Regulation of Hepatic Glucose Metabolism by FoxO Proteins, an Integrated Approach

FoxO proteins are ancient targets of insulin action and play an important role in mediating effects of insulin on gene expression and metabolism. Regulation of FoxO function in the liver is critical for the ability of insulin to maintain glucose homeostasis and suppress hepatic glucose production (HGP), and dysregulation of FoxO function is thought to contribute to the pathogenesis of diabetes mellitus. Signaling by the insulin/PI3 kinase/Akt pathway suppresses FoxO function, and FoxO proteins also are regulated by counterregulatory factors and sirtuin deacetylases which increase their activity. FoxO proteins promote gluconeogenic gene expression; however, effects of FoxO proteins on glycolytic, lipogenic, and lipid catabolic pathways also are important in mediating the effects of FoxOs on HGP. Recent studies indicate that hepatic FoxO proteins also exert important effects on extrahepatic tissues, including white and brown fat, that contribute to the regulation of HGP and systemic glucose utilization. Together, these observations indicate that FoxO proteins contribute to the regulation of systemic and hepatic glucose metabolism as part of a larger complex system engaged in the maintenance of metabolic homeostasis and the adaptation to changes in nutrient availability.