The long-term objective of the application is to address the pandemic of obesity in the U.S. through enhanced understanding of the endocrinology of the adipocyte and its liporegulatory and glucoregulatory roles. We propose to elucidate 1) the physiologic role of leptin, a major adipocyte hormone; 2) the pathway through which it works in obesity to protect against obesity's complications that result from fat accumulation in vital organs; 3) the relationship between leptin and ciliary neurotrophic factor (CNTF), a leptin-like hormone produced in brain and other tissues, including the pancreatic islets; and 4) the mechanism by which adipocytes recruit new adipocytes during overnutrition, thus creating the cellular equipment required for massive obesity. The work will demonstrate that the role of leptin is not to prevent obesity, but rather to regulate fatty acid metabolism throughout the body, protecting against overaccumulation of fat and its metabolic products in nonadipocytes; unfortunately, this protection ultimately wanes and the complications of obesity then ensue. It will enhance our understanding of the pathways through which leptin initially provides such protection, and may uncover new molecular targets for pharmacologic intervention that bypass the sites of resistance to leptin's protective actions. CNTF may be a means of bypassing leptin resistance because we are finding that it has many of the same actions as leptin on fatty acid metabolism and it may mediate certain of leptin's actions. Finally, we propose three independent strategies to identify the factor, called """"""""AMF,"""""""" that causes adipocyte precursor cells to mature into full-fledged adipocytes. We have evidence that this hormone is secreted by adipocytes to recruit precursor cells that then rapidly become new adipocytes. The result is a massive expansion of adipocytes, which is required for severe obesity to develop. Understanding this pathway is the first step in attempting to block the development of this common American health problem.
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