Insulin sensitivity and fatty acid partitioning in skeletal muscle after exercise

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效应归因于最近的运动课程，而不是长期训练所产生的适应性，或改善“健身”本身。因此，对肥胖、胰岛素抵抗患者的生活方式干预应针对性调整，以优化最近一次运动的代谢效应。然而，急性运动的“剂量”（即，强度、持续时间、消耗的能量）是改善肥胖症中胰岛素敏感性所必需的，并且对这种改善的机制仍然知之甚少。在肥胖个体中发现的过量脂肪酸可用性在很大程度上是他们抑制胰岛素敏感性的原因。这些脂肪酸在肌细胞内朝向细胞内脂肪酸中间体（例如，神经酰胺、二酰基甘油酯、脂肪酰辅酶A），以及由此产生的促炎途径的激活（例如，c-jun NH 2-末端激酶（JNK））介导这种应答。我们的工作假设是：肥胖成年人的单次运动将在第二天改善胰岛素敏感性，尽管脂肪酸的可用性和摄取持续升高，部分原因是急性运动将脂肪酸与脂肪酸中间体的积累分开，从而减少促炎途径的激活。我们将首先比较不同运动强度（50% vs. 65%VO2peak）和单次运动的不同能量消耗水平（200 vs. 350 kcal）对肥胖成人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[具体目标#1]。我们假设在50%和65%的VO 2峰值下运动时消耗350千卡，（分别为~60和~45分钟的运动），以及在65%VO2峰值下运动期间消耗200千卡（约30分钟的运动）将足以改变脂肪酸分配，减少促炎性应激，从而改善第二天的胰岛素敏感性，而在50%VO2峰值运动时消耗200千卡（运动40分钟）则不会。为了更明确地测试运动诱导的脂肪酸分配改变对胰岛素敏感性的贡献，我们将评估特定目标#1中发现的最小运动“剂量”是否可预防肥胖成人脂肪酸诱导的胰岛素抵抗[特定目标#2]。最后，我们将检查在数天、数周和数月内进行的低剂量运动（在50%VO2峰值下运动40分钟）对胰岛素敏感性、脂肪酸分配和促炎通路激活的累积效应[具体目标#3]。这些研究的结果将极大地提高我们对肥胖患者运动后胰岛素作用和脂肪酸分配的调节的理解。此外，这些发现将为制定生活方式计划提供有价值的信息，这些计划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。

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.