Metabolic inflexibility is related to elevated muscle anaerobic glycolysis

总结 肥胖和代谢综合征在美国很普遍，是导致发病率和死亡率的原因。 mortality.本申请中的研究旨在确定特定的代谢表型（增加的依赖性）是否 对骨骼肌无氧糖酵解和代谢能力的影响）在超重个体中是明显的， 接近严重肥胖者的体重。超重受试者将根据高和低空腹乳酸水平进行选择 浓度（厌氧糖酵解的指标），并进行葡萄糖钳夹与肌肉活检 在静止状态下获得（目标1）。一个严重肥胖的群体将接受与主要测试相同的测试。 变量为基础和胰岛素刺激的体内肌肉底物氧化（近红外光谱; NIRS）、肌肉乳酸盐释放（微透析）、RER以及丙酮酸和脂肪酸的肌肉匀浆氧化 acids.次要变量是静息/空腹血浆乳酸盐、全身乙酸盐氧化、肌纤维类型， 暴露于各种底物的透化纤维中的氧消耗，线粒体的数量， 蛋白质、VO 2峰值、REE、RER、体型（3D扫描仪）和身体组成（DEXA）。在目标2a中， 该钳夹将用于评估代谢灵活性。主要变量是代谢灵活性（ RER响应胰岛素+葡萄糖）;底物氧化（NIRS和肌肉匀浆氧化 丙酮酸和脂肪酸）;和无氧糖酵解（钳夹期间肌肉乳酸盐释放）。二次 变量是外周和肝脏胰岛素敏感性。在目标2b中，对3天高脂肪饮食的反应将是 在饮食前后进行肌肉活检。主要变量是 响应于HFD和底物氧化的代谢灵活性（NIRS，肌肉匀浆氧化， 丙酮酸和脂肪酸）和体内肌肉乳酸产生。次要变量是外围变量， 肝胰岛素敏感性目标2c将检查来自研究的原代细胞培养物的能力 受试者对胰岛素或脂质孵育有反应。主要变量是代谢灵活性， 葡萄糖+胰岛素（胰岛素刺激葡萄糖氧化和乳酸产生）和代谢灵活性， 对脂肪的反应（与脂肪酸孵育24小时后脂肪酸氧化增加）。目标3将确定是否 在严重肥胖的个体中恢复代谢灵活性的干预（胃旁路手术）将 也减少对无氧糖酵解的依赖。受试者将接受葡萄糖钳夹和肌肉活检 在手术前后。主要变量是代谢灵活性（响应葡萄糖的RER变化 + 钳夹期间的胰岛素）、底物氧化（NIRS，丙酮酸和脂肪酸的肌肉匀浆氧化） 和体内肌肉乳酸盐释放。次要变量为静息/空腹乳酸、外周和肝脏 胰岛素敏感性、全身乙酸氧化和培养的肌肉细胞的代谢灵活性。的意图 这项研究是为了确定有可能发生肥胖症的个人的指数。

Summary Obesity and the metabolic syndrome are prevalent in the United States and responsible for morbidity and mortality. The studies in this application aim to determine if a specific metabolic phenotype (increased reliance on anaerobic glycolysis in skeletal muscle and metabolic inflexibility) in overweight individuals is evident and approximates that of the severely obese. Overweight subjects will be selected for high and low fasting lactate concentrations (an indicator of anaerobic glycolysis) and undergo a glucose clamp with a muscle biopsy obtained in the resting state (Aim 1). A severely obese group will undergo the same tests with the primary variables being basal and insulin stimulated in vivo muscle substrate oxidation (near infrared spectrospopy; NIRS), muscle lactate release (microdialysis), RER, and muscle homogenate oxidation of pyruvate and fatty acids. Secondary variables are resting/fasting plasma lactate, whole body acetate oxidation, muscle fiber type, oxygen consumption in permeabilized fibers exposed to various substrates, quantities of mitochondrial proteins, VO2peak, REE, RER, body shape (3D-scanner) and body composition (DEXA). In Aim 2a, data from the clamp will be used to assess metabolic flexibility. The primary variables are metabolic flexibility (change in RER in response to insulin + glucose); substrate oxidation (NIRS and muscle homogenate oxidation of pyruvate and fatty acids); and anaerobic glycolysis (muscle lactate release during the clamp). Secondary variables are peripheral and hepatic insulin sensitivity. In Aim 2b, responses to a 3-day high fat diet will be determined and muscle biopsies obtained before and after the diet. The primary variables are indices of metabolic flexibility in response to the HFD and substrate oxidation (NIRS, muscle homogenate oxidation of pyruvate and fatty acids) and in vivo muscle lactate production. Secondary variables are peripheral and hepatic insulin sensitivity. Aim 2c will examine the ability of primary cell cultures derived from the research subject to respond to insulin or lipid incubation. The primary variables are metabolic flexibility in response to glucose + insulin (insulin stimulation of glucose oxidation and lactate production) and metabolic flexibility in response to fat (increase in fatty acid oxidation after 24 hr incubation with fatty acids). Aim 3 will determine if an intervention (gastric bypass surgery) which restores metabolic flexibility in severely obese individuals will also reduce dependence on anaerobic glycolysis. Subjects will undergo a glucose clamp and a muscle biopsy before and after the surgery. Primary variables are metabolic flexibility (change in RER in response to glucose + insulin during a clamp), substrate oxidation (NIRS, muscle homogenate oxidation of pyruvate and fatty acids) and in vivo muscle lactate release. Secondary variables are resting/fasting lactate, peripheral and hepatic insulin sensitivity, whole-body acetate oxidation, and metabolic flexibility of cultured muscle cells. The intent of this research is to determine indices of individuals at risk for the subsequent development of obesity.