Analysis of Lipolytic Trafficking in Muscle

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DESCRIPTION (provided by applicant): The storage and mobilization of lipids are fundamental cellular processes. In mammals, adipose tissue functions as a specialized lipid buffer that stores excess energy as triglyceride for systemic mobilization as free fatty acids (FFA). Nonetheless, virtually all cells have the ability to store and mobilize FFA; indeed, for some tissues FFA can provide the major source of metabolic energy. Excessive FFA can disrupt cellular function in a process that has been termed 'lipotoxicity," which is thought to be a major means by which obesity contributes to diabetes and cardiovascular disease. In theory, lipotoxicity can be brought about by excessive systemic supply of FFA from adipose tissue, or by an imbalance in FFA storage and mobilization in peripheral tissues. Thus, a mechanistic understanding of how cells assimilate, mobilize and channel FFA is an important biological question with broad implications for health and disease. Our long term goal is to provide a mechanistic understanding of cellular lipolysis so as to identify novel points of therapeutic intervention for the treatment of obesity and diabetes. We hypothesize that intracellular lipolysis in muscle is controlled by the orderly trafficking of specific proteins at the surface of specialized lipid droplets. This work will define the intracellular sites where lipolysis occurs, test specific models of dynamic protein- protein interactions, and determine the functional impact of those interactions in vitro and in vivo.