Local and Systemic Insulin Resistance Resulting From Hepatic Activation of IKK-beta and NF-kappaB

Nat Med. 2005 Feb;11(2):183-90. doi: 10.1038/nm1166. Epub 2005 Jan 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Carbohydrate Metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Dietary Fats / metabolism
  • Female
  • Hepatocytes / pathology
  • Hepatocytes / physiology*
  • Humans
  • I-kappa B Kinase
  • Insulin / metabolism
  • Insulin Resistance / physiology*
  • Interleukin-6 / metabolism
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Obesity / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Salicylates / metabolism
  • Signal Transduction / physiology

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • Dietary Fats
  • Insulin
  • Interleukin-6
  • NF-kappa B
  • Salicylates
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse