The cloning of the ob gene and its gene product, leptin, has led to the elucidation of a robust physiologic system that maintains fat stores at a relatively constant level. Leptin is a peptide hormone secreted by adipose tissue in proportion to its mass. Recessive mutations in the leptin gene are associated with massive obesity in mice and humans, establishing a genetic basis for obesity. Leptin circulates in blood and acts on the brain to regulate food intake and energy expenditure. When fat mass falls, plasma leptin levels fall, stimulating appetite and suppressing energy expenditure until fat mass is restored. When fat mass increases, leptin levels increase, suppressing appetite until weight is lost. This system maintains homeostatic control of adipose tissue mass. The discovery of leptin has advanced our understanding of metabolic disease in a number of respects. Its identification has revealed a new endocrine system regulating body weight. This system provides a means by which changes in nutritional state regulate other physiologic systems. A number of leptin deficiency syndromes that are treatable with leptin replacement have been identified. The majority of obese subjects are leptin resistant, which establishes that obesity is the result of hormone resistance. Leptin treatment results in weight loss in a subset of obese patients and can also synergize with other anti-obesity agents to reduce weight in the general population. Leptin provides an entry point for studying a complex human behavior. Finally, this research has established that there is a powerful biological basis for obesity, a fact that is (correctly) changing public perception about the pathogenesis of this medical condition.

Leptin is an adipocyte hormone that functions as an afferent signal in a negative feedback loop regulating body weight1,2,3,4, and acts by interacting with a receptor in the hypothalamus and other tissues5,6. Leptin treatment has potent effects on lipid metabolism, and leads to a large, specific reduction of adipose tissue mass after several days1,4. Here we show that leptin also acts acutely to increase glucose metabolism, although studies of leptin's effect on glucose metabolism have typically been confounded by the weight-reducing actions of leptin treatment, which by itself could affect glucose homoeostasis1,2,3. We have demonstrated acute in vivo effects of intravenous and intracerebroventricular administrations of leptin on glucose metabolism. A five-hour intravenous infusion of leptin into wild-type mice increased glucose turnover and glucose uptake, but decreased hepatic glycogen content. The plasma levels of insulin and glucose did not change. Similar effects were observed after both intravenous and intracerebroventricular infusion of leptin, suggesting that effects of leptin on glucose metabolism are mediated by the central nervous system (CNS). These data indicate that leptin induces a complex metabolic response with effects on glucose as well as lipid metabolism. This response is unique to leptin, which suggests that new efferent signals emanate from the CNS after leptin treatment.