Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance
Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance
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DOI：
10.1016/j.cmet.2007.10.013
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发表时间：
2008-01-01
期刊：
影响因子：
29
通讯作者：
Muoio, Deborah M.
中科院分区：
文献类型：
--
作者：
Koves, Timothy R.;Ussher, John R.;Muoio, Deborah M.
以前的研究表明，胰岛素抵抗的发展继发于脂肪氧化减少和细胞溶质脂质分子的积累，损害胰岛素信号传导。与此模型相反，本研究使用靶向代谢组学发现，骨骼肌中肥胖相关的胰岛素抵抗的特征在于过度β-氧化，在禁食至进食过渡期间转换为碳水化合物底物受损，以及三羧酸循环的有机酸中间体同时耗尽。在培养的肌管中，通过限制脂肪酸摄取到线粒体中的操作来防止脂质诱导的胰岛素抵抗。这些结果在缺乏丙二酰辅酶A脱羧酶（MCD）的小鼠中得到了重现，MCD是一种通过缓解丙二酰辅酶A介导的肉毒碱棕榈酰转移酶1抑制来促进线粒体β-氧化的酶。因此，mcd（-/-）小鼠表现出脂肪分解率降低，并抵抗饮食诱导的葡萄糖耐受不良，尽管肌内长链酰基辅酶A水平较高。这些发现揭示了骨骼肌胰岛素抵抗和脂质诱导的线粒体应激之间的密切联系。
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 palm itoyltransferase 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.