Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.
Journal: 2005/April - Nature Medicine
ISSN: 1078-8956
Abstract:
We show that NF-kappaB 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-kappaB 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-1beta and TNF-alpha, 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-beta. Hepatic expression of the IkappaBalpha 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-kappaB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.
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Nat Med 11(2): 183-190

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

Joslin Diabetes Center & Department of Medicine, Harvard Medical School, One Joslin Place, Boston, Massachusetts 02215, USA.
Present address: Vertex Pharmaceuticals, 130 Waverly Street, Cambridge, Massachusetts 02139, USA.
Present address: Hewlett Packard Caribe Ltd., Highway 110 North Km 5.1, Aguadilla, Puerto Rico 00603, USA. Correspondence should be addressed to S.E.S. (ude.dravrah.nilsoj@nosleohs.nevets).

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-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.

Abstract

Footnotes

Note: Supplementary information is available on the Nature Medicine website.

COMPETING INTERESTS STATEMENT

The authors declare that they have no competing financial interests.

Footnotes

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