Leptin and the Endocrine Control of Food Intake and Metabolism

Leptin is an adipose tissue hormone that maintains homeostatic control of adipose tissue mass. This endocrine system thus serves a critical evolutionary function by protecting individuals from the risks associated with being too thin (starvation) or too obese (predation). Mutations in leptin or its receptor cause massive obesity in mice and humans, and leptin can effectively treat obesity in leptin deficient patients. The identification of leptin has thus provided a framework for studying the regulation of feeding behavior and the pathogenesis of obesity.

While most obese patients have high endogenous levels of leptin indicating that they are leptin resistant , obese patients with low endogenous levels show robust weight loss with leptin treatment. Leptin also links changes in nutrition to adaptive responses in other physiologic systems with effects on insulin sensitivity, fertility, immune function and neuroendocrine function (among others). Leptin is an approved treatment for generalized lipodystrophy, a condition associated with severe diabetes, and has also shown promise for the treatment of other types of diabetes and for hypothalamic amenorrhea, an infertility syndrome in females. Studies of leptin gene regulation also suggest that leptin should be an effective treatment for the subset of obese patients with low endogenous levels of the hormone.

The identification of leptin has also advanced our understanding of the neural mechanisms that control feeding. Current research focuses on the function of specific neural populations in the hypothalamus and other brain regions to control feeding behavior and energy balance. The role of these neural populations is being evaluated by identifying molecular markers for specific subpopulations, and evaluating the effect of modulating their activity. In other studies, we are studying the transcriptional mechanisms that regulate leptin gene expression as well as the leptin regulated neural circuits that regulate metabolism.