Role of corepressors in the adipocyte

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DESCRIPTION (provided by applicant): Thiazolidinediones are used as medications in the treatment of Type 2 diabetes mellitus to enhance insulin sensitivity, and serve as ligands for the nuclear receptor PPARgamma. The binding of thiazolidinediones to PPARgamma results in the recruitment of coactivators to the PPARgamma-RXR complex. Many nuclear hormone receptors recruit an additional class of proteins, termed corepressors, in the absence of ligand or the presence of antagonist. The two main nuclear receptor corepressors are the silencing mediator of retinoid and thyroid hormone receptors (SMRT) and the nuclear receptor corepressor protein (NCoR). SMRT and NCoR mediate repression of transcriptional activity by recruiting a histone deacetylase complex, and act in an opposing fashion to coactivators. We have shown that SMRT and NCoR repress PPARgamma action and play a role in adipogenesis. However, the precise roles of nuclear receptor corepressors in adipocyte function and differentiation remain unclear. In addition, the function of these proteins in distinct tissues in vivo remains obscure because of a lack of suitable animal models. The proposed experiments will define the ability of SMRT and NCoR to modulate adipocyte function, adipocyte insulin signaling, and adipokine production. An adenoviral-mediated RNA interference system will be designed to reduce corepressor levels in 3T3-L1 cells at different time points of differentiation. In addition, an adipocyte-specific knock-out of the corepressor SMRT will be developed to examine the effects of the corepressors in the adipocyte in vivo. It is anticipated that an examination of corepressor action on adipocyte function will allow for a greater understanding of the balance of forces regulating adipocyte action and the development of obesity and insulin resistance.