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