Watt Matthew J, van Denderen Bryce J W, Castelli Laura A, Bruce Clinton R, Hoy Andrew J, Kraegen Edward W, Macaulay Lance, Kemp Bruce E
St. Vincent's Institute of Medical Research, Department of Medicine, University of Melbourne, Fitzroy, Victoria 3065, Australia.
Mol Endocrinol. 2008 May;22(5):1200-12. doi: 10.1210/me.2007-0485. Epub 2008 Jan 17.
Adipose triglyceride lipase (ATGL) is important for triglyceride (TG) metabolism in adipose tissue, and ATGL-null mice show increased adiposity. Given the apparent importance of ATGL in TG metabolism and the association of lipid deposition with insulin resistance, we examined the role of ATGL in regulating skeletal muscle lipid metabolism and insulin-stimulated glucose disposal. ATGL expression in myotubes was reduced by small interfering RNA and increased with a retrovirus encoding GFP-HA-ATGL. ATGL was also overexpressed in rats by in vivo electrotransfer. ATGL was down-regulated in skeletal muscle of obese, insulin-resistant mice and negatively correlated with intramyocellular TG levels. ATGL small interfering RNA in myotubes reduced TG hydrolase activity and increased TG content, whereas ATGL overexpression induced the reciprocal response, indicating that ATGL is an essential TG lipase in skeletal muscle. ATGL overexpression in myotubes increased the oxidation of fatty acid liberated from TG and diglyceride and ceramide contents. These responses in cells were largely recapitulated in rats overexpressing ATGL. When ATGL protein expression and TG hydrolase activity in obese, insulin-resistant rats were restored to levels observed in lean rats, TG content was reduced; however, the insulin resistance induced by the high-fat diet persisted. In conclusion, ATGL TG hydrolysis in skeletal muscle is a critical determinant of lipid metabolism and storage. Although ATGL content and TG hydrolase activity are decreased in obese, insulin-resistant phenotypes, overexpression does not rescue the condition, indicating reduced ATGL is unlikely to be a primary cause of obesity-associated insulin resistance.
脂肪甘油三酯脂肪酶（ATGL）对脂肪组织中的甘油三酯（TG）代谢很重要，而缺乏ATGL的小鼠会出现肥胖增加的情况。鉴于ATGL在TG代谢中明显的重要性以及脂质沉积与胰岛素抵抗的关联，我们研究了ATGL在调节骨骼肌脂质代谢和胰岛素刺激的葡萄糖处置中的作用。用小干扰RNA降低肌管中ATGL的表达，并通过编码GFP-HA-ATGL的逆转录病毒使其表达增加。ATGL也通过体内电穿孔在大鼠中过表达。在肥胖、胰岛素抵抗小鼠的骨骼肌中，ATGL表达下调，且与细胞内TG水平呈负相关。肌管中的ATGL小干扰RNA降低了TG水解酶活性并增加了TG含量，而ATGL过表达则引发了相反的反应，这表明ATGL是骨骼肌中一种必需的TG脂肪酶。肌管中ATGL过表达增加了从TG释放的脂肪酸的氧化以及甘油二酯和神经酰胺的含量。在过表达ATGL的大鼠中，细胞中的这些反应在很大程度上得到了重现。当肥胖、胰岛素抵抗大鼠的ATGL蛋白表达和TG水解酶活性恢复到瘦大鼠中观察到的水平时，TG含量降低；然而，高脂饮食诱导的胰岛素抵抗仍然存在。总之，骨骼肌中ATGL介导的TG水解是脂质代谢和储存的关键决定因素。尽管在肥胖、胰岛素抵抗表型中ATGL含量和TG水解酶活性降低，但过表达并不能挽救这种情况，这表明ATGL降低不太可能是肥胖相关胰岛素抵抗的主要原因。
