Horowitz Lecture

Leptin is an adipocyte hormone that regulates food intake providing an entry point for studies of the neural regulation of appetite. Leptin is secreted by adipose tissue in proportion to its mass and acts on the hypothalamus to maintain homeostatic control of adipose tissue mass. 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. By such a mechanism total energy stores are stably maintained within a relatively narrow range. The discovery of leptin has thus led to the elucidation of a robust physiologic system that maintains fat stores at a relatively constant level.

Recessive mutations in the leptin gene are associated with massive obesity in mice and some humans and treatment with recombinant leptin markedly reduces food intake and body weight in leptin deficient humans. The low leptin levels in patients with leptin mutations are also associated with multiple abnormalities including infertility, diabetes and immune abnormalities all of which are corrected by leptin treatment. These findings have established important links between energy stores and many other physiologic systems and led to the use of leptin as a treatment for an increasing number of other human conditions including a subset of obesity, some forms of diabetes including lipodystrophy and hypothalamic amennorhea, the cessation of menstruation seen in extremely thin women.  Identification of a physiologic system that controls energy balance establishes a biologic basis for obesity

Current studies seek to identify neurons in higher centers in brain that integrate multiple relevant signals and control whether or not feeding is initiated. Recent studies have explored the relationship between leptin and the reward value of food. In addition, new methods for identifying neurons based on changes in their state of activation or their pattern of projections have been developed as have methods for noninvasively activating cells using radio waves or a magnet. These new approaches are being applied to studies of the neural processes that control feeding, a complex motivational behavior.