Linking Mitochondrial Bioenergetics to Muscle Insulin Sensitivity

描述（由申请人提供）：线粒体是细胞内的细胞器，主要负责将代谢燃料转化为可被细胞其余部分使用的能量形式。这项研究的长期目标是了解线粒体功能/功能障碍在代谢性疾病病因学中的作用。该项目最重要的假设是，代谢底物供应过剩（“营养过剩”，特别是高脂肪饮食）和低能量需求（久坐不动的生活方式）造成的骨骼肌营养失衡，增加了线粒体过氧化氢生成和排放的倾向，代表了与饮食引起的肥胖相关的胰岛素敏感性降低的潜在主要因素。采用一种新颖的方法原位研究人肌纤维的线粒体功能，本项目的具体目的是：1)确定肥胖对久坐瘦弱与肥胖年轻人骨骼肌线粒体功能、细胞氧化还原平衡和胰岛素敏感性调节的影响；2)确定瘦人高热量/高脂肪摄入如何急性和/或慢性影响线粒体功能、细胞氧化还原平衡和胰岛素敏感性；3)确定增加体力活动是否能恢复肥胖个体或高热量/高脂肪饮食的瘦弱个体的氧化还原平衡和胰岛素敏感性；4)在培养的人原代肌管中研究线粒体ROS释放是否是脂质诱导的胰岛素抵抗的主要原因。

DESCRIPTION (provided by applicant): Mitochondria are organelles within cells that are largely responsible for converting metabolic fuel into a form of energy that can be used by the rest of the cell. The long term objective of this research is to understand the role of mitochondrial function/dysfunction may play in the etiology of metabolic disease. The overriding hypothesis of this project is that the nutritional imbalance in skeletal muscle created by an oversupply of metabolic substrates ("over nutrition", particularly from high fat diets) coupled with low energy demand (sedentary lifestyle) increases the propensity for mitochondrial hydrogen peroxide generation and emission, representing the potential primary factor for the decrease in insulin sensitivity associated with diet-induced obesity. Using a novel approach to study mitochondrial function in human myofibers in situ, the Specific Aims of this project are: 1) to determine the impact of obesity on the regulation of mitochondrial function, cellular redox balance and insulin sensitivity in skeletal muscle of sedentary lean verses obese young adults; 2) to determine how high calorie/high fat intake in lean humans acutely and/or chronically affects mitochondrial function, cellular redox balance and insulin sensitivity; 3) to determine whether increased physical activity restores redox balance and insulin sensitivity in obese individuals or in lean individuals consuming a high calorie/high fat diet; and 4) to investigate in cultured human primary myotubes whether mitochondrial ROS emission is a primary cause of lipid-induced insulin resistance.