Topic: Leptin

A mouse (left) with a defect in the ob gene that encodes for leptin can weigh three times as much as a normal mouse.

Leptin is a hormonal signal made by the body's fat cells that regulates food intake and energy expenditure. Leptin plays a key role in regulating appetite and body weight and it and its receptor are key components of a physiologic system that maintains constancy of weight in each individual over time. When an individual gains or loses weight, this system activates a potent biologic force that resists weight change by either increasing or decreasing the basic drive to eat. Differences in this molecular system, which is composed of many other factors, also explain why some people are prone to obesity while others are not.

Leptin is encoded by a gene called obese (ob). Studies at Rockefeller have shown that mice which are genetically altered to lack ob, and thus do not produce leptin, are massively obese, weighing as much as three times as normal. Moreover, mice that are injected with synthetic leptin become more active and lose weight. Human studies have confirmed the importance of the hormone: people lacking leptin eat copious amounts and are massively obese. Leptin treatment of these individuals, meanwhile, leads to substantial weight loss. Similar effects have been observed after leptin treatment of humans with leptin mutations, who are also massively obese prior to treatment. However mutations in the leptin gene are rare and most obese patients actually have high levels of leptin and are resistant to it. Ongoing studies seek to explain why some people are leptin sensitive and lean and others are leptin resistant and obese.

The discovery of leptin, from the Greek work leptos, or thin, as well as the discovery of the ob gene, was made by Rockefeller University's Jeffrey Friedman and colleagues in 1994. Prior to Friedman's research, little was known about the components of the biologic system that controls weight, and many scientists questioned the very existence of such a homeostatic system. The discovery of leptin provided a genetic explanation of obesity and has challenged the popular belief that lack of willpower causes people to be obese. In addition to its effects on weight, leptin also has powerful effects on reproduction, metabolism, other endocrine systems and even immune function. Leptin also has provided a new means for treating several metabolic conditions, such as some forms of diabetes, and for women with hypothalamic amenorrhea. More recently, leptin in combination with amylin, another hormone, has shown promise for treating obesity in the general population. Further studies of the efficacy and safety of the leptin-amylin combination are ongoing at a number of sites (however, not at Rockefeller University).