Ronald Cohen, MD.

My lab studies the function of corepressors in the adipocyte. The adipocyte is a complex endocrine cell that regulates feeding behavior and insulin sensitivity, and aberrant function of the adipocyte in obesity leads to insulin resistance and potentially to Type 2 diabetes. However, the relationship between adiposity and diabetes is complex; thiazolidinedione (TZD) medications increase fat mass, yet improve insulin sensitivity. Although TZDs serve as agonists for the peroxisome proliferator-activated receptor ? (PPAR?), the exact role of PPAR? and its corepressors in the regulation of insulin action remains unclear.

The two main nuclear receptor corepressors are the nuclear receptor corepressor protein (NCoR) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT). We have shown that SMRT and NCoR repress PPAR? transcriptional activity in 3T3-L1 cells, an in vitro model system to study adipocyte differentiation and function. SMRT, in particular, is recruited to PPAR? via specific residues in its C-terminal interacting domain. Our data suggest that SMRT and NCoR decrease the expression of key adipocyte-specific proteins during adipogenesis, and that endogenous levels of corepressors dictate the ability of cells to respond to TZDs.

We are using in vitro analysis of adipocyte cell lines and isolated murine adipocytes to evaluate corepressor effects on adipogenesis and adipocyte function. In addition, we are developing novel mouse models of corepressor deficiency to dissect the molecular mechanisms underlying the physiology of SMRT and NCoR action in the adipocyte and on insulin sensitivity in vivo. Understanding the roles of corepressors in adipocyte biology is crucial if we are to design novel approaches to the treatment of obesity and type 2 diabetes.