
  5. Tartaglia LA, Dembski M, Weng X, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995; 83:1263.
  6. Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem 2004; 50:1511.
  7. Manfredi-Lozano M, Roa J, Ruiz-Pino F, et al. Defining a novel leptin-melanocortin-kisspeptin pathway involved in the metabolic control of puberty. Mol Metab 2016; 5:844.
  8. Karakosta P, Chatzi L, Plana E, et al. Leptin levels in cord blood and anthropometric measures at birth: a systematic review and meta-analysis. Paediatr Perinat Epidemiol 2011; 25:150.
  9. Gautron L, Elmquist JK. Sixteen years and counting: an update on leptin in energy balance. J Clin Invest 2011; 121:2087.
  10. Chan JL, Heist K, DePaoli AM, 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; 111:1409.
  11. 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.
  12. Sienkiewicz E, Magkos F, Aronis KN, et al. Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism 2011; 60:1211.
  13. Matarese G, La Rocca C, Moon HS, et al. Selective capacity of metreleptin administration to reconstitute CD4+ T-cell number in females with acquired hypoleptinemia. Proc Natl Acad Sci U S A 2013; 110:E818.
  14. Chou SH, Chamberland JP, Liu X, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A 2011; 108:6585.
  15. Dardeno TA, Chou SH, Moon HS, et al. Leptin in human physiology and therapeutics. Front Neuroendocrinol 2010; 31:377.
  16. Shetty GK, Matarese G, Magkos F, 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.
  17. Dalamaga M, Chou SH, Shields K, et al. Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic perspectives. Cell Metab 2013; 18:29.
  18. Morton GJ. Hypothalamic leptin regulation of energy homeostasis and glucose metabolism. J Physiol 2007; 583:437.
  19. Triantafyllou GA, Paschou SA, Mantzoros CS. Leptin and Hormones: Energy Homeostasis. Endocrinol Metab Clin North Am 2016; 45:633.
  20. Laque A, Zhang Y, Gettys S, et al. Leptin receptor neurons in the mouse hypothalamus are colocalized with the neuropeptide galanin and mediate anorexigenic leptin action. Am J Physiol Endocrinol Metab 2013; 304:E999.
  21. Weigle DS, Duell PB, Connor WE, et al. Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels. J Clin Endocrinol Metab 1997; 82:561.
  22. 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.
  23. Blüher S, Mantzoros CS. Leptin in humans: lessons from translational research. Am J Clin Nutr 2009; 89:991S.
  24. Chan JL, Matarese G, Shetty GK, et al. Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans. Proc Natl Acad Sci U S A 2006; 103:8481.
  25. 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.
  26. 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.
  27. Moschos S, Chan JL, Mantzoros CS. Leptin and reproduction: a review. Fertil Steril 2002; 77:433.
  28. Chou SH, Mantzoros C. 20 years of leptin: role of leptin in human reproductive disorders. J Endocrinol 2014; 223:T49.
  29. Lyle RE, Kincaid SC, Bryant JC, et al. Human milk contains detectable levels of immunoreactive leptin. Adv Exp Med Biol 2001; 501:87.
  30. Havel PJ. Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis. Exp Biol Med (Maywood) 2001; 226:963.
  31. Mantzoros CS, Ozata M, Negrao AB, 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.
  32. Ducy P, Amling M, Takeda S, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000; 100:197.
  33. Foo JP, Polyzos SA, Anastasilakis AD, et al. The effect of leptin replacement on parathyroid hormone, RANKL-osteoprotegerin axis, and Wnt inhibitors in young women with hypothalamic amenorrhea. J Clin Endocrinol Metab 2014; 99:E2252.
  34. Schett G, Kiechl S, Bonora E, et al. Serum leptin level and the risk of nontraumatic fracture. Am J Med 2004; 117:952.
  35. Thomas T, Burguera B, Melton LJ 3rd, et al. Role of serum leptin, insulin, and estrogen levels as potential mediators of the relationship between fat mass and bone mineral density in men versus women. Bone 2001; 29:114.
