Lipid metabolism in obesity, weight loss, and exercise

描述（由申请人提供）：健康骨骼肌的一个关键特征是适应燃料供应变化的能力，这种现象称为代谢灵活性。因此，在瘦个体的骨骼肌中，暴露于脂质导致全局转录程序的激活，该程序增强多个基因的表达并促进脂质的氧化。我们实验室和其他人的研究表明，这种适应性反应至少部分是由PPARs介导的，PPARs是一种脂质激活的核激素受体家族。然而，这似乎不是肥胖症的情况，因为我们的研究结果还表明，骨骼肌中的脂肪酸氧化实际上与肥胖症有关，尽管细胞外和细胞内脂质升高，可能会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，从而导致脂质正平衡状态。该建议的中心焦点是测试我们的假设，A）脂肪酸介导的氧化能力调节在肥胖的骨骼肌中受损（目的1）; B）负责的机制涉及PPAR转录激活的缺陷（目标1和2）和C）运动训练，但不是减肥，恢复对脂质存在的响应能力并有效地氧化脂质（目的3和4）。这些假设将一起测试我们的中心假设，即肥胖症的人骨骼肌中的脂质氧化是有缺陷的，这至少部分是由于不能对脂质存在和/或其他刺激（运动训练的明显例外）做出反应，这些刺激通常会增强脂质氧化。我们的目标是：目标1：确定肥胖骨骼肌中脂质诱导的脂质氧化相关基因转录调控是否受损。目的2：评估肥胖介导的代谢紊乱与过氧化物酶体增殖物激活受体功能/功能障碍之间可能的因果关系。目的3：确定常见的临床干预是否恢复肥胖受试者中脂质诱导的脂质氧化和/或过氧化物酶体增殖物激活受体功能调节。目的4：研究收缩活动恢复肥胖个体脂质诱导的脂质氧化调节的机制。通俗地说，这一建议希望确定可能使个体易患肥胖症的因素，以及肥胖干预措施（减肥，运动）如何产生积极影响。

DESCRIPTION (provided by applicant): 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); B) that 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.