A Causal Role for Nuclear Receptor Pathways in Insulin Resistance

 描述（由申请人提供）：胰岛素抵抗是2型糖尿病的必要条件，也是肥胖、脂肪代谢障碍、炎症、类固醇使用、严重 疾病，以及各种其他条件和侮辱。长期以来，为什么如此多的完全不同的刺激都导致相同的临床表型一直是一个谜。此外，大多数关于胰岛素抵抗的研究都假设了细胞质、线粒体和ER相关途径的作用，如毒性脂质中间体、氧化应激或ER应激。尽管有强有力的证据表明转录和表观遗传因素一定在起作用，但很少有研究关注胰岛素抵抗的核机制。我们使用地塞米松（Dex）或TNFα（TNF）处理的3 T3-L1脂肪细胞中胰岛素抵抗的比较模型，以确定导致这种疾病的新途径。综合转录，表观基因组学和计算分析已经确定了两个重要的核激素受体：TNF介导的糖皮质激素受体（GR）作用和维生素D受体（VDR）。该提案将确定GR和VDR在小鼠和人类细胞中促进胰岛素抵抗的机制，并将确定介导这种效应的特定基因靶点。重要的是，它还将使用功能获得和功能丧失方法在体内验证我们的发现。总之，这一建议有可能表征两种新的途径胰岛素抵抗与固有的治疗潜力。

 DESCRIPTION (provided by applicant): Insulin resistance is a sine qua non of Type 2 diabetes and a frequent complication of obesity, lipodystrophy, inflammation, steroid use, critical illness, and a variety of other conditions and insults. It has long been a mystery how so many profoundly different stimuli all result in the same clinical phenotype. Furthermore, most studies of insulin resistance have posited the action of cytoplasmic, mitochondrial, and ER-related pathways, such as toxic lipid intermediates, oxidative stress, or ER stress. Very few studies have focused on nuclear mechanisms of insulin resistance, despite strong evidence that transcriptional and epigenetic factors must be in play. We have used a comparative model of insulin resistance in 3T3-L1 adipocytes treated with dexamethasone (Dex) or TNFα (TNF) to identify novel pathways that cause this disorder. Integrated transcriptional, epigenomic, and computational analysis have identified two nuclear hormone receptors as important; TNF-mediated glucocorticoid receptor (GR) action and the vitamin D receptor (VDR). This proposal will identify the mechanisms by which the GR and VDR promote insulin resistance in both murine and human cells, and will identify the specific gene targets that mediate this effect. Importantly, it will also validate our findings in vivo, using both gain- and loss-of-function approaches. Taken together, this proposal has the potential to characterize two novel pathways of insulin resistance with inherent therapeutic potential.