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首页> 外文期刊>Cell metabolism >Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance.
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Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance.

机译：线粒体超负荷和不完全的脂肪酸氧化有助于骨骼肌胰岛素抵抗。

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Previous studies have suggested that insulin resistance develops secondary to diminished fat oxidation and resultant accumulation of cytosolic lipid molecules that impair insulin signaling. Contrary to this model, the present study used targeted metabolomics to find that obesity-related insulin resistance in skeletal muscle is characterized by excessive beta-oxidation, impaired switching to carbohydrate substrate during the fasted-to-fed transition, and coincident depletion of organic acid intermediates of the tricarboxylic acid cycle. In cultured myotubes, lipid-induced insulin resistance was prevented by manipulations that restrict fatty acid uptake into mitochondria. These results were recapitulated in mice lacking malonyl-CoA decarboxylase (MCD), an enzyme that promotes mitochondrial beta-oxidation by relieving malonyl-CoA-mediated inhibition of carnitine palmitoyltransferase 1. Thus, mcd(-/-) mice exhibit reduced rates of fat catabolism and resist diet-induced glucose intolerance despite high intramuscular levels of long-chain acyl-CoAs. These findings reveal a strong connection between skeletal muscle insulin resistance and lipid-induced mitochondrial stress.
机译：先前的研究表明，胰岛素抵抗会继发于脂肪氧化减少以及由此损害胰岛素信号传导的胞质脂质分子的积累而发展。与该模型相反，本研究使用靶向代谢组学研究发现，骨骼肌中与肥胖相关的胰岛素抵抗的特征在于过度的β氧化，禁食过渡期间糖类底物的转换受损以及有机酸的同时消耗三羧酸循环的中间体。在培养的肌管中，通过限制脂肪酸摄取到线粒体中的操作防止了脂质诱导的胰岛素抵抗。这些结果在缺少丙二酰辅酶A脱羧酶（MCD）的小鼠中得到了概括，丙二酰辅酶A脱羧酶是一种通过减轻丙二酰辅酶A介导的肉碱棕榈酰转移酶1的抑制作用来促进线粒体β氧化的酶。因此，mcd（-/-）小鼠脂肪减少尽管肌内长链酰基辅酶A水平很高，但分解代谢和抵抗饮食引起的葡萄糖耐受不良。这些发现揭示了骨骼肌胰岛素抵抗与脂质诱导的线粒体应激之间的紧密联系。

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