Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo.
Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo.
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DOI：
10.1016/j.molmet.2014.06.004
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发表时间：
2014-09
影响因子：
8.1
通讯作者：
Richter EA
中科院分区：
文献类型：
--
作者：
Kleinert M;Sylow L;Fazakerley DJ;Krycer JR;Thomas KC;Oxbøll AJ;Jordy AB;Jensen TE;Yang G;Schjerling P;Kiens B;James DE;Ruegg MA;Richter EA
MTORC1和mTORC2的急性抑制对代谢的影响尚不清楚。单次注射mTOR激酶抑制剂AZD8055可引起小鼠短暂但显著的脂肪氧化和胰岛素抵抗增加，而mTORC1抑制剂雷帕霉素则没有作用。AZD8055，但不是雷帕霉素，降低了胰岛素刺激的肌肉对葡萄糖的摄取，尽管肌肉细胞中的GLUT4转位正常。AZD8055抑制MEF细胞的糖酵解。SIN1缺失使mTORC2活性降低，糖酵解受损，AZD8055对SIN1 KO MEF无影响。野生型SIN1的重新表达挽救了糖酵解。肌肉中缺乏mTORC2亚单位Rictor的小鼠不存在AZD8055注射后的葡萄糖耐量，在体内，尽管Akt活动正常，但Rictor缺陷肌肉对葡萄糖的摄取减少。综上所述，急性mTOR抑制在一定程度上通过阻断肌肉mTORC2而不利于葡萄糖的动态平衡，表明其在体内肌肉代谢中的重要性。
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.
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影响因子：
7.7
作者：
Houde VP;Brûlé S;Festuccia WT;Blanchard PG;Bellmann K;Deshaies Y;Marette A
通讯作者：
Marette A
影响因子：
8.1
作者：
Kocalis HE;Hagan SL;George L;Turney MK;Siuta MA;Laryea GN;Morris LC;Muglia LJ;Printz RL;Stanwood GD;Niswender KD
通讯作者：
Niswender KD
影响因子：
4.1
作者：
Mora, A;Lipina, C;Alessi, DR
通讯作者：
Alessi, DR
影响因子：
29
作者：
Hagiwara, Asami;Cornu, Marion;Hall, Michael N.
通讯作者：
Hall, Michael N.
影响因子：
64.5
作者：
Jacinto, Estela;Facchinetti, Valeria;Su, Bing
通讯作者：
Su, Bing