Regulation of interleukin-6-induced hepatic insulin resistance by mammalian target of rapamycin through the STAT3-SOCS3 pathway.
The proinflammatory cytokine interleukin (IL)-6 has been proposed to be one of the mediators that link obesity-derived chronic inflammation with insulin resistance. Signaling through the mammalian target of rapamycin (mTOR) has been found to impact insulin sensitivity under various pathological conditions, through serine phosphorylation and inhibition of insulin receptor substrate by the downstream effector of mTOR, ribosomal S6 kinase 1 (S6K1). However, an involvement of mTOR in IL-6-induced insulin resistance has not yet been reported. Here we show that rapamycin, the inhibitor of mTOR signaling, rescues insulin signaling and glycogen synthesis from IL-6 inhibition in HepG2 hepatocarcinoma cells as well as in mouse primary hepatocytes. IL-6 activates S6K1 in these cells, but unexpectedly, S6K1 is not involved in IL-6 inhibition of insulin signaling, since the effect of IL-6 persists in cells with drastically reduced S6K1 levels induced by RNA interference, suggesting that the function of mTOR signaling is through a mechanism different from the prevailing model of S6K1 phosphorylation of insulin receptor substrate-1. Interestingly, we find that the phosphorylation of STAT3 on Ser(727) and STAT3 transcriptional activity are regulated by mTOR upon IL-6 stimulation and that STAT3 is required for IL-6 inhibition of insulin signaling. Furthermore, IL-6-induced SOCS3 expression is inhibited by rapamycin, and ectopic expression of SOCS3 blocks the ability of rapamycin to enhance insulin sensitivity in the presence of IL-6. Taken together, we propose that mTOR plays a key role in IL-6-induced hepatic insulin resistance by regulating STAT3 activation and subsequent SOCS3 expression.
Kim
Jeong-Ho
JH
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Kim
Jae Eun
JE
Liu
Hui-Yu
HY
Cao
Wenhong
W
Chen
Jie
J
D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D017931:DNA Primers; D017930:Genes, Reporter; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000494:pharmacology*; D016086:Lentivirus / Q000235:genetics; D008113:Liver Neoplasms; D008156:Luciferases / Q000235:genetics; D011494:Protein Kinases / Q000187:drug effects / Q000502:physiology*; D034622:RNA Interference; D011994:Recombinant Proteins / Q000494:pharmacology; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D017931:DNA Primers; D007328:Insulin; D015850:Interleukin-6; D011994:Recombinant Proteins; D008156:Luciferases; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus