Role of Corepressor Complex in Modulating Pparγ Function in Matured Adipocytes

Obesity has been linked to many chronic diseases, such as insulin resistance, type 2 diabetes mellitus (T2DM), and cardiovascular diseases, therefore it has become a major health issue in westernized countries including Taiwan. Obesity is primarily due to hypertrophy and de novo differentiation of adipocytes in adipose tissue. In particular, hypertrophy of adipocytes leads to malfunction of adipocytes, which includes resistance to hormonal control and elevated secretion of proinflammatory cytokines and chemokines. The increased secretion of proinflammatory cytokines, such as tumor necrosis factor α (TNFα), in turn exacerbates adipocyte dysfunction. Thus to prevent obesity-associated diseases, one approach is to suppress inflammatory response as well as to improve adipocyte function. A key protein at the crossroads of inflammation and adipocyte biology is peroxisome proliferator-activated receptor γ (PPARγ), which controls differentiation of adipocytes and metabolic function of adipocytes, and is also the cellular target of insulin-sensitizing drug thiazolidinediones (TZDs). TZDs are synthetic agonists of PPARγ widely used in treating patients with diabetes. However, several side effects from treating TZDs have been documented, which largely limit the effectiveness of these drugs. Moreover, heterozygous depletion of PPARγ unexpectedly protects mice from high fat-induced insulin resistance, suggesting that full activation of PPARγ may not be the best for therapeutic purpose. Thus, it is important to understand the molecular regulation of PPARγ action, and to develop selective modulators of PPARγ. As a transcriptional factor, PPARγ can be closely regulated by its coregulators, which include the coactivators and corepressors. Recent studies have revealed that in macrophages, insulin-sensitizing effect of PPARγ may involve suppression of proinflammatory gene expression, by recruitment of the corepressor complex that includes corepressor and histone deacetylases (HDACs). However, it remains unknown if the corepressor complex modulates PPARγ actions in adipocytes, and if the same mechanism is utilized in adipocytes. Therefore this grant proposal aims to elucidate the role and mechanism of the corepressor complex in modulating PPARγ actions in two important adipocyte functions, including insulin-stimulated glucose uptake, and PPARγ-mediated suppression of TNFα-induced gene expression and lipolysis. Finally, it has been shown that visceral and subcutaneous fat depots respond differentially to TZD treatment in both patients and rodent models. Therefore we will also examine if the corepressor complex may play any role in such differential fat depot response to TZD in mice. This study will not only give us insight on the molecular mechanisms controlling PPARγ function in mature adipocytes, but also provide better therapeutic approaches in treating the diseases in the future.

Project ID:PC10001-1315
External Project ID:NSC99-2320-B182-020-MY2