Local and systemic insulin resistance resulting from hepatic activation of IKK-ßand NF-?B.

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

We show that NF-?B and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We havematched 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 diabetesphenotype, 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-1ßand TNF-a,was increased in LIKK mice to a similar extent as induced by HFD in in wild-type mice. Parallel increases were observed incytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 orsalicylate inhibition of IKK-ß. Hepatic expression of the I?Basuperrepressor (LISR) reversed the phenotypeof both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads tosubacute hepatic 'inflammation' through NF-?B activation and downstream cytokine production.This causes insulin resistance both locally in liver and systemically.

NF-kappa B; LIVER; OBESITY; TRANSGENIC mice; TYPE 2 diabetes; INSULIN resistance; CYTOKINES

Nature Medicine, 2005, Vol 11, Issue 2, p183

1078-8956

Academic Journal

10.1038/nm1166