title: Deletion of hepatic FoxO1/3/4 genes in mice significantly impacts on glucose metabolism through downregulation of gluconeogenesis and upregulation of glycolysis.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Xiwen
authors.initials: X
authors.lastname: Xiong
authors.forename: Rongya
authors.initials: R
authors.lastname: Tao
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: X Charlie
authors.initials: XC
authors.lastname: Dong
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D004041:Dietary Fats / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D004041:Dietary Fats; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C525394:FoxO4 protein, mouse; C467200:Foxo1 protein, mouse; C501860:Sirt6 protein, mouse; D005941:Glucokinase; D037761:Sirtuins; D005947:Glucose