Deletion of Hepatic FoxO1/3/4 Genes in Mice Significantly Impacts on Glucose Metabolism through Downregulation of Gluconeogenesis and Upregulation of Glycolysis

• DOI: 10.1371/journal.pone.0074340
• Publication Date: 2013-08-28T21:16:34Z
• Authors: Xiwen Xiong; Rongya Tao; Ronald A. DePinho; X. Charlie Dong
• Keywords: 0301 basic medicine; Science; Cell Cycle Proteins; Mice; 03 medical and health sciences; Glucokinase; Animals; Homeostasis; Sirtuins; Mice, Knockout; 2. Zero hunger; Forkhead Box Protein O1; Q; Forkhead Box Protein O3; R; Gluconeogenesis; Forkhead Transcription Factors; Dietary Fats; Up-Regulation; Glucose; Liver; Organ Specificity; Medicine; Glycolysis; Gene Deletion; Research Article

Forkhead transcription factors FoxO1/3/4 have pleiotrophic functions including anti-oxidative stress and metabolism. With regard to glucose metabolism, most studies have been focused on FoxO1. To further investigate their hepatic functions, we generated liver-specific FoxO1/3/4 knockout mice (LTKO) and examined their collective impacts on glucose homeostasis under physiological and pathological conditions. As compared to wild-type mice, LTKO mice had lower blood glucose levels under both fasting and non-fasting conditions and they manifested better glucose and pyruvate tolerance on regular chow diet. After challenged by a high-fat diet, wild-type mice developed type 2 diabetes, but LTKO mice remained euglycemic and insulin-sensitive. To understand the underlying mechanisms, we examined the roles of SIRT6 (Sirtuin 6) and Gck (glucokinase) in the FoxO-mediated glucose metabolism. Interestingly, ectopic expression of SIRT6 in the liver only reduced gluconeogenesis in wild-type but not LTKO mice whereas knockdown of Gck caused glucose intolerance in both wild-type and LTKO mice. The data suggest that both decreased gluconeogenesis and increased glycolysis may contribute to the overall glucose phenotype in the LTKO mice. Collectively, FoxO1/3/4 transcription factors play important roles in hepatic glucose homeostasis.