title: Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action.
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) 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.
authors.affiliation: Institute for Genetics, University of Cologne, Center of Molecular Medicine Cologne, 2nd Department for Internal Medicine University Hospital, Germany.
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.forename: Peter
authors.initials: P
authors.lastname: Ströhle
authors.forename: A Christine
authors.initials: AC
authors.lastname: Könner
authors.forename: Sabine
authors.initials: S
authors.lastname: Gruber
authors.forename: Sulay
authors.initials: S
authors.lastname: Tovar
authors.forename: Hella S
authors.initials: HS
authors.lastname: Brönneke
authors.forename: Lisa
authors.initials: L
authors.lastname: Juntti-Berggren
authors.forename: Luo-Sheng
authors.initials: LS
authors.lastname: Li
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
mesh_terms: D050154:Adiposity; D000818:Animals; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007328:Insulin; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D006003:Glycogen; D005947:Glucose