The nuclear hormone receptor PPAR_/is a critical regulator of adipocyte differentiation and glucose metabolism, and hence a potential link between obesity and diabetes. PPARgamma, activity is regulated allosterically by activating ligands such as thiazolidinedione (TZD) antidiabetic drugs as well as by phosphorylation, which inhibits PPARgamma, activity. A major goal of this laboratory is to understand the relationships between regulation of PPARgamma, activity, adipogenesis, and insulin resistance.
Specific Aim 1 is to determine the physiological role of PPARgamma phosphorylation. We hypothesize that phosphorylation regulates cell- and tissue-specificity of PPARgamma activity. Preliminary evidence indicates that mice whose PPARgamma prevent cannot be phosphorylated (S 112A) are protected from diet-induced insulin resistance. The metabolic effects of PPARgamma phosphorylation will be further dissected by comparing S112A mice with mice whose PPARgamma is mutated to mimic the less active, phosphorylated state (S 112D) in different genetic backgrounds and on TZD therapy.
Specific Aim 2 is to determine the effects of PPARgamma phosphorylation on adipogenesis. We will test the hypothesis that phosphorylation of PPARgamma by plays a physiological role in adipogenesis by studying fibroblasts from S112A and S 112D mutant mice. These models are ideal for exploring the putative role of PPARgamma phosphorylation in the regulation of adipogenesis by cytokines and growth factors. We are also interested in adipocyte target genes that contribute to insulin sensitization by PPARgamma ligands. We have identified glycerol kinase (GyK) as a novel adipocyte target of PPARgamma ligands.
In Specific Aim 3, we will determine the metabolic consequences of GyK induction in adipose tissue. We hypothesize that induction of GyK contributes to reduction in serum FFA levels and thereby to insulin sensitivity caused by TZD treatment. This will be directly tested by expressing GyK in adipose tissue of transgenic mice, whose glucose and lipid homeostasis will characterized. Finally, in Specific Aim 4, in which we will determine mechanisms by which PPARgamma activation selectively modulates adipoeytes gene expression. GyK induction is TZD-dependent, whereas the PPARgamma target aP2 is induced in the same adipocytes without endogenous ligand. We will use molecular and cellular techniques to test the hypothesis that the difference between adipocyte aP2 and GyK regulation is due to the PPARgamma binding sites, leading to differential cofactor recruitment or histone modification. These studies have important implications for designing selective PPARgamma, modulators (SPPARMs) that improve insulin sensitivity with fewer side effects. Together, this proposal addresses major questions about the molecular mechanisms underlying PPARgamma regulation of gene expression and metabolism, and will provide new understanding of obesity and type 2 diabetes, which are epidemic in our society.
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