The long-term goal of these studies is to find new therapeutic strategies for the treatment of obesity. In the previous funding period, we showed that leucine is a direct acting nutrient signal that robustly stimulates a fundamental growth-stimulating pathway in adipose tissue involving the mammalian target of rapamycin (mTOR). MTOR and the substrates it regulates have critical roles in translational regulation of protein synthesis, adipocyte differentiation, leptin, de novo lipogenesis, cell cycle progression, hypertrophic growth of post-mitotic tissues and tissue morphogenesis. In view of the emerging obesity epidemic it is important to understand how nutrient signals such as leucine impact adipose tissue physiology. The proposed studies will focus on leucine regulation of protein synthesis and the mTOR signaling pathway in adipocytes. Two fundamental questions drive the proposed studies. How does leucine bring about its effects? What are the physiological roles of mTOR and the leucine signal to protein synthesis in adipose tissue? We will address these questions in three specific aims. (1) It has been proposed that signals arising from mitochondrial metabolism of leucine are required for mTOR activation. To address this possibility, a genetic approach will be used to block the first step in leucine metabolism selectively in adipose tissue in order to examine the consequences on leucine regulation of protein synthesis and mTOR signaling. (2) To test the hypotheses that leucine signaling is different in animals that are obese or have a genetic propensity to become obese and; greater in visceral (intraabdominal) adipose tissue depots, known to represent a greater risk for obesity-associated co-morbidities, compared to subcutaneous adipose tissue depots; and to examine the mechanism of such differences. (3) Biochemical, transgenic and proteomic approaches will be used to uncover the physiological role of mTOR and its role in leucine signaling. The proposed studies will elucidate how leucine regulates mTOR and the roles of leucine stimulation of mTOR in adipose tissue physiology and obesity.
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