A new PPG application is proposed to identify and characterize gene networks in adipocytes and macrophages that influence insulin action. A combination of molecular, cellular, genetic and bioinformatics approaches will be used to define the components and behaviors of these networks at a genome-wide scale. The proposed studies will test the hypothesis that macrophage/adipocyte interactions result in altered programs of inflammatory gene expression in both cell types that contribute to insulin resistance. We will further test the hypothesis that PPARy agonists exert insulin-sensitizing effects by counter-regulating feed forward mechanisms that amplify inflammation within obese adipose tissue. Microarray and genome-wide location analysis will be performed to define the roles of NCoR/SMRT corepressor complexes as transcriptional checkpoints in PPARy-, NF-KB-, and AP-1-dependent gene expression and determine the importance of these complexes in mediating anti-inflammatory actions of PPARy agonists. Candidate genes identified by microarray studies and associated bioinformatics approaches will be tested for their pathophysiological roles in high fat diet-induced insulin resistance in mouse models. The results of these studies are likely to lead to new insights into the mechanisms underlying obesity-associated insulin resistance that can be exploited for development of novel therapeutic approaches.
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