This application proposes that experiments that will contribute to our understanding of the causes of obesity and Type 2 diabetes and could improve our ability to treat these conditions. Toward that end we propose to establish the precise sites of action of the hormone leptin and the molecular mechanisms that account for its novel metabolic effects. Leptin is a hormone that is produced by adipose tissue and sends nutritional signals to a number of other tissues including brain. Leptin functions as an afferent signal in a feedback loop that maintains constancy of the total body fat mass. A mutation in the leptin gene in ob/ob mice or some human subjects leads to severe obesity. In most cases, obesity is the result of a relative insensitivity to the effects of this hormone. In leptin sensitive animals, this hormone exerts a number of novel metabolic effects. It reduces the cellular levels of lipid and improves insulin action. Leptin is also capable of correcting the severe diabetes that develops in human subjects with lipodystrophy (the absence of fat tissue). This effect is the result at least in part, of the ability of leptin to reduce lipid content in liver and other tissues. In recent work we have shown that leptin's effects on cellular lipid content and body weight is the result of its ability to repress SCD1, an enzyme that converts saturated fatty acids to mono-unsaturated fatty acids. In this application, we propose to follow up on these results by 1) using modern methods in genetics to study the effects of selective ablation of the receptor for leptin in a variety of tissues, 2) study the mechanism by which repression of SCD1 reduces body weight and cellular lipid content 3) assessing the role of other gene products in mediating the biologic response to leptin 4) studying the mechanism by which leptin regulates SCD1 and other genes. This latter effort will make use of biologic and computational approaches. In aggregate, these studies will add to our understanding of the molecular mechanisms regulating body weight and metabolism and potentially lead to new therapeutic approaches. ? ?
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