Muscle lipid metabolism & triacylglycerol accumulation

描述(申请人提供)：肌肉中三酰甘油(TAG)的含量随着肥胖而增加，与胰岛素敏感性呈负相关。肥胖症患者肌肉内TAG沉积增加的机制目前尚不清楚。这项建议的目的是研究肥胖个体骨骼肌脂代谢，并找出导致肌肉内标签积累的机制(S)。我们的主要假设是，肥胖者的骨骼肌将游离脂肪酸分配给脂肪储存，导致肌肉内标签的积累。这一假设是基于我们的初步工作，在肥胖的骨骼肌中，我们观察到游离脂肪酸的摄取和氧化减少，并且大部分摄取被分配到储存中。这些数据构成了我们工作假说的基础，即TAG合成能力随着肥胖而增加，从而促进骨骼肌中脂肪的储存。我们的第二个假设是，众所周知的减肥可以减少肌肉中的脂肪，它将纠正导致标签积累的脂肪代谢缺陷(S)。这项建议的具体目的是：1)确定非肥胖和肥胖个体肌肉中的TAG含量和TAG合成和水解率；2)从特定的目标1确定同一组织中TAG合成和水解的限速酶活性；以及3)确定减肥对肥胖者肌肉内TAG含量和TAG合成和水解能力的影响。

DESCRIPTION (provided by applicant): Intramuscular triacylglycerol (TAG) content is increased with obesity and negatively associated with insulin sensitivity. The mechanisms that account for increased intramuscular TAG deposition with obesity are not clear at this time. The purpose of this proposal is to examine lipid metabolism in human skeletal muscle from obese individuals and discern the mechanism(s) responsible for intramuscular TAG accumulation. It is our primary hypothesis that human skeletal muscle from obese individuals partitions free fatty acids towards lipid storage resulting in intramuscular TAG accumulation. This hypothesis is based on our preliminary work, where in obese skeletal muscle we observed reduced free fatty acid uptake and oxidation, and a majority of uptake was partitioned to storage. These data form the basis for our working hypothesis, that TAG synthetic capacity is increased with obesity, promoting lipid storage in skeletal muscle. Our secondary hypothesis is that weight loss, which is known to decrease intramuscular lipid, will correct the defect(s) in lipid metabolism responsible for TAG accumulation. The specific aims of this proposal are to: 1) determine intramuscular TAG content and rates of TAG synthesis and hydrolysis in muscle from nonobese and obese individuals; 2)determine activity of rate-limiting enzymes of TAG synthesis and hydrolysis in the same tissue from specific aim 1; and 3)determine the effects of weight loss on intramuscular TAG content and capacities for TAG synthesis and hydrolysis in obese individuals.