  36. Blain H, Vuillemin A, Guillemin F, et al. Serum leptin level is a predictor of bone mineral density in postmenopausal women. J Clin Endocrinol Metab 2002; 87:1030.
  37. Sato M, Takeda N, Sarui H, et al. Association between serum leptin concentrations and bone mineral density, and biochemical markers of bone turnover in adult men. J Clin Endocrinol Metab 2001; 86:5273.
  38. Ruhl CE, Everhart JE. Relationship of serum leptin concentration with bone mineral density in the United States population. J Bone Miner Res 2002; 17:1896.
  39. Blum M, Harris SS, Must A, et al. Leptin, body composition and bone mineral density in premenopausal women. Calcif Tissue Int 2003; 73:27.
  40. Lorentzon M, Landin K, Mellström D, Ohlsson C. Leptin is a negative independent predictor of areal BMD and cortical bone size in young adult Swedish men. J Bone Miner Res 2006; 21:1871.
  41. Farooqi IS, Matarese G, Lord GM, 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.
  42. Ozata M, Ozdemir IC, Licinio J. 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; 84:3686.
  43. Papathanassoglou E, El-Haschimi K, Li XC, 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; 176:7745.
  44. Procaccini C, Pucino V, Mantzoros CS, Matarese G. Leptin in autoimmune diseases. Metabolism 2015; 64:92.
  45. Mantzoros CS, Magkos F, Brinkoetter M, et al. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 2011; 301:E567.
  46. Fiorenza CG, Chou SH, Mantzoros CS. Lipodystrophy: pathophysiology and advances in treatment. Nat Rev Endocrinol 2011; 7:137.
  47. Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004; 351:987.
  48. Licinio J, Caglayan S, Ozata M, 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.
  49. Farooqi IS, Bullmore E, Keogh J, et al. Leptin regulates striatal regions and human eating behavior. Science 2007; 317:1355.
  50. Blüher M, Mantzoros CS. From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century. Metabolism 2015; 64:131.
  51. Hwang JJ, Chan JL, Ntali G, et al. Leptin does not directly regulate the pancreatic hormones amylin and pancreatic polypeptide: interventional studies in humans. Diabetes Care 2008; 31:945.
  52. Chan JL, Stoyneva V, Kelesidis T, et al. Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin. Diabetologia 2006; 49:169.
  53. Farooqi IS, Keogh JM, Kamath S, et al. Partial leptin deficiency and human adiposity. Nature 2001; 414:34.
  54. Clément K, Vaisse C, Lahlou N, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392:398.
  55. Farooqi IS, Wangensteen T, Collins S, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 2007; 356:237.
  56. Coppari R, Bjørbæk C. Leptin revisited: its mechanism of action and potential for treating diabetes. Nat Rev Drug Discov 2012; 11:692.
  57. Quarta C, Sánchez-Garrido MA, Tschöp MH, Clemmensen C. Renaissance of leptin for obesity therapy. Diabetologia 2016; 59:920.
  58. Moon HS, Dalamaga M, Kim SY, et al. Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals. Endocr Rev 2013; 34:377.
  59. Tsoukas MA, Farr OM, Mantzoros CS. Leptin in congenital and HIV-associated lipodystrophy. Metabolism 2015; 64:47.
  60. Lee JH, Chan JL, Sourlas E, 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; 91:2605.
  61. Nagy GS, Tsiodras S, Martin LD, et al. Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin. Clin Infect Dis 2003; 36:795.
  62. Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387:903.
  63. Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341:879.
  64. Moon HS, Matarese G, Brennan AM, et al. Efficacy of metreleptin in obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance. Diabetes 2011; 60:1647.
  65. Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999; 282:1568.
  66. Rosenbaum M, Goldsmith R, Bloomfield D, et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest 2005; 115:3579.
  67. Strohacker K, McCaffery JM, MacLean PS, Wing RR. Adaptations of leptin, ghrelin or insulin during weight loss as predictors of weight regain: a review of current literature. Int J Obes (Lond) 2014; 38:388.
  68. Sahin-Efe A, Polyzos SA, Dincer F, et al. Intracellular leptin signaling following effective weight loss. Metabolism 2015; 64:888.