EXERCISE AND SKELETAL MUSCLE FATTY ACID METABOLISM

描述：高胰岛素血症和胰岛素抵抗很普遍。 肥胖者经常观察到的代谢特征 通常与氧化代谢缺陷有关。尽管 葡萄糖-脂肪酸循环的机制传统上被用来解释 底物相互作用，它在调控中的首要地位的决定性证据 缺乏对肌肉氧化代谢的研究。从收集到的证据 不同的组织，最近提出了一种替代机制，它 提示葡萄糖和FFA氧化的相互调节可能是 通过丙二酰辅酶A水平的变化而联系在一起。丙二酰辅酶A，一种有效的 肉毒碱棕榈酰转移酶抑制剂，由乙酰辅酶A在 乙酰辅酶A羧基酶催化的羧化反应。这个 研究人员提议调查细胞因素，最终将 通过调节其产量对丙二酰辅酶A水平的影响。肌肉 宫缩、胰岛素和长链酰辅酶A的可用性将被用作 通过共价修饰修饰丙二酰辅酶A水平的因素 乙酰辅酶A羧基酶。葡萄糖可获得性与运动诱导的变化 在葡萄糖代谢中将被用作调节丙二酰辅酶A水平的因素 通过改变乙酰辅酶A羧基酶的底物供应。在 目前的建议调查人员计划采用原位灌流 后肢准备以解决以下假设：(1) 细胞内葡萄糖的可获得性决定氧化速率 细胞机制在静息和收缩肌肉中的代谢 这意味着丙二酰辅酶A，(2)碳水化合物和脂肪的燃料来源 通过调节对拟议的细胞调控机制的影响 乙酰辅酶A可利用性，以及3)胰岛素直接影响 已提出的细胞机制是通过同时调节葡萄糖和 脂肪酸代谢。我们将结合使用示踪剂方法 动静脉平衡测量，分析CoA酯水平和 碳水化合物和脂肪酸代谢定量的酶活性 以预定的葡萄糖摄取速率灌流大鼠的后肢 休息和肌肉收缩。丙二酰辅酶A水平将首次 与骨骼肌中的脂肪酸氧化速率相关。

DESCRIPTION: Hyperinsulinemia and insulin resistance are prevalent metabolic characteristics frequently observed in obese individuals and are usually associated with defects in oxidative metabolism. Although the mechanism of the glucose-fatty acid cycle is traditionally used to explain substrate interactions, definitive evidence of its primacy in the regulation of muscle oxidative metabolism is lacking. From evidence collected in different tissues, an alternative mechanism was recently proposed which suggests that reciprocal regulation of glucose and FFA oxidation may be linked through changes in malonyl-CoA levels. Malonyl-CoA, a potent inhibitor of carnitine palmitoyl transferase, is formed from acetyl-CoA in a carboxylation reaction catalyzed by acetyl-CoA carboxylase. The investigators propose to investigate cellular factors that will ultimately impact on malonyl-CoA levels by modulating its rate of production. Muscle contractions, insulin, and long chain acylCoA availability will be used as factors to modify malonyl-CoA levels through covalent modification of acetyl-CoA carboxylase. Glucose availability and exercise-induced changes in glucose metabolism will be used as factors to modify malonyl-CoA levels through changes in substrate supply for acetyl-CoA carboxylase. In the current proposal the investigators plan to employ the in situ perfused hindlimb preparation to address the following hypotheses: (1) that intracellular glucose availability determines the rate of oxidative metabolism in resting and contracting muscles through a cellular mechanism that implicates malonyl-CoA, (2) that carbohydrate and lipid fuel sources impact on the proposed cellular mechanism of regulation by modulating acetyl-CoA availability, and 3) that insulin directly impacts on the proposed cellular mechanism of regulation by modulating both glucose and fatty acid metabolism. We will use tracer methodology in conjunction with arteriovenous balance measurements, analysis of CoA ester levels and of enzyme activities to quantify carbohydrate and fatty acid metabolism in hindlimbs of rats perfused at predetermined rates of glucose uptake during rest and muscle contractions. For the first time, malonyl-CoA levels will be correlated to the rate of fatty acid oxidation in skeletal muscle.