Targeting Dynamin-related protein 1-mediated mitochondrial fission to correct insulin resistance in obesity

项目总结 美国成年人的肥胖率(身体质量指数≥30)已接近40%。肥胖是 伴随着许多代谢问题，这些问题导致慢性病的风险显著增加， 如2型糖尿病(T2D)、胰岛素抵抗和心血管疾病。的主要功能之一 肥胖和T2D的一个先兆是骨骼肌中胰岛素作用受损，导致胰岛素抵抗。 因此，发现调节骨骼肌胰岛素敏感性和全身血糖的新靶点 动态平衡是迫切需要的。这样的新靶点可能被开发成胰岛素的新治疗方法。 阻力和T2D。动力蛋白相关蛋白1(Dynamin-Related Protein 1，DRP1)是线粒体分裂的关键调控因子。过份 DRp1的激活导致线粒体的异常分裂，导致线粒体动力学失衡和 功能障碍。我们最近报道，由于肥胖的胰岛素，Drp1在骨骼肌中过度激活 这种过度激活与骨骼肌中胰岛素作用受损呈负相关。在……里面 此外，在高脂饮食导致胰岛素抵抗的动物中，药物或基因抑制DRp1 改善骨骼肌胰岛素作用和全身葡萄糖稳态。然而，更多的研究仍在进行中 需要了解Drp1介导的线粒体分裂对胰岛素的因果贡献 抵抗。我们假设过度的Drp1介导的线粒体分裂与肥胖诱导有关 骨骼肌胰岛素抵抗和抑制骨骼肌Drp1足以改善线粒体 完整性，减少mtROS的产生，并改善胰岛素信号，从而改善骨骼肌胰岛素 抵抗和改善全身血糖动态平衡。在目标1中，我们将利用骨骼肌特有的 Drp1基因敲除小鼠和临床相关的人类骨骼肌细胞培养模型，以及新的 线粒体质量监测工具(PMitoTimer)用于确定Drp1介导的线粒体分裂在糖尿病中的作用 肥胖诱导的骨骼肌胰岛素抵抗的调节。这些研究将确定因果关系 Drp1在肥胖大鼠骨骼肌胰岛素抵抗中的调节作用及其机制 行动。在目标2中，我们将利用Drp1的药理抑制剂来确定其有效性和 靶向Drp1介导的线粒体分裂在减轻肥胖诱导的胰岛素中的作用 抵抗。拟议研究的成功完成将提供对贡献的基本见解 DRp1介导的线粒体分裂在肥胖诱导的胰岛素抵抗和T2D发展中的作用。在……里面 此外，本科生将在人类和动物研究方面获得广泛的经验 各种生物医学技术，同时探索线粒体动力学对发育的贡献 以探索治疗胰岛素抵抗和T2D的新治疗策略。

PROJECT SUMMARY The prevalence of obesity (Body Mass Index ≥ 30) in the U.S. adults has reached nearly 40%. Obesity is accompanied by many metabolic problems that contribute to a significantly higher risk for chronic diseases, such as type 2 diabetes (T2D), insulin resistance and cardiovascular diseases. One of the key features of obesity and a forerunner of T2D is the impaired insulin action in skeletal muscle, resulting in insulin resistance. Therefore, the discovery of new targets to regulate skeletal muscle insulin sensitivity and whole-body glucose homeostasis is urgently needed. Such new targets could be exploited for new therapeutic treatments for insulin resistance and T2D. Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission. Excessive activation of Drp1 leads to aberrant mitochondrial fission causing imbalanced mitochondrial dynamics and dysfunction. We have recently reported that Drp1 is overactivated in skeletal muscle from obese insulin resistant humans and this overactivation is adversely correlated to impaired insulin action in skeletal muscle. In addition, in animals rendered insulin resistance with high-fat diet, pharmacological or genetic inhibition of Drp1 improves skeletal muscle insulin action and whole-body glucose homeostasis. However, more studies are still needed in order to understand the causal contribution of Drp1-mediated mitochondrial fission to insulin resistance. We hypothesize that excessive Drp1-mediated mitochondrial fission contributes to obesity-induced skeletal muscle insulin resistance and inhibition of skeletal muscle Drp1 is sufficient to improve mitochondrial integrity, reduce mtROS production, and improve insulin signaling, thereby ameliorating skeletal muscle insulin resistance and improving whole-body glucose homeostasis. In Aim 1, we will utilize skeletal muscle-specific Drp1 knockout mouse and clinical-relevant human skeletal muscle cell culture models, along with novel mitochondrial quality-monitoring tool (pMitoTimer) to define the role of Drp1-mediated mitochondrial fission in the regulation of obesity-induced skeletal muscle insulin resistance. These studies will determine the causal role of Drp1 in regulating skeletal muscle insulin resistance in obesity in vivo, and its underling mechanism of action. In Aim 2, we will utilize a pharmacological inhibitor of Drp1 to determine the effectiveness and therapeutic potential of targeting Drp1-mediated mitochondrial fission in alleviating obesity-induced insulin resistance. The successful completion of the proposed study will provide fundamental insights on contribution of Drp1-mediated mitochondrial fission to the development of obesity-induced insulin resistance and T2D. In addition, undergraduate students will gain extensive experience in both human and animal research using a variety of biomedical techniques while exploring the contribution of mitochondrial dynamics to the development of metabolic diseases to explore novel therapeutic strategies in treating insulin resistance and T2D.