骨骼肌胰岛素抵抗：线粒体超载和β-氧化
Mitochondrial Overload and Incomplete Fatty Acid Oxidation Contribute to Skeletal Muscle Insulin ResistancePrevious 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 β-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 β-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.
http://www.cellmetabolism.org/content/article/abstract?uid=PIIS1550413107003063
作者单位
1 Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC 27710, USA
2 Department of Medicine, Duke University, Durham, NC 27710, USA
3 Department of Pharmacology & Cancer Biology, Duke University, Durham, NC 27710, USA
4 Cardiovascular Research Group, University of Alberta, Edmonton, AB T6G 2S2, Canada
以前的研究已经表明胰岛素抵抗继发于脂肪氧化的减弱及其导致的胞浆脂质的积聚，后者削弱了胰岛素信号通路。
与此模型相反，本研究应用霸向代谢组学发现肥胖相关的骨骼肌胰岛素抵抗的特征是：β-氧化过度；在饥饿-饱食转变过渡过程中，碳水化合物底物的转化受损；在三羧酸循环过程中，有机酸中间产物的同时耗竭。
这些发现揭示了骨骼肌抵抗和脂质诱导的线粒体应急之间的强相关性。
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