Lipid metabolism in obesity weight loss and exercise

肥胖减肥和运动中的脂质代谢

• 批准号: 8006102
• 负责人: Joseph A Houmard
• 金额: $ 12.06万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8006102
• 关键词: Address; Body Weight decreased; Cell Culture Techniques; Clinical; Data; Defect; Depressed mood; Enzymes; Equilibrium; Exercise; Exposure to; Family; Fatty Acids; Functional disorder; Genes; Genetic Transcription; Human; Impairment; Individual; Insulin Resistance; Intervention; Intramuscular; Laboratories; Lipids; MAP Kinase Gene; MAPK14 gene; Mediating; Metabolic; Modeling; Molecular; Muscle; Muscle Cells; Muscle Fibers; Nuclear Hormone Receptors; Obesity; Oxidative Regulation; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Play; Regulation; Research Personnel; Role; Skeletal Muscle; Stimulus; Stress; System; Testing; Training; Transcriptional Activation; Transcriptional Regulation; Up-Regulation; extracellular; fatty acid oxidation; flexibility; genetic manipulation; in vivo; intervention effect; lipid metabolism; overexpression; oxidation; oxidized lipid; programs; response; weight loss intervention

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.

健康骨骼肌的一个关键特征是能够适应燃料供应的变化，这是一种现象 被称为新陈代谢灵活性。因此，在瘦人的骨骼肌中，暴露在脂肪中 导致全球转录程序的激活，从而增强多个基因和 促进脂质的氧化。我们实验室和其他机构的研究表明，这种适应性反应 至少部分是由PPAR介导的，PPAR是一种脂质激活的核激素受体家族。然而， 肥胖的情况似乎并非如此，因为我们的发现也表明骨骼中的脂肪酸氧化 肥胖实际上会抑制肌肉，尽管细胞外和细胞内的脂肪应该升高 可能是激活了促进脂肪氧化的转录机制。这些发现表明 介导脂质氧化上调的分子机制因肥胖而受损， 从而促进了正脂肪平衡的状态。这项提案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骨骼肌中受到损害， 肥胖(目标1)；肥胖的机制涉及PPAR转录激活缺陷 (目标1和2)和C|运动训练，而不是减肥，恢复了对脂肪的反应能力 存在并有效地氧化脂质(目标3和4)。这些假设将共同考验我们的中心 有肥胖的人骨骼肌中的脂肪氧化是有缺陷的假设，这至少是由于 部分原因是无法对脂质的存在和/或其他刺激做出反应(显著的运动例外 训练)，这通常会增强脂质氧化。我们的目标是：目标1：确定脂质诱导的 肥胖症患者骨骼肌中脂质氧化相关基因的转录调控受损。目标 2评估肥胖引起的代谢不灵活和肥胖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措施是否能恢复血脂- 诱导肥胖受试者的脂质氧化和/或PPAR功能的调节。目标4：检查 收缩活动恢复脂质诱导的肥胖患者脂质氧化调节的机制 个人。通俗地讲，这项提案希望确定可能使个人倾向于 肥胖症及其干预措施(减肥、运动)如何产生积极效果。