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Submitted on July 16, 2004
Accepted on December 6, 2004
Department of Anatomy & Physiology and Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy, Québec G1V 4G2, Canada
* To whom correspondence should be addressed. E-mail: andre.marette{at}crchul.ulaval.ca.
The mTOR pathway integrates insulin and nutrient signaling in numerous cell types. Recent studies further suggest that this pathway negatively modulates insulin signaling to phosphatidylinositol-3-kinase (PI3K)/Akt in adipose and muscle cells. However, it is still unclear if the activation of the mTOR pathway is increased in obesity and if it could be involved in the promotion of insulin resistance. In this paper, we show that basal (fasting state) activation of mTOR and its downstream target S6K1 are markedly elevated in liver and skeletal muscle of obese rats fed a high-fat diet compared with chow-fed lean controls. Time-course studies further revealed that mTOR and S6K1 activation by insulin was accelerated in tissues of obese rats, in association with increased inhibitory phosphorylation of insulin receptor substrate (IRS)-1 on Ser636/639 and impaired Akt activation. The relationship between mTOR/S6K1 overactivation and impaired insulin signaling to Akt was further examined in hepatic cells in vitro. Insulin caused a time-dependent activation of mTOR and S6K1 in HepG2 cells. This was associated with increased IRS-1 phosphorylation on Ser636/639. Inhibition of mTOR/S6K1 by rapamycin blunted insulin-induced Ser636/639 phosphorylation of IRS-1 leading to a rapid (
5 min) and persistent increase in IRS-1-associated PI3K activity and Akt phosphorylation. These results show that activation of the mTOR pathway is increased in liver and muscle of high-fat fed obese rats. In vitro studies with rapamycin further suggest that mTOR/S6K1 overactivation contributes to elevated serine phosphorylation of IRS-1, leading to impaired insulin signaling to Akt in liver and muscle of this dietary model of obesity.
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