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

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

Research output: Contribution to journalArticle

40 Citations (Scopus)

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.

Original languageEnglish
Article numbere74340
JournalPLoS One
Volume8
Issue number8
DOIs
StatePublished - Aug 28 2013

Fingerprint

Gluconeogenesis
gluconeogenesis
glycolysis
Glycolysis
Metabolism
Up-Regulation
Down-Regulation
Genes
Glucose
liver
glucose
metabolism
Liver
mice
Transcription Factor 3
genes
Glucokinase
glucokinase
Nutrition
Homeostasis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Deletion of Hepatic FoxO1/3/4 Genes in Mice Significantly Impacts on Glucose Metabolism through Downregulation of Gluconeogenesis and Upregulation of Glycolysis. / Xiong, Xiwen; Tao, Rongya; DePinho, Ronald A.; Dong, X.

In: PLoS One, Vol. 8, No. 8, e74340, 28.08.2013.

Research output: Contribution to journalArticle

@article{8bb77a27c1bc4f9fa1503de731cd65a0,
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.",
author = "Xiwen Xiong and Rongya Tao and DePinho, {Ronald A.} and X. Dong",
year = "2013",
month = "8",
day = "28",
doi = "10.1371/journal.pone.0074340",
language = "English",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - Deletion of Hepatic FoxO1/3/4 Genes in Mice Significantly Impacts on Glucose Metabolism through Downregulation of Gluconeogenesis and Upregulation of Glycolysis

AU - Xiong, Xiwen

AU - Tao, Rongya

AU - DePinho, Ronald A.

AU - Dong, X.

PY - 2013/8/28

Y1 - 2013/8/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84883205274&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84883205274&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0074340

DO - 10.1371/journal.pone.0074340

M3 - Article

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 8

M1 - e74340

ER -