Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB

Dongsheng Cai, Minsheng Yuan, Daniel F. Frantz, Peter A. Melendez, Lone Hansen, Jongsoon Lee, Steven E. Shoelson

Research output: Contribution to journalArticle

1532 Scopus citations

Abstract

We show that NF-κB 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-κB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-β 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-β and TNF-α, 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-β. Hepatic expression of the 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-κB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.

Original languageEnglish (US)
Pages (from-to)183-190
Number of pages8
JournalNature Medicine
Volume11
Issue number2
DOIs
StatePublished - Feb 1 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Cai, D., Yuan, M., Frantz, D. F., Melendez, P. A., Hansen, L., Lee, J., & Shoelson, S. E. (2005). Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nature Medicine, 11(2), 183-190. https://doi.org/10.1038/nm1166