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Drug Insight: the role of leptin in human physiology and pathophysiology—emerging clinical applications

Nature Clinical Practice Endocrinology & Metabolism volume 2, pages 318–327 (2006)Cite this article

Abstract

Leptin is an adipocyte-secreted hormone with a key role in energy homeostasis. Studies in animal models, in humans with congenital complete leptin deficiency, and observational and interventional studies in humans with relative leptin deficiency (lower than normal leptin levels) have all indicated that leptin regulates multiple physiological functions, primarily in states of energy deficiency. This information led to proof-of-concept clinical trials involving leptin administration to individuals with relative or complete leptin deficiency. These conditions include congenital complete leptin deficiency, due to mutations in the leptin gene, and states of relative leptin deficiency including lipoatrophy and some forms of hypothalamic amenorrhea. Leptin, in replacement doses, normalizes neuroendocrine, metabolic and immune function in patients with these conditions, but further clinical studies are required to determine its long-term efficacy and safety. Management of leptin-deficient states with replacement doses of leptin holds promise as a therapeutic option. In addition, elucidation of the mechanisms underlying leptin resistance, which characterizes hyperleptinemic states such as human obesity and diabetes, might provide novel therapeutic targets for these prevalent clinical problems.

Key Points

  • The main action of leptin is to regulate multiple physiological functions in states of energy deficiency

  • Common forms of human obesity are characterized by leptin resistance; the mechanisms of this resistance are unknown

  • Leptin therapy is useful in complete congenital leptin deficiency and might be useful in the management of states of relative leptin deficiency, such as hypothalamic amenorrhea and lipodystrophy

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Figure 1: The downstream effects of leptin deficiency and excess

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References

  1. Zhang Y et al. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425–432

    Article  CAS  Google Scholar 

  2. Friedman JM and Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395: 763–770

    Article  CAS  Google Scholar 

  3. Heymsfield SB et al. (1999) Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282: 1568–1575

    Article  CAS  Google Scholar 

  4. Mantzoros CS (1999) The role of leptin in human obesity and disease: a review of current evidence. Ann Intern Med 130: 671–680

    Article  CAS  Google Scholar 

  5. Matarese G et al. (2005) Leptin in immunology. J Immunol 174: 3137–3142

    Article  CAS  Google Scholar 

  6. Zhang F et al. (1997) Crystal structure of the obese protein leptin-E100. Nature 387: 206–209

    Article  CAS  Google Scholar 

  7. Licinio J et al. (1997) Human leptin levels are pulsatile and inversely related to pituitary–adrenal function. Nat Med 3: 575–579

    Article  CAS  Google Scholar 

  8. Considine RV et al. (1996) Serum immunoreactive leptin concentrations in normal-weight and obese humans. N Engl J Med 334: 292–295

    Article  CAS  Google Scholar 

  9. Chan JL et al. (2003) The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest 111: 1409–1421

    Article  CAS  Google Scholar 

  10. Kolaczynski JW et al. (1996) Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro. Diabetes 45: 699–701

    Article  CAS  Google Scholar 

  11. Saad MF et al. (1997) Sexual dimorphism in plasma leptin concentration. J Clin Endocrinol Metab 82: 579–584

    CAS  PubMed  Google Scholar 

  12. Rosenbaum M et al. (1996) Effects of gender, body composition, and menopause on plasma concentrations of leptin. J Clin Endocrinol Metab 81: 3424–3427

    CAS  PubMed  Google Scholar 

  13. Lee GH et al. (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379: 632–635

    Article  CAS  Google Scholar 

  14. Elmquist JK et al. (1998) Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol 395: 535–547

    Article  CAS  Google Scholar 

  15. 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: 7001–7005

    Article  CAS  Google Scholar 

  16. Bjorbaek C et al. (1998) Expression of leptin receptor isoforms in rat brain microvessels. Endocrinology 139: 3485–3491

    Article  CAS  Google Scholar 

  17. Schwartz MW et al. (1996) Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med 2: 589–593

    Article  CAS  Google Scholar 

  18. Chan JL et al. (2002) Regulation of circulating soluble leptin receptor levels by gender, adiposity, sex steroids, and leptin: observational and interventional studies in humans. Diabetes 51: 2105–2112

    Article  CAS  Google Scholar 

  19. Ren D et al. (2005) Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice. Cell Metab 2: 95–104

    Article  CAS  Google Scholar 

  20. Sahu A (2003) Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. Front Neuroendocrinol 24: 225–253

    Article  CAS  Google Scholar 

  21. Schwartz MW and Porte D Jr (2005) Diabetes, obesity, and the brain. Science 307: 375–379

    Article  CAS  Google Scholar 

  22. Cowley MA et al. (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411: 480–484

    Article  CAS  Google Scholar 

  23. Pinto S et al. (2004) Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304: 110–115

    Article  CAS  Google Scholar 

  24. Feng N et al. (2005) Co-occurrence of two partially inactivating polymorphisms of MC3R is associated with pediatric-onset obesity. Diabetes 54: 2663–2667

