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Article
Nature Medicine 11, 183 - 190 (2005)
Published online: 30 January 2005 | doi:10.1038/nm1166
Local and systemic insulin resistance resulting from hepatic activation of IKK-
and NF-
B
Dongsheng Cai1, Minsheng Yuan1, Daniel F Frantz1,2, Peter A Melendez1,3, Lone Hansen1, Jongsoon Lee1 & Steven E Shoelson1
Abstract
We show that NF-
B and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We have
matched this state of chronic, subacute 'inflammation' by low-level activation of NF-B in the liver of transgenic mice,
designated LIKK, by selectively expressing constitutively active IKK-b in hepatocytes. These mice exhibit a type 2 diabetes
phenotype, characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance,
including effects in muscle. The hepatic production of proinflammatory cytokines, including IL-6, IL-1
and TNF-
,
was increased in LIKK mice to a similar extent as induced by HFD in in wild-type mice. Parallel increases were observed in
cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 or
salicylate inhibition of IKK-. Hepatic expression of the IB superrepressor (LISR) reversed the phenotype
of both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads to
subacute hepatic 'inflammation' through NF-B activation and downstream cytokine production.
This causes insulin resistance both locally in liver and systemically.
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