Insulin sensitivity and fatty acid partitioning in skeletal muscle after exercise

运动后骨骼肌中的胰岛素敏感性和脂肪酸分配

• 批准号: 8453447
• 负责人: Jeffrey F Horowitz
• 金额: $ 29.69万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-13 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8453447
• 关键词: Acute; Acyl Coenzyme A; Adult; Body Weight decreased; Ceramides; Development; Dose; Educational Status; Energy Metabolism; Exercise; Fatty Acids; Health Benefit; Heparin; Individual; Inflammatory; Infusion procedures; Insulin; Insulin Resistance; JUN gene; Life Style; Lipids; Measures; Mediating; Mediator of activation protein; Metabolic; Muscle; Muscle Cells; Nuclear; Obesity; Pathway interactions; Patients; Phosphorylation; Plasma; Regulation; Serine; Skeletal Muscle; Stress; Testing; Training; Training Programs; Work; fatty acid metabolism; fitness; improved; inflammatory marker; insulin sensitivity; kinase inhibitor; lifestyle intervention; obesity treatment; oxidation; prevent; programs; public health relevance; response; stem; stress-activated protein kinase 1; uptake

DESCRIPTION (provided by applicant): Exercise is a key component of the successful management of many obesity-related metabolic complications, including insulin resistance. Importantly, many of the beneficial metabolic effects of endurance exercise training are attributed to the most recent exercise session(s), rather than to adaptations resulting from prolonged training, or to improved "fitness", per se. Therefore, lifestyle interventions for obese, insulin resistant patients should be tailored to optimize the metabolic effects of the most recent exercise session(s). However, the "dose" of acute exercise (i.e., intensity, duration, energy expended) necessary to improve insulin sensitivity in obesity is not known, and the mechanisms responsible for this improvement are still poorly understood. The excessive fatty acid availability found in obese individuals is largely responsible for their suppressed insulin sensitivity. "Partitioning" of these fatty acids within the myocyte toward oxidation, storage, or accumulation of intracellular fatty acid intermediates (e.g., ceramide, diacylglyceride, fatty acyl-CoA), and the resultant activation of pro-inflammatory pathways (e.g., c-jun NH2-terminal kinase (JNK)) mediate this response. Our working hypothesis is: A single session of exercise in obese adults will improve insulin sensitivity the next day despite a persistent elevation in fatty acid availability and uptake, in part because acute exercise will partition fatty acids away from accumulation of fatty acid intermediates, and thereby reduce the activation of pro-inflammatory pathways. We will first compare the effect of different exercise intensities (50% vs. 65% VO2peak) and different levels of energy expenditure (200 vs 350kcal) of a single exercise session on insulin sensitivity and muscle fatty acid metabolism measured the day after exercise in obese adults [Specific Aim #1]. We hypothesize that expending 350 kcal during exercise at both 50% and 65% VO2peak (~60 and ~45 min of exercise, respectively), as well as expending 200 kcal during exercise at 65% VO2peak (~30min of exercise) will be sufficient to alter fatty acid partitioning, reduce pro-inflammatory stress, and thereby improve insulin sensitivity the next day, but expending 200 kcal during exercise at 50% VO2peak (~40min of exercise) will not. To more definitively test the contribution of exercise-induced alterations in fatty acid partitioning on insulin sensitivity we will assess whether the minimum "dose" of exercise found in Specific Aim #1 protects against fatty acid-induced insulin resistance in obese adults [Specific Aim #2]. Finally, we will examine the cumulative effect of low doses of exercise (40 min of exercise at 50% VO2peak) performed over days, weeks, and months on insulin sensitivity, fatty acid partitioning, and activation of pro-inflammatory pathways [Specific Aim #3]. Findings from these studies will vastly improve our understanding about the regulation of insulin action and fatty acid partitioning after exercise in obesity. Moreover, these findings will provide valuable information for the development of lifestyle programs aimed at maximizing the key metabolic benefits of each exercise session in obese, insulin resistant patients.

描述（由申请人提供）：运动是成功管理许多肥胖相关代谢并发症（包括胰岛素抵抗）的关键组成部分。重要的是，耐力运动训练的许多有益的代谢作用归因于最近的运动训练，而不是长时间训练所产生的适应或“健康”本身的改善。因此，应针对肥胖、胰岛素抵抗患者进行生活方式干预，以优化最近运动的代谢效果。然而，改善肥胖患者胰岛素敏感性所需的急性运动“剂量”（即强度、持续时间、消耗的能量）尚不清楚，而且对这种改善的机制仍知之甚少。肥胖个体体内脂肪酸过多，很大程度上是其胰岛素敏感性受到抑制的原因。这些脂肪酸在肌细胞内“分配”，以氧化、储存或积累细胞内脂肪酸中间体（例如，神经酰胺、二酰甘油、脂肪酰辅酶A），以及由此产生的促炎途径（例如，c-jun）的激活NH2 末端激酶 (JNK) 介导此反应。我们的工作假设是：尽管脂肪酸的利用率和摄取持续升高，但肥胖成年人的单次运动将改善第二天的胰岛素敏感性，部分原因是剧烈运动会将脂肪酸从脂肪酸中间体的积累中分离出来，从而减少促炎途径的激活。我们首先将比较单次运动的不同运动强度（50% vs. 65% VO2peak）和不同水平的能量消耗（200 vs 350kcal）对肥胖者运动后第二天测量的胰岛素敏感性和肌肉脂肪酸代谢的影响成人[具体目标#1]。我们假设，在 50% 和 65% 摄氧量峰值（分别为约 60 分钟和约 45 分钟的运动）运动期间消耗 350 kcal，以及在 65% 摄氧量峰值（约 30 分钟的运动）运动期间消耗 200 kcal 就足够了改变脂肪酸分配，减少促炎应激，从而提高第二天的胰岛素敏感性，但在 50% 运动期间消耗 200 kcal VO2peak（约 40 分钟的运动）不会。为了更明确地测试运动引起的脂肪酸分配变化对胰岛素敏感性的影响，我们将评估特定目标 #1 中发现的最小运动“剂量”是否可以防止肥胖成人免受脂肪酸诱导的胰岛素抵抗[具体目标 # 2]。最后，我们将检查数天、数周和数月内进行的低剂量运动（50% VO2peak 运动 40 分钟）对胰岛素敏感性、脂肪酸分配和促炎途径激活的累积影响[具体目标# 3]。这些研究的结果将极大地提高我们对肥胖运动后胰岛素作用和脂肪酸分配调节的理解。此外，这些发现将为制定生活方式计划提供有价值的信息，旨在最大限度地提高肥胖、胰岛素抵抗患者每次运动的关键代谢益处。