Mitochondrial Bioenergetics and Etiology of Insulin Resistance

描述（由申请人提供）：肥胖和肥胖/糖尿病患者骨骼肌线粒体含量和整体电子传递链活性严重下降（50-70%）。这些数据表明，肥胖，或者更可能是导致肥胖的营养过剩，会导致线粒体功能的逐渐下降，最终导致线粒体的溶解和丧失。线粒体功能障碍也与胰岛素抵抗的病因有关；然而，导致线粒体功能障碍的潜在机制及其与胰岛素抵抗发展的潜在联系，特别是在肥胖的背景下，尚不清楚。这项研究的长期目标是确定线粒体完整性和胰岛素敏感性的丧失是否源于一种常见的代谢紊乱，即氧化应激。我们的假设是，过度营养，特别是高脂肪饮食，会显著增加骨骼肌中线粒体活性氧（ROS）排放的倾向，导致线粒体功能障碍和胰岛素抵抗的发展。该项目的具体目标是：1)确定高脂肪饮食导致线粒体功能丧失的机制；2)确定线粒体衍生的氧化应激是否是营养过剩导致线粒体功能丧失和骨骼肌胰岛素抵抗发展的主要因素。该项目将利用新开发的渗透纤维方法，保留骨骼肌纤维中线粒体的天然网状结构，并利用最先进的药理学药物和转基因模型来操纵线粒体ROS的产生和清除。与公共卫生相关。实现这一应用的目标将确定线粒体来源的氧化应激是饮食诱导的线粒体功能障碍和骨骼肌胰岛素抵抗的主要原因。这将从根本上改变代谢失衡的背景，即细胞如何实时调节和控制能量平衡，因此将提供线粒体生物能量学与已知导致（营养过剩、久坐不动的生活方式）、预防（代谢平衡、身体活动）和治疗（热量限制、身体活动增加）胰岛素抵抗和II型糖尿病的因素之间的机制联系。

DESCRIPTION (provided by applicant): Mitochondrial content and overall electron transport chain activity are severely depressed (50-70%) in skeletal muscle of obese arid obese/diabetic patients. These data imply that obesity, or more likely the over nutrition that causes obesity, leads to a progressive decline in mitochondrial function, eventually culminating in the dissolution and loss of mitochondria. Mitochondrial dysfunction has also been implicated in the etiology of insulin resistance; however, the underlying mechanisms leading to mitochondrial dysfunction and their potential link to the development of insulin resistance, particularly in the context of obesity, are unknown. The long term objective of this research is to determine if the loss of mitochondrial integrity and insulin sensitivity stem from a common metabolic disturbance, i.e., oxidative stress. Our hypothesis is that over nutrition, particularly from high fat diets, dramatically increases the propensity for mitochondrial reactive oxygen species (ROS) emission in skeletal muscle, leading to both mitochondrial dysfunction and the development of insulin resistance. The specific aims of this project are designed to 1) determine the mechanisms responsible for the loss of mitochondrial function induced by a high fat diet, and 2) determine if mitochondrial-derived oxidative stress is a primary factor linking over nutrition to the loss of mitochondrial function and development of insulin resistance in skeletal muscle. The project will utilize a newly developed permeabilized fiber approach that preserves the natural reticular structure of mitochondria in skeletal myofibers, and state of the art pharmacological agents and transgenic models to manipulate mitochondrial ROS production and scavenging. Relevance to Public Health. Achieving the aims of this application will establish mitochondrial derived oxidative stress as a primary cause of diet-induced mitochondrial dysfunction and insulin resistance in skeletal muscle. This will fundamentally alter the context in which metabolic imbalance is viewed, i.e., how cells regulate and govern energy balance in real-time, and will therefore provide a mechanistic link between mitochondrial bioenergetics and the factors known to cause (over nutrition, sedentary lifestyle), prevent (metabolic balance, physical activity), and treat (caloric restriction, increased physical activity) insulin resistance and type II diabetes.