Linking Mitochondrial Bioenergetics to Muscle Insulin Sensitivity

描述(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供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的病因学中可能发挥的作用。该项目的首要假设是，由于代谢底物供应过剩(“营养过剩”，尤其是来自高脂肪饮食)，加上低能量需求(久坐不动的生活方式)，骨骼肌中的营养失衡增加了线粒体过氧化氢的生成和释放的倾向，这是与饮食诱导的肥胖相关的胰岛素敏感性降低的潜在主要因素。利用一种新的方法对人体肌纤维线粒体功能进行原位研究，本项目的具体目的是：1)确定肥胖对久坐不动的瘦人和肥胖青年骨骼肌线粒体功能、细胞氧化还原平衡和胰岛素敏感性的调节的影响；2)确定瘦人的高热量/高脂肪摄入对线粒体功能、细胞氧化还原平衡和胰岛素敏感性的急性和/或慢性影响；3)确定增加的体力活动是否恢复了肥胖者或高热量/高脂肪饮食的瘦人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的释放是否是脂质诱导的胰岛素抵抗的主要原因。公共卫生相关性：本研究旨在确定过度营养和缺乏体力活动导致人体骨骼肌线粒体功能改变和胰岛素抵抗的代谢失衡的机制(S)。这一点非常重要，因为有必要从根本上了解胰岛素抵抗的原因，以便制定适当的预防措施和治疗方法，以减少肥胖症和糖尿病流行病对健康和经济的影响。

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. PUBLIC HEALTH RELEVANCE: This research seeks to identify the mechanism(s) by which metabolic imbalance caused by over nutrition and physical inactivity leads to altered mitochondrial function and insulin resistance in skeletal muscle of humans. This is highly significant, as a fundamental understanding of the causes of insulin resistance is necessary in order to devise adequate preventive measures and treatments to reduce the health and financial impact of the obesity and diabetes epidemics.