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

作者：Minsheng Yuan, Nicky Konstantopoulos, Jongsoon Lee, Lone Hansen, Zhiwei Li, Michael Karin, Steven E. Shoelson · 发表于：Science · 年份：2001 · DOI：10.1126/science.1061620 · 被引用次数：1879 · 研究领域：NF-κB Signaling Pathways、Adipokines, Inflammation, and Metabolic Diseases、Cytokine Signaling Pathways and Interactions

We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the IkappaB kinase beta (IKKbeta) attenuated insulin signaling in cultured cells, whereas IKKbeta inhibition reversed insulin resistance. Thus, IKKbeta, rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikkbeta+/-) 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 IKKbeta pathway as a target for insulin sensitization.