Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action.
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.
Wunderlich
F Thomas
FT
Institute for Genetics, University of Cologne, Center of Molecular Medicine Cologne, 2nd Department for Internal Medicine University Hospital, Germany.
Ströhle
Peter
P
Könner
A Christine
AC
Gruber
Sabine
S
Tovar
Sulay
S
Brönneke
Hella S
HS
Juntti-Berggren
Lisa
L
Li
Luo-Sheng
LS
van Rooijen
Nico
N
Libert
Claude
C
Berggren
Per-Olof
PO
Brüning
Jens C
JC
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
D007328:Insulin; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D006003:Glycogen; D005947:Glucose