SKELETAL MUSCLE DE NOVO LIPOGENESIS AND THE GLUCOSE-FATTY ACID CYCLE

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DESCRIPTION (provided by applicant): This proposal aims to provide a foundation to prepare the applicant as an independent scientist. The principal investigator (PI) has previously undergone PhD training in the field of muscle and exercise physiology and completed the first two years as a postdoctoral trainee under the mentorship of Dr. Clay Semenkovich. Dr. Semenkovich is a recognized leader in physiology and metabolism and has a track record for training successful scientists. The proposed training plan will provide continual refinement of the PI's scientific skills. The PI will also take advantage of the enormous breadth of resources at Washington University. The proposed research seeks to identify the potential roles that de novo lipogenesis plays in skeletal muscle "glucose-fatty acid cycle". In the past few years, the Semenkovich laboratory successfully generated and characterized mice with tissue-specific deletion of fatty acid synthase (FAS) and provided evidence that de novo-generated lipids have distinct signaling roles in multiple tissues. The PI has generated mice with skeletal muscle specific deletion of FAS to study skeletal muscle metabolism in the absence of de novo synthesized fatty acids, a situation that has never been possible. The preliminary evidence suggests that FAS generates PPAR ligands in skeletal muscle. In this application, we will test the hypothesis that FAS is involved in high-fat diet- and exercise-induced skeletal muscle adaptive responses in lipid and glucose metabolism and that this effect is mediated through the activation of PPARs.