Role of corepressors in the adipocyte

描述（由申请人提供）：噻唑烷二酮类药物用于治疗2型糖尿病，以提高胰岛素敏感性，并作为核受体PPARgamma的配体。噻唑烷二酮与PPARgamma的结合导致共激活剂向PPARgamma- rxr复合物募集。在没有配体或拮抗剂的情况下，许多核激素受体会招募一类额外的蛋白质，称为辅抑制因子。两种主要的核受体辅抑制因子是类视黄醇和甲状腺激素受体（SMRT）的沉默介质和核受体辅抑制蛋白（NCoR）。SMRT和NCoR通过募集组蛋白去乙酰化酶复合物介导转录活性的抑制，并以与共激活剂相反的方式起作用。我们已经证明SMRT和NCoR抑制PPARgamma的作用并在脂肪形成中发挥作用。然而，核受体辅抑制因子在脂肪细胞功能和分化中的确切作用尚不清楚。此外，由于缺乏合适的动物模型，这些蛋白质在体内不同组织中的功能仍然不清楚。拟议的实验将确定SMRT和NCoR调节脂肪细胞功能、脂肪细胞胰岛素信号传导和脂肪因子产生的能力。腺病毒介导的RNA干扰系统将被设计用于降低3T3-L1细胞在不同分化时间点的辅抑制素水平。此外，将开发一种脂肪细胞特异性敲除辅助抑制因子SMRT的方法，以检查辅助抑制因子在体内脂肪细胞中的作用。预计对脂肪细胞功能的协同抑制作用的研究将有助于更好地理解调节脂肪细胞作用的力量平衡以及肥胖和胰岛素抵抗的发展。

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.