PPARgamma is a nuclear receptor whose transcriptional activity is regulated by ligands including endogenous lipid and prostaglandin molecules and synthetic, thiazolidinedione drugs (TZDs). Published evidence from the sponsor's lab indicates that endogenous PPARgamma ligands normally dampen insulin action. In contrast, TZD ligands are potent insulin-sensitizing agents that ameliorate insulin resistance in a variety of disease states in rodents and humans. To understand the etiology of insulin resistance and its associated disease states (e.g. type 2 diabetes, obesity), it is crucial to identify and characterize genes that modulate insulin sensitivity.
The aims of this proposal are to identify ligand-specific, direct and indirect target genes regulated by PPARgamma, characterize the mechanisms by which specific gene promoters are directly PPARgamma-regulated, and screen for PPARgamma-regulated genes that affect insulin action. A large set of PPARgamma-regulated genes have been identified in our lab using DNA microarrays in preliminary studies. The ligand-specific sensitivity of these genes to direct, PPARgamma-regulation will be examined in dose response and time course experiments, coregulator recruitment and histone acetylation studies, and ligand-ligand antagonism studies. Candidate insulin-sensitizing genes, commonly regulated by insulin-sensitizing PPARgamma ligands, will be screened for their ability to mediate insulin action in 3T3-L1 adipocytes. Information regarding the genes that mediate insulin sensitivity and the mechanisms governing their PPARgamma-regulated expression will clarify how insulin action is mediated and expedite the design of improved therapies for insulin-mediated disease.
