PMID- 17993646
OWN - NLM
STAT- MEDLINE
DCOM- 20080320
LR  - 20220409
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 2
DP  - 2008 Jan 11
TI  - Regulation of interleukin-6-induced hepatic insulin resistance by mammalian 
      target of rapamycin through the STAT3-SOCS3 pathway.
PG  - 708-15
AB  - 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.
FAU - Kim, Jeong-Ho
AU  - Kim JH
AD  - Department of Cell and Developmental Biology, University of Illinois at 
      Urbana-Champaign, Urbana, Illinois 61801, USA.
FAU - Kim, Jae Eun
AU  - Kim JE
FAU - Liu, Hui-Yu
AU  - Liu HY
FAU - Cao, Wenhong
AU  - Cao W
FAU - Chen, Jie
AU  - Chen J
LA  - eng
GR  - R01 AR48914/AR/NIAMS NIH HHS/United States
GR  - R01DK76039/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20071110
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA Primers)
RN  - 0 (Insulin)
RN  - 0 (Interleukin-6)
RN  - 0 (Recombinant Proteins)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Carcinoma, Hepatocellular
MH  - Cell Line, Tumor
MH  - DNA Primers
MH  - Genes, Reporter
MH  - Homeostasis
MH  - Humans
MH  - Insulin/pharmacology
MH  - *Insulin Resistance
MH  - Interleukin-6/*pharmacology
MH  - Lentivirus/genetics
MH  - Liver Neoplasms
MH  - Luciferases/genetics
MH  - Protein Kinases/drug effects/*physiology
MH  - RNA Interference
MH  - Recombinant Proteins/pharmacology
MH  - Ribosomal Protein S6 Kinases/genetics
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
EDAT- 2007/11/13 09:00
MHDA- 2008/03/21 09:00
CRDT- 2007/11/13 09:00
PHST- 2007/11/13 09:00 [pubmed]
PHST- 2008/03/21 09:00 [medline]
PHST- 2007/11/13 09:00 [entrez]
AID - S0021-9258(20)68978-5 [pii]
AID - 10.1074/jbc.M708568200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Jan 11;283(2):708-15. doi: 10.1074/jbc.M708568200. Epub 2007 
      Nov 10.