FoxO1 Links Insulin Resistance to Proinflammatory Cytokine IL-1β Production in Macrophages

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 interleukin (IL)-1 beta 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-1 beta expression in cultured macrophages and correlated FoxO1 activity in peritoneal macrophages with IL-1 beta production profiles in mice with low-grade inflammation or insulin resistance. RESULTS-FoxO1 selectively promoted IL-1 beta production in cultured macrophages. This effect correlated with the ability of FoxO1 to bind and enhance IL-1 beta promoter activity. Mutations of the FoxO1. binding site within the IL-1 beta promoter abolished FoxO1 induction of IL-1 beta expression. Macrophages from insulin-resistant obese db/db mice or lipopolysaccharide-inflicted mice were associated with increased FoxO1 production, correlating with elevated levels of IL-1 beta mRNA in macrophages and IL-1 beta protein in plasma. In nonstimulated macrophages, FoxO1 remained inert with benign effects on IL-1 beta expression. In response to inflammatory stimuli, FoxO1 activity was augmented because of an impaired ability of insulin to phosphorylate FoxO1 and promote its nuclear exclusion. This effect along with nuclear factor-kappa B acted to stimulate IL-1 beta production in activated macrophages. CONCLUSIONS-FoxO1 signaling through nuclear factor-kappa B plays an important role in coupling proinflammatory cytokine production to insulin resistance in obesity and diabetes. Diabetes 58:2624-2633, 2009