Interleukin-6 depletion selectively improves hepatic insulin action in obesity.
Obesity and insulin resistance are considered chronic inflammatory states, in part because circulating IL-6 is elevated. Exogenous IL-6 can induce hepatic insulin resistance in vitro and in vivo. The importance of endogenous IL-6, however, to insulin resistance of obesity is unresolved. To test the hypothesis that IL-6 contributes to the inflammation and insulin resistance of obesity, IL-6 was depleted in Lep(ob) mice by injection of IL-6-neutralizing antibody. In untreated Lep(ob) mice, signal transducer and activator of transcription-3 (STAT3) activation was increased compared with that in lean controls, consistent with an inflammatory state. With IL-6 depletion, activation of STAT3 in liver and adipose tissue and expression of haptoglobin were reduced. Expression of the IL-6-dependent, hepatic acute phase protein fibrinogen was also decreased. Using the hyperinsulinemic-euglycemic clamp technique, insulin-dependent suppression of endogenous glucose production was 89% in IL-6-depleted Lep(ob) mice, in contrast to only 32% in Lep(ob) controls, indicating a marked increase in hepatic insulin sensitivity. A significant change in glucose uptake in skeletal muscle after IL-6 neutralization was not observed. In a direct comparison of hepatic insulin signaling in Lep(ob) mice treated with anti-IL-6 vs. IgG-treated controls, insulin-dependent insulin receptor autophosphorylation and activation of Akt (pSer473) were increased by nearly 50% with IL-6 depletion. In adipose tissue, insulin receptor signaling showed no significant change despite major reductions in STAT3 phosphorylation and haptoglobin expression. In diet-induced obese mice, depletion of IL-6 improved insulin responsiveness in 2-h insulin tolerance tests. In conclusion, these results indicate that IL-6 plays an important and selective role in hepatic insulin resistance of obesity.
Klover
Peter J
PJ
Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642, USA.
Clementi
Alicia H
AH
Mooney
Robert A
RA
D000273:Adipose Tissue / Q000503:physiopathology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006242:Haptoglobins / Q000235:genetics; D007074:Immunoglobulin G / Q000494:pharmacology; D007249:Inflammation; D007328:Insulin / Q000502:physiology*; D008099:Liver / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000503:physiopathology*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011972:Receptor, Insulin / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*; D000093242:Interleukin-6 Inhibitors
D000906:Antibodies; D004268:DNA-Binding Proteins; D006242:Haptoglobins; D007074:Immunoglobulin G; D007328:Insulin; D011972:Receptor, Insulin; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000093242:Interleukin-6 Inhibitors; C494087:Stat3 protein, mouse