Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkβ

Science  31 Aug 2001:
Vol. 293, Issue 5535, pp. 1673-1677
DOI: 10.1126/science.1061620

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We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the IκB kinase β (IKKβ) attenuated insulin signaling in cultured cells, whereas IKKβ inhibition reversed insulin resistance. Thus, IKKβ, rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikkβ +/−) protected against the development of insulin resistance during high-fat feeding and in obese Lepob/ob mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKβ pathway as a target for insulin sensitization.

  • * These authors contributed equally to this work.

  • To whom correspondence should be addressed. E-mail: Steven.Shoelson{at}

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