From the conceptual basis to the discovery of leptin

Two years ago, the Lasker Award was shared by Douglas Coleman and Jeffrey Friedman for their discovery of leptin, a hormone that exerts a key role in the central regulation of appetite and body weight. Douglas Coleman is recognized as the researcher who raised the hypothesis and predicted that a circulating satiety factor was lacking in the ob/ob mouse, and predicted that this factor acted at the hypothalamic level to modulate food intake. After three decades, in an attempt to identify the genes that were mutated in the ob/ob mouse, Jeffrey Friedman found that the ob gene encodes a protein hormone that reverses obesity and other abnormalities of this genetic rodent model of obesity. This discovery was a landmark event in physiology, and revolutionized our understanding of energy homeostasis. This short review aims to summarize the main steps that lead to the identification of leptin, the product of the ob gene.

► The presence of circulating satiety factor was suggested from parabiosis experiments.
► D. Coleman hypothesized that a circulating factor was lacking in ob/ob mice.
► J. Friedman identified the ob gene encoding leptin that regulates food intake.
► In humans, common obesity is rather associated with a central leptin resistance.
► Beyond its involvement in body weight regulation, leptin has pleiotropic functions.