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

靶向 Dynamin 相关蛋白 1 介导的线粒体裂变来纠正肥胖中的胰岛素抵抗

• 批准号: 10359518
• 负责人: Kai Zou
• 金额: $ 45.58万
• 依托单位: UNIVERSITY OF MASSACHUSETTS BOSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359518
• 关键词: Adult; Animal Experimentation; Animals; Biological Assay; Body mass index; Cardiovascular Diseases; Cell Culture Techniques; Characteristics; Chronic Disease; Data; Development; Diet; Dose; Dynamin; Epidemic; Equilibrium; Functional disorder; Genes; Genetic; Glucose Intolerance; Health; High Fat Diet; Human; Hydrogen Peroxide; Impairment; In Vitro; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Lead; Link; Measures; Mediating; Metabolic; Metabolic Diseases; Mitochondria; Modeling; Monitor; Morphology; Mus; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Pharmacological Treatment; Pharmacology; Phosphorylation; Phosphorylation Site; Play; Prevalence; Production; Proteins; Public Health; Reactive Oxygen Species; Regulation; Reporting; Research; Risk; Role; Safety; Sampling; Skeletal Muscle; Tamoxifen; Techniques; Therapeutic; Time; Tissues; Up-Regulation; Validation; Western Blotting; base; blood glucose regulation; clinically relevant; effectiveness evaluation; experience; feeding; follow-up; glucose metabolism; high risk; improved; in vivo; inhibitor/antagonist; insight; insulin sensitivity; insulin signaling; knock-down; mitochondrial fitness; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; obesity development; phosphoproteomics; tool; undergraduate student

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.

项目摘要 美国成年人肥胖（体重指数≥ 30）的患病率已接近40%。肥胖是 伴随着许多代谢问题，这些问题导致慢性疾病的风险显著增加， 如2型糖尿病（T2D）、胰岛素抵抗和心血管疾病。的关键特征之一 肥胖和T2D的前兆是骨骼肌中受损的胰岛素作用，导致胰岛素抵抗。 因此，发现新的靶点来调节骨骼肌胰岛素敏感性和全身葡萄糖 我们迫切需要体内平衡。这些新的靶点可以用于胰岛素的新的治疗方法 阻力和T2D。动力蛋白相关蛋白1（Drp1）是线粒体分裂的关键调节因子。过度 Drp1的激活导致异常的线粒体分裂，引起不平衡的线粒体动力学， 功能障碍我们最近报道，Drp1在骨骼肌中被过度激活， 抵抗的人，并且这种过度活化与骨骼肌中受损的胰岛素作用不利地相关。在 此外，在高脂饮食导致胰岛素抵抗的动物中，药物或遗传抑制Drp1 改善骨骼肌胰岛素作用和全身葡萄糖稳态。然而，更多的研究仍然 为了理解Drp1介导的线粒体分裂对胰岛素的因果作用， 阻力我们假设过量的Drp1介导的线粒体分裂有助于肥胖诱导的 骨骼肌胰岛素抵抗和骨骼肌Drp1的抑制足以改善线粒体 完整性，减少mtROS的产生，并改善胰岛素信号传导，从而改善骨骼肌胰岛素 抵抗力和改善全身葡萄糖稳态。在目标1中，我们将利用骨骼肌特异性 Drp 1敲除小鼠和临床相关的人骨骼肌细胞培养模型，沿着新的 线粒体质量监测工具（pMitoTimer），以确定Drp1介导的线粒体分裂在 肥胖诱导的骨骼肌胰岛素抵抗的调节。这些研究将确定 Drp 1在体内调节肥胖骨骼肌胰岛素抵抗中的作用及其潜在机制 行动上在目标2中，我们将利用Drp 1的药理学抑制剂来确定其有效性， 靶向Drp1介导的线粒体分裂在减轻肥胖诱导的胰岛素中的治疗潜力 阻力拟议研究的成功完成将提供有关贡献的基本见解 Drp1介导的线粒体分裂与肥胖诱导的胰岛素抵抗和T2D的发展有关。在 此外，本科生将获得丰富的经验，在人类和动物研究使用 各种生物医学技术，同时探索线粒体动力学对发展的贡献 目的是探索治疗胰岛素抵抗和2型糖尿病的新的治疗策略。