Abstract

Objective: Macrophages play an important role in the pathogenesis of insulin resistance via the production of proinflammatory cytokines. Our goal is to decipher the molecular linkage between proinflammatory cytokine production and insulin resistance in macrophages.

Research Design and Methods: We determined cytokine profiles in cultured macrophages and identified IL-1beta gene as a potential target of FoxO1, a key transcription factor that mediates insulin action on gene expression. We studied the mechanism by which FoxO1 mediates insulin-dependent regulation of IL-1beta expression in cultured macrophages, and correlated FoxO1 activity in peritoneal macrophages with IL-1beta production profiles in mice with low-grade inflammation or insulin resistance.

Results: FoxO1 selectively promoted IL-1beta production in cultured macrophages. This effect correlated with the ability of FoxO1 to bind and enhance IL-1beta promoter activity. Mutations of the FoxO1 binding site within the IL-1beta promoter abolished FoxO1 induction of IL-1beta expression. Macrophages from insulin resistant obese db/db mice or lipopolysaccharide (LPS)-inflicted mice were associated with increased FoxO1 production, correlating with elevated levels of IL-1beta mRNA in macrophages and IL-1beta protein in plasma. In unstimulated macrophages, FoxO1 remained inert with benign effects on IL-1beta expression. In response to inflammatory stimuli, FoxO1 activity was augmented due to an impaired ability of insulin to phosphorylate FoxO1 and promote its nuclear exclusion. This effect along with NF-kappaB acted to stimulate IL-1beta production in activated macrophages.

Conclusion: FoxO1 signaling through NF-kappaB plays an important role in coupling proinflammatory cytokine production to insulin resistance in obesity and diabetes.