Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance.
The mammalian target of rapamycin (mTOR) pathway integrates insulin and nutrient signaling in numerous cell types. Recent studies also suggest that this pathway negatively modulates insulin signaling to phosphatidylinositol 3-kinase/Akt in adipose and muscle cells. However, it is still unclear whether 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 is markedly elevated in liver and skeletal muscle of obese rats fed a high fat diet compared with chow-fed, lean controls. Time-course studies also 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-1 (IRS-1) on Ser636/Ser639 and impaired Akt activation. The relationship between mTOR/S6K1 overactivation and impaired insulin signaling to Akt was also 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/Ser639. Inhibition of mTOR/S6K1 by rapamycin blunted insulin-induced Ser636/Ser639 phosphorylation of IRS-1, leading to a rapid (approximately 5 min) and persistent increase in IRS-1-associated phosphatidylinositol 3-kinase 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 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.
Khamzina
Leila
L
Department of Anantomy and Physiology and Lipid Research Unit, Laval University Hospital Research Center, 2705 Laurier boulevard, Ste-Foy, Québec, Canada G1V 4G2.
Veilleux
Alain
A
Bergeron
Sébastien
S
Marette
André
A
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005508:Food Deprivation; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism; D009765:Obesity / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D012694:Serine; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546845:mTOR protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2