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

D Cai, M Yuan, DF Frantz, PA Melendez, L Hansen… - Nature medicine, 2005 - nature.com
D Cai, M Yuan, DF Frantz, PA Melendez, L Hansen, J Lee, SE Shoelson
Nature medicine, 2005nature.com
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-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 …
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-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-1β 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 IκBα 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.
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