Muscle lipid metabolism & triacylglycerol accumulation

描述（由申请方提供）：肌内三酰甘油（TAG）含量随肥胖而增加，与胰岛素敏感性呈负相关。目前尚不清楚肥胖症肌内TAG沉积增加的机制。该提案的目的是检查肥胖个体的人骨骼肌中的脂质代谢，并辨别肌内TAG积累的机制。我们的主要假设是来自肥胖个体的人骨骼肌将游离脂肪酸分配到脂质储存，导致肌内TAG积累。这一假设是基于我们的初步工作，其中在肥胖骨骼肌中，我们观察到游离脂肪酸摄取和氧化减少，并且大部分摄取被分配到储存。这些数据形成了我们工作假设的基础，即TAG合成能力随着肥胖而增加，促进骨骼肌中的脂质储存。我们的第二个假设是，体重减轻，这是已知的减少肌内脂质，将纠正在脂质代谢的缺陷负责TAG积累。该提案的具体目的是：1）确定非肥胖和肥胖个体肌肉中的肌内TAG含量和TAG合成与水解速率; 2）确定特定目的1中相同组织中TAG合成和水解的限速酶活性; 3）确定体重减轻对肥胖个体肌内TAG含量和TAG合成与水解能力的影响。

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.