ENDOGENOUS LIGANDS FOR PPAR-GAMMA

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The nuclear hormone receptor, peroxisome proliferator activated receptor gamma (PPAR gamma) is expressed preferentially in adipose tissue, where it is responsible for coordinating adipocyte gene expression and differentiation. Adipocytes are an important component of the energy equilibrium of vertebrate organisms; providing an abundant energy reserve upon demand. The excessive development of adipose tissue results in obesity, which is a significant risk factor for non-insulin- dependent diabetes mellitus and a number of cardiovascular diseases. Fatty acids, such as arachidonic acid (AA) are known to induce adipogenesis, however their mechanism of action is not known. Recently, an AA metabolite, 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), has been shown to be a ligand for PPAR gamma. Whether 15d-PGJ2 is the physiologically relevant ligand for PPAR gamma is not certain and thus raises the possibility that other lipid metabolites may serve as endogenous ligands for PPAR gamma. Therefore, the primary objective of this research proposal is to determine endogenous ligand(s) for PPAR gamma and to investigate the physiological and biochemical mediators of their release. The specific aims involve: 1; Characterization of the major fatty acids/metabolites in 3T3-F442A preadipocytes. 2. Elucidation of the fatty acids/metabolites that stimulate PPAR gamma and induce adipocyte differentiation. 3. Determination as to whether agonists known to induce adipocyte differentiation (eg. IGF-1, glucocorticoids), exert their actions via the release of endogenous fatty acids/metabolites, and if so investigate the second messenger systems they employ.