FoxO1: A conductor of insulin signaling to glucose and lipid metabolism

Abstract

Excessive hepatic glucose production and very low-density lipoprotein (VLDL) secretion contributes to the pathogenesis of hyperglycemia and hypertriglyceridemia-two pathological traits that are intertwined in insulin resistant subjects with obesity and type 2 diabetes. To date, the molecular basis that links insulin resistance to hepatic overproduction of glucose and VLDL is poorly understood. Preclinical and clinical investigation leads to the characterization of the forkhead box O1 (FoxO1) as a significant transcription factor that integrates insulin signaling to hepatic glucose and lipid metabolism. FoxO1 is abundantly expressed in the liver and its transcription activity is tightly regulated by insulin. Insulin inhibits FoxO1 activity via a distinct mechanism by altering its subcellular redistribution. Insulin signaling bifurcates at FoxO1 in the liver to govern two metabolic pathways, namely gluconeogenesis and VLDL assembly. This effect helps synchronize hepatic insulin signaling to simultaneously adjust the rates of hepatic glucose production and VLDL secretion in response to nutrient availability. Such FoxO1-dependent mechanism seems pivotal for the liver to rapidly adapt to metabolic shift between fasting to feeding states for maintaining normal glucose and lipid homeostasis. In this article, we center our review on the role of FoxO1 in the liver. We provide mechanistic insights into how FoxO1 orchestrates insulin action on hepatic glucose and lipid metabolism in healthy individuals, and how FoxO1 dysregulation, resulting from insulin resistance, contributes to the dual pathogenesis of hyperglycemia and hyperlipidemia in obesity and type 2 diabetes. Finally, we discuss whether FoxO1 is a potential therapeutic target for improving blood glucose and lipid profiles in insulin resistant subjects with obesity and type 2 diabetes.