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.

健康骨骼肌的关键特征是能够适应燃料供应的变化，这是一种现象 称为代谢灵活性。因此，在精益个体的骨骼肌中，暴露于脂质 导致一个全球转录程序的激活，该程序增强了多个基因的表达和 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 至少部分由PPARS（一个脂肪激活的核激素受体家族）PPAR介导。然而， 肥胖似乎并非如此，因为我们的发现还表明骨骼中的脂肪酸氧化 肌肉实际上因肥胖而抑郁，尽管较高的细胞外脂质应 大概会激活促进脂质氧化的转录机械。这些发现表明 肥胖，介导脂质氧化上调的分子机制受到肥胖的损害 从而导致脂质平衡阳性的状态。该提议的主要重点是测试我们的 假设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）； SJTHAT负责的机制涉及PPAR转录激活缺陷 （目标1和2）和C |运动训练，但不减肥，可以恢复对脂质的反应能力 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中心 假设人骨骼肌中肥胖脂质氧化有缺陷，至少在 部分，无法应对脂质的存在和/或其他刺激（显着的运动 训练）通常会增强脂质氧化。我们的目标是：目标1：确定脂质引起的 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不灵活性与 PPAR功能/功能障碍。目标3：确定常见的临床干预措施是否恢复脂质 在肥胖受试者中诱导的脂质氧化和/或PPAR功能的调节。目标4：检查 收缩活性恢复肥胖中脂质氧化的调节的机制 个人。用外行，该提议希望确定可能使个人倾向于 肥胖以及肥胖的干预措施（减肥，运动）如何引起其积极影响。