Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle - Evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents
Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle - Evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents
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DOI：
10.2337/db07-0093
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发表时间：
2007-08-01
期刊：
影响因子：
7.7
通讯作者：
Cooney, Gregory J.
中科院分区：
文献类型：
--
作者：
Turner, Nigel;Bruce, Clinton R.;Cooney, Gregory J.
骨骼肌线粒体脂肪酸氧化能力的降低被认为是导致肌内脂质积累及其随后对胰岛素作用的有害影响的主要因素。在这里，我们研究了与脂质供过于求相关的胰岛素抵抗啮齿动物模型中线粒体脂肪酸氧化能力的标志物。C57BL/6J小鼠分别饲喂高脂饲料5周和20周。研究人员测量了肌肉线粒体脂肪酸氧化能力的几个指标，包括c -14-棕榈酸酯氧化、分离线粒体中棕榈酰辅酶a氧化、氧化酶活性（柠檬酸合成酶、β -羟酰基辅酶a脱氢酶、中链酰基辅酶a脱氢酶和肉毒碱棕榈酰转移酶1）以及参与线粒体代谢的蛋白质表达。酶活性和线粒体蛋白表达也在其他啮齿类动物胰岛素抵抗模型的肌肉中进行了检测。与标准饮食对照组相比，脂肪喂养小鼠肌肉中棕榈酸氧化率升高（5周+23%，P < 0.05, 20周+29%，P < 0.05），分离线粒体中棕榈酰辅酶a氧化率升高（20周+49%，P < 0.01）。此外，脂肪喂养动物的氧化酶活性和过氧化物酶体增殖物激活受体γ辅助激活因子(PGC)-1 α、解偶联蛋白（UCP） 3和线粒体呼吸链亚基的蛋白表达显著升高。在脂肪喂养大鼠、肥胖Zucker大鼠和db/db小鼠的肌肉中也存在类似的模式，观察到氧化酶活性和PGC-1 α、UCP3和线粒体呼吸链亚基的表达增加。这些发现表明，高脂质利用率不会通过降低肌肉线粒体脂肪酸氧化能力导致啮齿类动物肌内脂质积累和胰岛素抵抗。
A reduced capacity for mitochondrial fatty acid oxidation in skeletal muscle has been proposed as a major factor leading to the accumulation of intramuscular lipids and their subsequent deleterious effects on insulin action. Here, we examine markers of mitochondrial fatty acid oxidative capacity in rodent models of insulin resistance associated with an oversupply of lipids. C57BL/6J mice were fed a high-fat diet for either 5 or 20 weeks. Several markers of muscle mitochondrial fatty acid oxidative capacity were measured, including C-14-palmitate oxidation, palmitoyl-CoA oxidation in isolated mitochondria, oxidative enzyme activity (citrate synthase, beta-hydroxyacyl CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, and carnitine palmitoyl-transferase 1), and expression of proteins involved in mitochondrial metabolism. Enzyme activity and mitochondrial protein expression were also examined in muscle from other rodent models of insulin resistance. Compared with standard diet-fed controls, muscle from fat-fed mice displayed elevated palmitate oxidation rate (5 weeks +23%, P < 0.05, and 20 weeks +29%, P < 0.05) and increased palmitoyl-CoA oxidation in isolated mitochondria (20 weeks +49%, P < 0.01). Furthermore, oxidative enzyme activity and protein expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 alpha, uncoupling protein (UCP) 3, and mitochondrial respiratory chain subunits were significantly elevated in fat-fed animals. A similar pattern was present in muscle of fat-fed rats, obese Zucker rats, and db/db mice, with increases observed for oxidative enzyme activity and expression of PGC-1 alpha, UCP3, and subunits of the mitochondrial respiratory chain. These findings suggest that high lipid availability does not lead to intramuscular lipid accumulation and insulin resistance in rodents by decreasing muscle mitochondrial fatty acid oxidative capacity.