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Physiology of leptin

Author
George A Bray, MD
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, neuroendocrine function, and immune function [1]. 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) [2]. These mice, which grew poorly and had infertility due to gonadal hypofunction, were used for cloning studies that resulted in the isolation of leptin [3]. 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 [4]. 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) [5]. 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 [4].

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 [8]. 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 [9], 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 [11]. Leptin mRNA and secretion by adipocytes declines rapidly during starvation [12]. 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 [12]. Transport of leptin across the blood-brain barrier may control the entrance of leptin into the brain and modulate its action on food intake.

            

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Literature review current through: Nov 2016. | This topic last updated: Mon Aug 11 00:00:00 GMT+00:00 2014.
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