Lipid metabolism in obesity weight loss and exercise

健康骨骼肌的一个关键特征是适应燃料供应变化的能力， 称为代谢灵活性。因此，在瘦个体的骨骼肌中，暴露于脂质 导致增强多个基因表达的全局转录程序的激活， 促进脂质氧化。我们实验室和其他机构的研究表明，这种适应性反应 至少部分由PPARs介导，PPARs是脂质激活的核激素受体家族。然而，在这方面， 这似乎不是肥胖的情况，因为我们的研究结果还表明，骨骼肌中的脂肪酸氧化 肌肉实际上是抑郁与肥胖，尽管升高的额外和细胞内脂质， 可能激活促进脂质氧化的转录机制。这些发现表明 介导脂质氧化上调的分子机制在肥胖症中受损， 从而促进正脂质平衡状态。本提案的核心重点是测试我们的 假设，A}脂肪酸介导的氧化能力调节在骨骼肌中受损， 肥胖症（目标1）; SJ，该机制涉及过氧化物酶体增殖物激活受体转录激活缺陷 (Aims 1和2）和C|运动训练，而不是减肥，恢复了对脂质的反应能力， 存在并有效地氧化脂质（目标3和4）。这些假设将共同测试我们的核心 假设肥胖症的人骨骼肌中的脂质氧化是有缺陷的，这是由于，至少在 部分原因是无法对脂质存在和/或其他刺激做出反应（运动明显例外 训练），通常增强脂质氧化。我们的目的是：目的1：确定是否脂质诱导 在肥胖症的骨骼肌中，参与脂质氧化的基因的转录调节受损。目的 2.评估肥胖介导的代谢紊乱与肥胖症之间可能的因果关系。 PPAR功能/功能障碍。目的3：确定常见的临床干预是否能恢复血脂水平， 诱导调节肥胖受试者的脂质氧化和/或PPAR功能。目标4：审查 收缩活动恢复肥胖患者脂质氧化的脂质诱导调节的机制 个体通俗地说，这项建议希望确定可能使个人倾向于 肥胖以及肥胖干预措施（减肥、运动）如何产生积极效果。

A key feature of healthy skeletal muscle is the ability to adapt to changes in fuel supply, a phenomenon known as metabolic flexibility. Accordingly, in the skeletal muscle of lean individuals, exposure to lipid results in the activation of a global transcription program that enhances the expression of multiple genes and promotes the oxidation of lipid. Studies from our laboratory and others suggest that this adaptive response is at least partially mediated by the PPARs, a family of lipid-activated nuclear hormone receptors. However, this does not appear to be the case with obesity, as our findings also show that fatty acid oxidation in skeletal muscle is actually depressed with obesity despite elevated extra- and intracellular lipids that should presumably activate the transcriptional machinery which promotes lipid oxidation. These findings suggest that the molecular mechanisms which mediate the up-regulation of lipid oxidation are impaired with obesity, thereby contributing to a state of positive lipid balance. The central focus of this proposal is to test our hypotheses that, A} fatty acid-mediated regulation of oxidative capacity is impaired in skeletal muscle with obesity (Aim 1); SJthat the mechanism responsible involves a defect in PPAR transcriptional activation (Aims 1 & 2) and C| that exercise training, but not weight loss, restores the ability to respond to lipid presence and effectively oxidize lipid (Aims 3 & 4). These hypotheses will together test our central hypothesis that with obesity lipid oxidation in human skeletal muscle is defective which is due, at least in part, to an inability to respond to lipid presence and/or other stimuli (with the notable exception of exercise training) that normally enhance lipid oxidation. Our aims are: Aim 1: To determine whether lipid-induced transcriptional regulation of genes involved in lipid oxidation is impaired in skeletal muscle with obesity. Aim 2\ To evaluate a possible cause-and-effect relationship between obesity-mediated metabolic inflexibility and PPAR function/dysfunction. Aim 3: To determine whether common clinical interventions restore lipid- induced regulation of lipid oxidation and/or PPAR function in obese subjects. Aim 4: To examine mechanisms by which contractile activity restores lipid-induced regulation of lipid oxidation in obese individuals. In lay terms, this proposal hopes to determine factors that may predispose individuals towards obesity and how interventions (weight loss, exercise) for obesity induce their positive effects.