    Article  CAS  Google Scholar 

  25. El-Haschimi K et al. (2003) Leptin resistance—or why leptin fails to work in obesity. Exp Clin Endocrinol Diabetes 111: 2–7

    Article  CAS  Google Scholar 

  26. Hallschmid M et al. (2006) Overweight humans are resistant to the weight-reducing effects of melanocortin4–10 . J Clin Endocrinol Metab 91: 522–525

    Article  CAS  Google Scholar 

  27. Harris RB et al. (1998) A leptin dose–response study in obese (ob/ob) and lean (+/−) mice. Endocrinology 139: 8–19

    Article  CAS  Google Scholar 

  28. Schwartz MW 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

    Article  CAS  Google Scholar 

  29. al Barazanji KA et al. (1997) Effects of intracerebroventricular infusion of leptin in obese Zucker rats. Obes Res 5: 387–394

    Article  CAS  Google Scholar 

  30. Garg A and Misra A (2004) Lipodystrophies: rare disorders causing metabolic syndrome. Endocrinol Metab Clin North Am 33: 305–331

    Article  CAS  Google Scholar 

  31. Shimomura I et al. (1998) Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 12: 3182–3194

    Article  CAS  Google Scholar 

  32. Moitra J et al. (1998) Life without white fat: a transgenic mouse. Genes Dev 12: 3168–3181

    Article  CAS  Google Scholar 

  33. Kim JK et al. (2000) Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 275: 8456–8460

    Article  CAS  Google Scholar 

  34. Gavrilova O et al. (2000) Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 105: 271–278

    Article  CAS  Google Scholar 

  35. Ebihara K et al. (2001) Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes. Diabetes 50: 1440–1448

    Article  CAS  Google Scholar 

  36. Hollander P et al. (2000) A randomized double-blinded placebo-controlled study to determine the effects of subcutaneous recombinant methionyl human leptin on glycemic control in obese subjects with diet-treated type 2 diabetes mellitus. Abstract from the 60th Scientific Sessions of the American Diabetes Association: 2000 June 9–13; San Antonio, TX, USA

    Google Scholar 

  37. Steppan CM et al. (2000) Leptin is a potent stimulator of bone growth in ob/ob mice. Regul Pept 92: 73–78

    Article  CAS  Google Scholar 

  38. Gordeladze JO et al. (2002) Leptin stimulates human osteoblastic cell proliferation, de novo collagen synthesis, and mineralization: impact on differentiation markers, apoptosis, and osteoclastic signaling. J Cell Biochem 85: 825–836

    Article  CAS  Google Scholar 

  39. Cornish J et al. (2002) Leptin directly regulates bone cell function in vitro and reduces bone fragility in vivo. J Endocrinol 175: 405–415

    Article  CAS  Google Scholar 

  40. Ducy P et al. (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100: 197–207

    Article  CAS  Google Scholar 

  41. Takeda S et al. (2002) Leptin regulates bone formation via the sympathetic nervous system. Cell 111: 305–317

    Article  CAS  Google Scholar 

  42. Rahmouni K et al. (2005) Obesity-associated hypertension: new insights into mechanisms. Hypertension 45: 9–14

    Article  CAS  Google Scholar 

  43. Welt CK et al. (2004) Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 351: 987–997

    Article  CAS  Google Scholar 

  44. Farooqi IS et al. (2002) Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 110: 1093–1103

    Article  CAS  Google Scholar 

  45. Moran SA et al. (2004) Changes in body composition in patients with severe lipodystrophy after leptin replacement therapy. Metabolism 53: 513–519

    Article  CAS  Google Scholar 

  46. Chehab FF et al. (1996) Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet 12: 318–320

    Article  CAS  Google Scholar 

  47. Ahima RS et al. (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382: 250–252

    Article  CAS  Google Scholar 

  48. Licinio J et al. (2004) Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA 101: 4531–4536

    Article  CAS  Google Scholar 

  49. Farooqi IS et al. (1999) Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341: 879–884

    Article  CAS  Google Scholar 

  50. Mantzoros CS et al. (1997) 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 82: 1066–1070

    CAS  PubMed  Google Scholar 

  51. Oral EA et al. (2002) Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 87: 3110–3117

    Article  CAS  Google Scholar 

  52. Clement K et al. (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392: 398–401

    Article  CAS  Google Scholar 

  53. Ohtake M et al. (1977) Studies on hypothermia and thyroid function in the obese (ob/ob) mouse. Am J Physiol 233: R110–R115

    CAS  PubMed  Google Scholar 

  54. LaPaglia N et al. (1998) Leptin alters the response of the growth hormone releasing factor–growth hormone–insulin-like growth factor-I axis to fasting. J Endocrinol 159: 79–83

    Article  CAS  Google Scholar 

  55. Dubuc PU (1977) Basal corticosterone levels of young og/ob mice. Horm Metab Res 9: 95–97

    Article  CAS  Google Scholar 

  56. Heiman ML et al. (1997) Leptin inhibition of the hypothalamic–pituitary–adrenal axis in response to stress. Endocrinology 138: 3859–3863

