Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action

Cell Metab. 2010 Sep 8;12(3):237-49. doi: 10.1016/j.cmet.2010.06.011.


The contribution of interleukin (IL)-6 signaling in obesity-induced inflammation remains controversial. To specifically define the role of hepatic IL-6 signaling in insulin action and resistance, we have generated mice with hepatocyte-specific IL-6 receptor (IL-6R) alpha deficiency (IL-6Ralpha(L-KO) mice). These animals showed no alterations in body weight and fat content but exhibited a reduction in insulin sensitivity and glucose tolerance. Impaired glucose metabolism originated from attenuated insulin-stimulated glucose transport in skeletal muscle and fat. Surprisingly, hepatic IL-6Ralpha-disruption caused an exaggerated inflammatory response during euglycemic hyperinsulinemic clamp analysis, as revealed by increased expression of IL-6, TNF-alpha, and IL-10, as well as enhanced activation of inflammatory signaling such as phosphorylation of IkappaBalpha. Neutralization of TNF-alpha or ablation of Kupffer cells restored glucose tolerance in IL-6Ralpha(L-KO) mice. Thus, our results reveal an unexpected role for hepatic IL-6 signaling to limit hepatic inflammation and to protect from local and systemic insulin resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity
  • Animals
  • Energy Metabolism
  • Glucose / metabolism
  • Glycogen / biosynthesis
  • Homeostasis
  • Humans
  • Inflammation / metabolism*
  • Insulin / metabolism*
  • Insulin Resistance / physiology
  • Interleukin-10 / metabolism
  • Interleukin-6 / metabolism*
  • Kupffer Cells / metabolism
  • Liver / cytology*
  • Liver / metabolism
  • Liver / pathology*
  • Mice
  • Mice, Knockout
  • Receptors, Interleukin-6 / genetics
  • Receptors, Interleukin-6 / metabolism
  • Signal Transduction / physiology*
  • Tumor Necrosis Factor-alpha / metabolism


  • Insulin
  • Interleukin-6
  • Receptors, Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Glycogen
  • Glucose