Role of Hepatic RNA Silencing in Insulin Resistance and Obesity

项目概要/摘要 生活方式和饮食趋势的急剧变化引发了慢性代谢性疾病在全球范围内的迅速流行。 疾病，包括2型糖尿病（T2 D）和非酒精性脂肪肝疾病（NAFLD/脂肪变性）。需要 T2 D和代谢性疾病的更有效治疗从未如此紧迫。 该提案调查了T2 D是由T2 D的功能失调引起的创新假设。 肝Argonaute 2（Ago 2），RNA诱导沉默复合物（RISC）的主要成分。我们的新型 初步数据表明，肝Ago 2在调节线粒体功能中起着核心作用， T2 D的发病机制在哺乳动物中，有四种Argonaute家族蛋白质在RNA中发挥关键作用 沉默其中，Ago 2独特地具有核酸内切酶活性，这对于细菌的生物发生是至关重要的。 特异性miRNA和mRNA切割。在肝Ago 2缺陷状态下， 已知损害葡萄糖代谢，被选择性抑制，而mRNA增强 线粒体功能增强。有趣的是，我们的初步结果表明，二甲双胍治疗 诱导与其核酸内切酶活性相关的Ago 2功能变化。这些初步数据表明 肝脏Ago 2在调节葡萄糖稳态中的独特和关键作用，使我们假设， Ago 2通过miRNA生物合成和RNA沉默调节肝脏中的葡萄糖和脂质代谢， 影响线粒体功能此外，我们假设Ago 2介导的RNA沉默的增加有助于 肝脂肪变性和胰岛素抵抗，降低Ago 2功能介导的治疗效果 二甲双胍。 本研究将：（1）确定T2 D中重要的Ago 2内切酶活性 发病机制;（2）分析Ago 2在二甲双胍改善糖代谢的治疗作用中的作用 在T2 D中;（3）描绘在T2 D和二甲双胍血糖控制中至关重要的Ago 2依赖性mRNA沉默 行动上 本申请的目的是获得对肝Ago 2-β受体的作用的清楚的机制理解。 miRNA轴在T2 D的发病机制和治疗中的作用。该计划的长期目标是确定 T2 D的新预防和治疗策略。

Project Summary/Abstract Drastic changes in lifestyle and dietary trends have triggered a rapid, worldwide epidemic of chronic metabolic diseases including type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD/steatosis). The need for more effective treatments of T2D and metabolic diseases has never been more urgent. This proposal investigates the innovative hypothesis that T2D results from deregulated function of hepatic Argonaute 2 (Ago2), a main component of the RNA-induced silencing complex (RISC). Our novel preliminary data indicates hepatic Ago2 plays a central role in regulating mitochondrial function in the pathogenesis of T2D. In mammals, there are four Argonaute family proteins that play crucial roles in RNA silencing. Among them, Ago2 uniquely possesses endonuclease activity that is critical for the biogenesis of specific miRNAs and for mRNA cleavage. In the hepatic Ago2-deficient state, expressions of miRNAs, which are known to impair glucose metabolism, are selectively suppressed, whereas mRNAs enhancing mitochondrial function are increased. Intriguingly, our preliminary results identified that metformin treatment induces Ago2 functional changes associated with its endonuclease activity. These preliminary data suggest unique and pivotal roles for hepatic Ago2 in regulating glucose homeostasis, leading us to hypothesize that Ago2 regulates glucose and lipid metabolism in the liver through miRNA biogenesis and RNA silencing that affects mitochondrial function. Further, we hypothesize that increased Ago2-mediated RNA silencing contribute to hepatic steatosis and insulin resistance, and decreased Ago2 function mediates the therapeutic effect of metformin. Studies in this proposal will: (1) determine the Ago2 endonuclease activity important in T2D pathogenesis; (2) dissect Ago2 function in the therapeutic effect of metformin for improved glucose metabolism in T2D; (3) delineate Ago2-dependent mRNA silencing critical in glycemic control in T2D and in metformin's action. The goal of this application is to gain a clear mechanistic understanding of the role of the hepatic Ago2- miRNA axis in the pathogenesis and in the treatment of T2D. The long-term goal of this program is to identify novel preventive and therapeutic strategies for T2D.