    Article  CAS  Google Scholar 

  57. Heiman ML et al. (1997) Leptin inhibition of the hypothalamic–pituitary–adrenal axis in response to stress. Endocrinology 138: 3859–3863

    Article  CAS  Google Scholar 

  58. Mancuso P et al. (2002) Leptin-deficient mice exhibit impaired host defense in Gram-negative pneumonia. J Immunol 168: 4018–4024

    Article  CAS  Google Scholar 

  59. Loffreda S et al. (1998) Leptin regulates proinflammatory immune responses. FASEB J 12: 57–65

    Article  CAS  Google Scholar 

  60. Caldefie-Chezet F et al. (2003) Leptin regulates functional capacities of polymorphonuclear neutrophils. Free Radic Res 37: 809–814

    Article  CAS  Google Scholar 

  61. Lord GM et al. (1998) Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394: 897–901

    Article  CAS  Google Scholar 

  62. Howard JK et al. (1999) Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J Clin Invest 104: 1051–1059

    Article  CAS  Google Scholar 

  63. Chan JL et al. (2005) 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-α receptor levels in humans with relative leptin deficiency. J Clin Endocrinol Metab 90: 1625–1631

    Article  CAS  Google Scholar 

  64. Canavan B et al. (2005) Effects of physiological leptin administration on markers of inflammation, platelet activation, and platelet aggregation during caloric deprivation. J Clin Endocrinol Metab 90: 5779–5785

    Article  CAS  Google Scholar 

  65. Mantzoros CS et al. (1997) Leptin concentrations in relation to body mass index and the tumor necrosis factor-α system in humans. J Clin Endocrinol Metab 82: 3408–3413

    CAS  PubMed  Google Scholar 

  66. Chan JL et al. (2005) 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 90: 1618–1624

    Article  CAS  Google Scholar 

  67. Farooqi IS and O'Rahilly S (2005) Monogenic obesity in humans. Annu Rev Med 56: 443–458

    Article  CAS  Google Scholar 

  68. Petersen KF et al. (2002) Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 109: 1345–1350

    Article  CAS  Google Scholar 

  69. Fogteloo AJ et al. (2003) 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 16: 109–114

    CAS  PubMed  Google Scholar 

  70. Lejeune MP et al. (2003) Effect of dietary restraint during and following pegylated recombinant leptin (PEG-OB) treatment of overweight men. Int J Obes Relat Metab Disord 27: 1494–1499

    Article  CAS  Google Scholar 

  71. Rosenbaum M et al. (2005) Low dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest 115: 3579–3586

    Article  CAS  Google Scholar 

  72. Miller KK et al. (1998) Decreased leptin levels in normal weight women with hypothalamic amenorrhea: the effects of body composition and nutritional intake. J Clin Endocrinol Metab 83: 2309–2312

    CAS  PubMed  Google Scholar 

  73. Oral EA et al. (2002) Leptin-replacement therapy for lipodystrophy. N Engl J Med 346: 570–578

    Article  CAS  Google Scholar 

  74. Javor ED et al. (2005) Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes 54: 1994–2002

    Article  CAS  Google Scholar 

  75. Ebihara K et al. (2004) Long-term leptin-replacement therapy for lipoatrophic diabetes. N Engl J Med 351: 615–616

    Article  CAS  Google Scholar 

  76. Musso C et al. (2005) 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 54: 255–263

    Article  CAS  Google Scholar 

  77. Grinspoon S and Carr A (2005) Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 352: 48–62

    Article  CAS  Google Scholar 

  78. Lee JH et al. (2006) r-metHuLeptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy (HAART). J Clin Endocrinol Metab in press

  79. Hegyi K et al. (2004) Leptin-induced signal transduction pathways. Cell Biol Int 28: 159–169

    Article  CAS  Google Scholar 

  80. Niswender KD et al. (2004) Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis. Trends Endocrinol Metab 15: 362–369

    Article  CAS  Google Scholar 

  81. Maroni P et al. (2005) Intracellular signal transduction pathways induced by leptin in C2C12 cells. Cell Biol Int 29: 542–550

    Article  CAS  Google Scholar 

  82. Chan JL and Mantzoros CS (2005) Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet 366: 74–85

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by NIH Grant DK-58785. CS Mantzoros is supported by a Bessel Award from the Alexander von Humboldt Foundation.

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  1. AM Brennan is a Clinical Research Fellow and CS Mantzoros is Clinical Research Overseer and an Associate Professor

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  1. the Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Aoife M Brennan & Christos S Mantzoros

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Correspondence to Christos S Mantzoros.

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Christos S Mantzoros has received grant support for clinical research projects from Amgen Inc.

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Brennan, A., Mantzoros, C. Drug Insight: the role of leptin in human physiology and pathophysiology—emerging clinical applications. Nat Rev Endocrinol 2, 318–327 (2006). https://doi.org/10.1038/ncpendmet0196

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