Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of <i>Ikkβ</i>

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 Lep ob/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.