Journal
CELL METABOLISM
Volume 12, Issue 3, Pages 237-249Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2010.06.011
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Funding
- CMMC
- Novartis Foundation
- German Research Foundation (DFG [1492-7-1, SFB 635, SFB 832]
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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-6R alpha(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-6R alpha-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 I kappa B alpha. Neutralization of TNF-alpha or ablation of Kupffer cells restored glucose tolerance in IL-6R alpha(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.
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