期刊
JOURNAL OF ENDOCRINOLOGY
卷 202, 期 3, 页码 441-451出版社
BIOSCIENTIFICA LTD
DOI: 10.1677/JOE-09-0202
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资金
- NIDDK NIH HHS [R15 DK057625, DK-57625] Funding Source: Medline
- NIGMS NIH HHS [S06 GM048680, T34 GM008395, GM-08395, GM-48680] Funding Source: Medline
The serine/threonine protein kinase, mammalian target of rapamycin (mTOR) is regulated by insulin and nutrient availability and has been proposed to play a central role as a nutrient sensor in skeletal muscle. mTOR associates with its binding partners, raptor and rictor, to form two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) respectively. We have investigated the assembly of mTORC1/2 and the activation of their downstream Substrates (i.e. Akt, S6K1) in response to known effectors of mTOR, excess lipid availability and AMP-activated protein kinase (AMPK) activation/exercise training in rat skeletal muscle. The hi vivo formation of MTORC1 and 2 and the activation of their respective downstream substrates were increased in response to chronic (8 weeks) consumption of a high-fat diet. Diet-induced mTORC activation and skeletal muscle insulin resistance were reversed by 4 weeks of exercise training, which was associated with enhanced muscle AMPK activation. In order to determine whether AMPK activation reverses lipid-induced mTOR activation, L6 myotubes were exposed to 0.4 mM palmitate to activate mTORC1/2 in the absence or presence of 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR,). Palmitate exposure (4 11) increased insulin-stimulated S6K1 Thr389 phosphorylation by 60%, indicating activation of mTORC1. AMPK activation with 1 mM AICAR abolished lipid-induced mTOR activation in vitro. Our data implicates reductions in mTOR complex activation with the reversal of lipid-induced skeletal muscle insulin resistance in response to exercise training or AICAR and identifies mTOR, as a potential target for the treatment of insulin resistance. journal of Endocrinology (2009) 202, 441-451
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