Inactivation of Hepatic Foxo1 by Insulin Signaling Is Required for Adaptive Nutrient Homeostasis and Endocrine Growth Regulation

X. Dong, Kyle D. Copps, Shaodong Guo, Yedan Li, Ramya Kollipara, Ronald A. DePinho, Morris F. White

Research output: Contribution to journalArticle

239 Citations (Scopus)

Abstract

The forkhead transcription factor Foxo1 regulates expression of genes involved in stress resistance and metabolism. To assess the contribution of Foxo1 to metabolic dysregulation during hepatic insulin resistance, we disrupted Foxo1 expression in the liver of mice lacking hepatic Irs1 and Irs2 (DKO mice). DKO mice were small and developed diabetes; analysis of the DKO-liver transcriptome identified perturbed expression of growth and metabolic genes, including increased Ppargc1a and Igfbp1, and decreased glucokinase, Srebp1c, Ghr, and Igf1. Liver-specific deletion of Foxo1 in DKO mice resulted in significant normalization of the DKO-liver transcriptome and partial restoration of the response to fasting and feeding, near normal blood glucose and insulin concentrations, and normalization of body size. These results demonstrate that constitutively active Foxo1 significantly contributes to hyperglycemia during severe hepatic insulin resistance, and that the Irs1/2 → PI3K → Akt → Foxo1 branch of insulin signaling is largely responsible for hepatic insulin-regulated glucose homeostasis and somatic growth.

Original languageEnglish (US)
Pages (from-to)65-76
Number of pages12
JournalCell Metabolism
Volume8
Issue number1
DOIs
StatePublished - Jul 2 2008
Externally publishedYes

Fingerprint

Homeostasis
Insulin
Food
Liver
Growth
Transcriptome
Insulin Resistance
Forkhead Transcription Factors
Glucokinase
Body Size
Phosphatidylinositol 3-Kinases
Hyperglycemia
Blood Glucose
Fasting
Gene Expression
Glucose
Genes

Keywords

  • HUMDISEASE

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Inactivation of Hepatic Foxo1 by Insulin Signaling Is Required for Adaptive Nutrient Homeostasis and Endocrine Growth Regulation. / Dong, X.; Copps, Kyle D.; Guo, Shaodong; Li, Yedan; Kollipara, Ramya; DePinho, Ronald A.; White, Morris F.

In: Cell Metabolism, Vol. 8, No. 1, 02.07.2008, p. 65-76.

Research output: Contribution to journalArticle

Dong, X. ; Copps, Kyle D. ; Guo, Shaodong ; Li, Yedan ; Kollipara, Ramya ; DePinho, Ronald A. ; White, Morris F. / Inactivation of Hepatic Foxo1 by Insulin Signaling Is Required for Adaptive Nutrient Homeostasis and Endocrine Growth Regulation. In: Cell Metabolism. 2008 ; Vol. 8, No. 1. pp. 65-76.
@article{0e0c28ed3ce34f6bbc3207df7c99daae,
title = "Inactivation of Hepatic Foxo1 by Insulin Signaling Is Required for Adaptive Nutrient Homeostasis and Endocrine Growth Regulation",
abstract = "The forkhead transcription factor Foxo1 regulates expression of genes involved in stress resistance and metabolism. To assess the contribution of Foxo1 to metabolic dysregulation during hepatic insulin resistance, we disrupted Foxo1 expression in the liver of mice lacking hepatic Irs1 and Irs2 (DKO mice). DKO mice were small and developed diabetes; analysis of the DKO-liver transcriptome identified perturbed expression of growth and metabolic genes, including increased Ppargc1a and Igfbp1, and decreased glucokinase, Srebp1c, Ghr, and Igf1. Liver-specific deletion of Foxo1 in DKO mice resulted in significant normalization of the DKO-liver transcriptome and partial restoration of the response to fasting and feeding, near normal blood glucose and insulin concentrations, and normalization of body size. These results demonstrate that constitutively active Foxo1 significantly contributes to hyperglycemia during severe hepatic insulin resistance, and that the Irs1/2 → PI3K → Akt → Foxo1 branch of insulin signaling is largely responsible for hepatic insulin-regulated glucose homeostasis and somatic growth.",
keywords = "HUMDISEASE",
author = "X. Dong and Copps, {Kyle D.} and Shaodong Guo and Yedan Li and Ramya Kollipara and DePinho, {Ronald A.} and White, {Morris F.}",
year = "2008",
month = "7",
day = "2",
doi = "10.1016/j.cmet.2008.06.006",
language = "English (US)",
volume = "8",
pages = "65--76",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - Inactivation of Hepatic Foxo1 by Insulin Signaling Is Required for Adaptive Nutrient Homeostasis and Endocrine Growth Regulation

AU - Dong, X.

AU - Copps, Kyle D.

AU - Guo, Shaodong

AU - Li, Yedan

AU - Kollipara, Ramya

AU - DePinho, Ronald A.

AU - White, Morris F.

PY - 2008/7/2

Y1 - 2008/7/2

N2 - The forkhead transcription factor Foxo1 regulates expression of genes involved in stress resistance and metabolism. To assess the contribution of Foxo1 to metabolic dysregulation during hepatic insulin resistance, we disrupted Foxo1 expression in the liver of mice lacking hepatic Irs1 and Irs2 (DKO mice). DKO mice were small and developed diabetes; analysis of the DKO-liver transcriptome identified perturbed expression of growth and metabolic genes, including increased Ppargc1a and Igfbp1, and decreased glucokinase, Srebp1c, Ghr, and Igf1. Liver-specific deletion of Foxo1 in DKO mice resulted in significant normalization of the DKO-liver transcriptome and partial restoration of the response to fasting and feeding, near normal blood glucose and insulin concentrations, and normalization of body size. These results demonstrate that constitutively active Foxo1 significantly contributes to hyperglycemia during severe hepatic insulin resistance, and that the Irs1/2 → PI3K → Akt → Foxo1 branch of insulin signaling is largely responsible for hepatic insulin-regulated glucose homeostasis and somatic growth.

AB - The forkhead transcription factor Foxo1 regulates expression of genes involved in stress resistance and metabolism. To assess the contribution of Foxo1 to metabolic dysregulation during hepatic insulin resistance, we disrupted Foxo1 expression in the liver of mice lacking hepatic Irs1 and Irs2 (DKO mice). DKO mice were small and developed diabetes; analysis of the DKO-liver transcriptome identified perturbed expression of growth and metabolic genes, including increased Ppargc1a and Igfbp1, and decreased glucokinase, Srebp1c, Ghr, and Igf1. Liver-specific deletion of Foxo1 in DKO mice resulted in significant normalization of the DKO-liver transcriptome and partial restoration of the response to fasting and feeding, near normal blood glucose and insulin concentrations, and normalization of body size. These results demonstrate that constitutively active Foxo1 significantly contributes to hyperglycemia during severe hepatic insulin resistance, and that the Irs1/2 → PI3K → Akt → Foxo1 branch of insulin signaling is largely responsible for hepatic insulin-regulated glucose homeostasis and somatic growth.

KW - HUMDISEASE

UR - http://www.scopus.com/inward/record.url?scp=45549090182&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=45549090182&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2008.06.006

DO - 10.1016/j.cmet.2008.06.006

M3 - Article

VL - 8

SP - 65

EP - 76

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 1

ER -