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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2005-02

AUTHORS

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

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. More... »

PAGES

183-190

References to SciGraph publications

  • 2003-12. Inflammatory pathways and insulin action in INTERNATIONAL JOURNAL OF OBESITY
  • 1998-09. Is Type II diabetes mellitus a disease of the innate immune system? in DIABETOLOGIA
  • 2002-10. JMM – Past and Present in JOURNAL OF MOLECULAR MEDICINE
  • 2003-12. Inflammation and the IKKβ/IκB/NF-κB axis in obesity- and diet-induced insulin resistance in INTERNATIONAL JOURNAL OF OBESITY
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nm1166

    DOI

    http://dx.doi.org/10.1038/nm1166

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1008419757

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/15685173


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