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

F. Thomas Wunderlich, Peter Ströhle, A. Christine Könner, Sabine Gruber, Sulay Tovar, Hella S. Brönneke, Lisa Juntti-Berggren, Luo Sheng Li, Nico Van Rooijen, Claude Libert, Per Olof Berggren, Jens C. Brüning

Research output: Contribution to journalArticlepeer-review

144 Scopus citations

Abstract

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) α deficiency (IL-6RαL-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-6Rα-disruption caused an exaggerated inflammatory response during euglycemic hyperinsulinemic clamp analysis, as revealed by increased expression of IL-6, TNF-α, and IL-10, as well as enhanced activation of inflammatory signaling such as phosphorylation of IκBα. Neutralization of TNF-α or ablation of Kupffer cells restored glucose tolerance in IL-6RαL-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.

Original languageEnglish (US)
Pages (from-to)237-249
Number of pages13
JournalCell Metabolism
Volume12
Issue number3
DOIs
StatePublished - Sep 8 2010

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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