Molecular Physiology Group, Department of Nutrition, Exercise and Sports, August Krogh Centre, University of Copenhagen, Copenhagen, Denmark.
Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
Mol Metab. 2014 Jun 27;3(6):630-41. doi: 10.1016/j.molmet.2014.06.004. eCollection 2014 Sep.
The effect of acute inhibition of both mTORC1 and mTORC2 on metabolism is unknown. A single injection of the mTOR kinase inhibitor, AZD8055, induced a transient, yet marked increase in fat oxidation and insulin resistance in mice, whereas the mTORC1 inhibitor rapamycin had no effect. AZD8055, but not rapamycin reduced insulin-stimulated glucose uptake into incubated muscles, despite normal GLUT4 translocation in muscle cells. AZD8055 inhibited glycolysis in MEF cells. Abrogation of mTORC2 activity by SIN1 deletion impaired glycolysis and AZD8055 had no effect in SIN1 KO MEFs. Re-expression of wildtype SIN1 rescued glycolysis. Glucose intolerance following AZD8055 administration was absent in mice lacking the mTORC2 subunit Rictor in muscle, and in vivo glucose uptake into Rictor-deficient muscle was reduced despite normal Akt activity. Taken together, acute mTOR inhibition is detrimental to glucose homeostasis in part by blocking muscle mTORC2, indicating its importance in muscle metabolism in vivo.
急性抑制 mTORC1 和 mTORC2 对代谢的影响尚不清楚。单次注射 mTOR 激酶抑制剂 AZD8055 可诱导小鼠脂肪氧化和胰岛素抵抗短暂而显著增加，而 mTORC1 抑制剂雷帕霉素则没有作用。AZD8055 可降低培养肌肉中胰岛素刺激的葡萄糖摄取，尽管肌肉细胞中的 GLUT4 易位正常。AZD8055 抑制 MEF 细胞中的糖酵解。SIN1 缺失阻断 mTORC2 活性会损害糖酵解，而 AZD8055 在 SIN1 KO MEFs 中没有作用。野生型 SIN1 的重新表达可恢复糖酵解。在肌肉中缺乏 mTORC2 亚基 Rictor 的小鼠中，AZD8055 给药后葡萄糖耐量不足，并且尽管 Akt 活性正常，但缺乏 Rictor 的肌肉中的体内葡萄糖摄取减少。综上所述，急性 mTOR 抑制在一定程度上通过阻断肌肉 mTORC2 对葡萄糖稳态有害，表明其在体内肌肉代谢中的重要性。
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