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，以增强胰岛素敏感性，并作为核受体PPAR伽马的配体。噻唑烷二酮与PPARGamma的结合导致共激活剂招募到PPARGamma-RXR复合体。许多核激素受体在缺乏配体或拮抗剂存在的情况下，招募一类额外的蛋白质，称为辅阻遏物。两种主要的核受体辅阻遏物是维甲酸和甲状腺激素受体的沉默介体(SMRT)和核受体辅阻遏物蛋白(NCoR)。SMRT和NCoR通过招募组蛋白脱乙酰酶复合体来调节转录活性的抑制，并以与辅助激活因子相反的方式发挥作用。我们已经证明SMRT和NCoR抑制PPAR的伽马作用，并在脂肪形成中发挥作用。然而，核受体辅阻遏物在脂肪细胞功能和分化中的确切作用仍不清楚。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和脂肪因子产生的能力。将设计一种腺病毒介导的RNA干扰系统，以降低3T3-L1细胞在不同分化时间点的辅阻遏子水平。此外，将开发一种针对脂肪细胞的辅抑制子SMRT敲除，以检查体内脂肪细胞中辅抑制子的作用。预计对脂肪细胞功能的辅抑制子作用的研究将有助于更好地了解调节脂肪细胞活动的力量的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.