Interleukin-6 depletion selectively improves hepatic insulin action in obesity

Endocrinology. 2005 Aug;146(8):3417-27. doi: 10.1210/en.2004-1468. Epub 2005 Apr 21.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipose Tissue / physiopathology*
  • Animals
  • Antibodies / pharmacology
  • DNA-Binding Proteins / metabolism*
  • Haptoglobins / genetics
  • Immunoglobulin G / pharmacology
  • Inflammation
  • Insulin / physiology*
  • Interleukin-6 / antagonists & inhibitors*
  • Liver / physiopathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Obesity / physiopathology*
  • Phosphorylation
  • Polymerase Chain Reaction
  • Receptor, Insulin / metabolism
  • STAT3 Transcription Factor
  • Signal Transduction / physiology
  • Trans-Activators / metabolism*


  • Antibodies
  • DNA-Binding Proteins
  • Haptoglobins
  • Immunoglobulin G
  • Insulin
  • Interleukin-6
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Trans-Activators
  • Receptor, Insulin