Journal Article

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

Xiong, Xiwen, DePinho, Ronald A., Dong, X. Charlie, Tao, Rongya

2013

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Blood glucose / Diabetes mellitus / Dietary Fats - pharmacology / Ectopic expression / Fasting / Forkhead Box Protein O1 / Forkhead Box Protein O3 / Forkhead protein / Forkhead Transcription Factors - genetics / Forkhead Transcription Factors - metabolism / FOXO1 protein / Gene Deletion / Glucokinase / Glucokinase - genetics / Glucokinase - metabolism / Gluconeogenesis / Gluconeogenesis - drug effects / Gluconeogenesis - physiology / Glucose / Glucose - genetics / Glucose - metabolism / Glucose tolerance / Glycolysis / Glycolysis - drug effects / Glycolysis - physiology / High fat diet / Homeostasis / Homeostasis - drug effects / Homeostasis - physiology / Insulin / Insulin resistance / Intolerance / Kinases / Liver / Liver - metabolism / Metabolism / Mice / Mice, Knockout / Organ Specificity - genetics / Oxidative metabolism / Oxidative stress / Pyruvic acid / Rodents / Sirtuins - genetics / Sirtuins - metabolism / Transcription factors / Up-Regulation - drug effects / Up-Regulation - physiology