Physiology of leptin
- George A Bray, MD
George A Bray, MD
- Boyd Professor Emeritus, Pennington Biomedical Research Center/Louisiana State University
- Professor of Medicine Emeritus, Louisiana State University Health Science Center
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, neuroendocrine function, and immune function . Leptin was discovered as a result of studies of ob/ob mice, a strain of hyperphagic obese mice that lost weight when their circulation was attached to normal mice (parabiosis) . These mice, which grew poorly and had infertility due to gonadal hypofunction, were used for cloning studies that resulted in the isolation of leptin . Humans with leptin deficiency were soon identified. Administration of leptin to leptin-deficient humans or animals resulted in a marked decrease in food intake, weight loss to nearly normal levels, and improved growth . Other obese rodents, diabetic (db/db) mouse and fatty (Zucker) rat, and humans have genetic defects in the LEPR [5-7]. These findings demonstrated that a molecular defect could produce obesity in animals and human beings and gave hope that human obesity might result from a defect in this gene. (See "Pathogenesis of obesity".)
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 has similarities to the gp130 group of cytokine receptors. There are at least five forms of the leptin receptor (LEPR) . The most widely distributed is the short form of the receptor, which is present in most tissues and may serve to transport leptin into the brain. The long form of the receptor is located in areas where leptin is thought to act, including hypothalamic and other brainstem nuclei. There is also a circulating form of the LEPR that binds leptin and may modulate its action .
The signaling system on the intracellular portion of the LEPR belongs to the janus kinase signal transduction and translation system (JAK STAT). It is the Stat-3 form of the STAT system that is thought to carry out the intracellular signaling . The suppressors of cytokine signaling (SOCS3) are a counter-regulatory system that inhibits leptin. Protein tyrosine phosphatase 1B is also an inhibitor of LEPR signaling, and its deficiency protects from leptin resistance in fat fed animals.
BIOLOGY OF LEPTIN
Leptin is produced primarily in fat cells and also in the placenta, where it is regulated by estradiol , and the stomach, where it is released into the intestine and then absorbed [4,10]. Large fat cells produce more leptin than small ones, and serum leptin concentrations are highly correlated with body fat content in newborn infants, children, and adults and predict birth weight . Leptin mRNA and secretion by adipocytes declines rapidly during starvation . These processes are stimulated by insulin, glucocorticoids and tumor necrosis factor-alpha, another product of adipocytes. These observations suggest that leptin signals the brain about the quantity of stored fat.
Regulation of feeding by leptin — Food intake is reduced by systemic leptin administration in normal-weight experimental animals, but the response decreases as the animals become obese. However, when leptin is injected into the ventricular system of the brain of obese animals, they remain responsive . Transport of leptin across the blood-brain barrier may control the entrance of leptin into the brain and modulate its action on food intake.
- Procaccini C, Jirillo E, Matarese G. Leptin as an immunomodulator. Mol Aspects Med 2012; 33:35.
- Coleman DL. Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 1973; 9:294.
- Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372:425.
- 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.
- Tartaglia LA, Dembski M, Weng X, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995; 83:1263.
- 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.
- 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.
- Lavens D, Piessevaux J, Tavernier J. Review: Negative regulation of leptin receptor signalling. Eur Cytokine Netw 2006; 17:211.
- 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.
- Cammisotto P, Bendayan M. A review on gastric leptin: the exocrine secretion of a gastric hormone. Anat Cell Biol 2012; 45:1.
- 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.
- Gautron L, Elmquist JK. Sixteen years and counting: an update on leptin in energy balance. J Clin Invest 2011; 121:2087.
- Morton GJ. Hypothalamic leptin regulation of energy homeostasis and glucose metabolism. J Physiol 2007; 583:437.
- 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.
- 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.
- 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.
- Lyle RE, Kincaid SC, Bryant JC, et al. Human milk contains detectable levels of immunoreactive leptin. Adv Exp Med Biol 2001; 501:87.
- 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.
- 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.
- Schorr U, Blaschke K, Turan S, et al. Relationship between angiotensinogen, leptin and blood pressure levels in young normotensive men. J Hypertens 1998; 16:1475.
- Hirose H, Saito I, Tsujioka M, et al. The obese gene product, leptin: possible role in obesity-related hypertension in adolescents. J Hypertens 1998; 16:2007.
- Agata J, Masuda A, Takada M, et al. High plasma immunoreactive leptin level in essential hypertension. Am J Hypertens 1997; 10:1171.
- Hariri M, Ghiasvand R, Shiranian A, et al. Does omega-3 fatty acids supplementation affect circulating leptin levels? A systematic review and meta-analysis on randomized controlled clinical trials. Clin Endocrinol (Oxf) 2015; 82:221.
- Bodary PF, Westrick RJ, Wickenheiser KJ, et al. Effect of leptin on arterial thrombosis following vascular injury in mice. JAMA 2002; 287:1706.
- 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.
- Steppan CM, Crawford DT, Chidsey-Frink KL, et al. Leptin is a potent stimulator of bone growth in ob/ob mice. Regul Pept 2000; 92:73.
- Hamrick MW, Pennington C, Newton D, et al. Leptin deficiency produces contrasting phenotypes in bones of the limb and spine. Bone 2004; 34:376.
- Schett G, Kiechl S, Bonora E, et al. Serum leptin level and the risk of nontraumatic fracture. Am J Med 2004; 117:952.
- 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.
- 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.
- 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.
- 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.
- Blum M, Harris SS, Must A, et al. Leptin, body composition and bone mineral density in premenopausal women. Calcif Tissue Int 2003; 73:27.
- 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.
- 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.
- 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.
- 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.
- Mantzoros CS, Magkos F, Brinkoetter M, et al. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 2011; 301:E567.
- Farooqi IS, Keogh JM, Kamath S, et al. Partial leptin deficiency and human adiposity. Nature 2001; 414:34.
- 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.
- Farooqi IS, Bullmore E, Keogh J, et al. Leptin regulates striatal regions and human eating behavior. Science 2007; 317:1355.
- 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.
- Roth JD, Roland BL, Cole RL, et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc Natl Acad Sci U S A 2008; 105:7257.
- Ravussin E, Smith SR, Mitchell JA, et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring) 2009; 17:1736.
- 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.
- 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.