Integrated Regulation of Hepatic Lipid and Glucose Metabolism by Adipose Triacylglycerol Lipase and FoxO Proteins

Metabolism is a highly integrated process that is coordinately regulated between tissues and within individual cells. FoxO proteins are major targets of insulin action and contribute to the regulation of gluconeogenesis, glycolysis, and lipogenesis in the liver. However, the mechanisms by which FoxO proteins exert these diverse effects in an integrated fashion remain poorly understood. We report that FoxO proteins also exert important effects on intrahepatic lipolysis and fatty acid oxidation via the regulation of adipose triacylglycerol lipase (ATGL), which mediates the first step in lipolysis, and its inhibitor, the G0/S1 switch 2 gene (G0S2). We also find that ATGL-dependent lipolysis plays a critical role in mediating diverse effects of FoxO proteins in the liver, including effects on gluconeogenic, glycolytic, and lipogenic gene expression and metabolism. These results indicate that intrahepatic lipolysis plays a critical role in mediating and integrating the regulation of glucose and lipid metabolism downstream of FoxO proteins. [Display omitted] •FoxO1 regulates expression of ATGL lipase and G0S2, its inhibitor, in the liver•FoxO1 promotes intrahepatic lipolysis and FAO via ATGL-dependent effects•FoxO1 effects on glucokinase and PEPCK gene expression are ATGL dependent•ATGL-dependent lipolysis regulates glucose/lipid metabolism downstream from FoxO FoxO proteins are major targets of insulin that regulate hepatic glucose metabolism. Zhang et al. report that FoxO proteins also promote triacylglycerol catabolism through regulation of ATGL and its inhibitor, G0S2, and that ATGL-dependent lipolysis plays an important role in mediating the effects of FoxO on liver glucose and lipid metabolism.