IKK-beta Links Inflammation to Obesity-Induced Insulin Resistance

Nat Med. 2005 Feb;11(2):191-8. doi: 10.1038/nm1185. Epub 2005 Jan 30.

Abstract

Inflammation may underlie the metabolic disorders of insulin resistance and type 2 diabetes. IkappaB kinase beta (IKK-beta, encoded by Ikbkb) is a central coordinator of inflammatory responses through activation of NF-kappaB. To understand the role of IKK-beta in insulin resistance, we used mice lacking this enzyme in hepatocytes (Ikbkb(Deltahep)) or myeloid cells (Ikbkb(Deltamye)). Ikbkb(Deltahep) mice retain liver insulin responsiveness, but develop insulin resistance in muscle and fat in response to high fat diet, obesity or aging. In contrast, Ikbkb(Deltamye) mice retain global insulin sensitivity and are protected from insulin resistance. Thus, IKK-beta acts locally in liver and systemically in myeloid cells, where NF-kappaB activation induces inflammatory mediators that cause insulin resistance. These findings demonstrate the importance of liver cell IKK-beta in hepatic insulin resistance and the central role of myeloid cells in development of systemic insulin resistance. We suggest that inhibition of IKK-beta, especially in myeloid cells, may be used to treat insulin resistance.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / immunology
  • Dietary Fats
  • Glucose Tolerance Test
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • I-kappa B Kinase
  • Inflammation / metabolism*
  • Insulin / metabolism
  • Insulin Resistance / physiology*
  • Mice
  • Mice, Knockout
  • Myeloid Cells / cytology
  • Myeloid Cells / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Obesity / metabolism*
  • Phenotype
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction / physiology

Substances

  • Cytokines
  • Dietary Fats
  • Insulin
  • NF-kappa B
  • Protein-Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse