Elsevier

The Lancet

Volume 351, Issue 9104, 7 March 1998, Pages 737-742
The Lancet

Review
Leptin

https://doi.org/10.1016/S0140-6736(97)06348-4Get rights and content

Summary

Leptin (from the Greek leptos=thin) was identified only 3 years ago. It has attracted huge attention both scentifically, with more than 600 publications, and in the media, where this protein has been portrayed as the way to a cure for obesity. Indeed, leptin was first described as an adipocyte-derived signalling factor, which, after interaction with its receptors, induced a complex response including control of bodyweight and energy expenditure. Leptin seems in addition to its role in metabolic control to have important roles in reproduction and neuroendocrine signalling. Human obesity is a complex disorder, with many factors playing a part; the pathophysiology of leptin is not as simple as it seems to be in rodent models of obesity.

Section snippets

Leptin, cytokine acting as adipostat

Leptin, a 167 aminoacid protein transcribed from the ob gene, was originally cloned in the mouse during research directed at identifying the molecular defect in an obesityprone strain, the ob/ob mouse.7 The name leptin is derived from the Greek leptos which means thin. The human leptin gene is on chromosome 7q31; its DNA has more than 15 000 base-pairs and there are three exons, the major coding sites driving protein synthesis. Leptin is mainly produced in white adipose tissue; very small

Sites of action

Several lines of evidence suggest that the hypothalamus is a critical target for the satiety effects leptin. Induction of obesity follows experimental lesions of the ventromedial hypothalamus; leptin has a more potent anorectic effect when administered centrally rather than peripherally;8, 11 the ob protein is specifically bound to hypothalamic plasma membranes;11 and leptin receptor is expressed in the hypothalamus.16, 30 Leptin is transported through the blood/brain barrier via a saturable

Leptin as signal of plenty

From the evidence summarised above came the suggestion that leptin has an adipostatic function and can decrease bodyweight in obesity. Several observations, however, question whether prevention of obesity or weight gain is leptin's prime or only function.

Mutations in the leptin gene in human obesity have proved elusive47, 48 and genetic markers flanking the human OB gene seem to be at best only weakly linked to extreme obesity.48, 49, 50 This is not too surprising, given the polygenic and

A regulatory role, again?

Most clinical studies of leptin's role in the developing of obesity have indicated an association between established obesity and high levels of leptin mRNA or protein. Conclusions based on steady-state data reflecting the relation between an established obesity and leptin levels are bound to be incomplete and will miss any regulatory or dynamic effects that leptin might have in the early development of changes in bodyweight. Studies of this issue do suggest that there is an important

Regulation of leptin expression

In view of the important potential regulatory role of leptin, it is important to understand the genetic and environmental factors contributing to the variability in basal leptin mRNA and plasma levels. Since leptin expression is restricted to adipose tissue and since basal leptin levels are closely related to triglyceride stores and adipose tissue mass, it was important to define the molecular mechanism underlying adipose-tissue-specific gene expression. The cloning and initial characterisation

Leptin's future

Leptin was first described as an adipocyte-derived signalling factor which, after interaction with specific receptors, induces a pleiotropic response including control of bodyweight and energy expenditure. Although research has moved ahead rapidly there are still more questions about leptin than there are definite answers. We should soon have the outcome of clinical studies, using leptin or leptinomimetic agents, designed to identify effects on bodyweight and metabolic control in man. Also

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