Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase 2

Kosuke Matsuo, Mirela Delibegovic, Izumi Matsuo, Naoto Nagata, Siming Liu, Ahmed Bettaieb, Yannan Xi, Kazushi Araki, Wentian Young, Barbara B. Kahn, Benjamin G. Neel, Fawaz G. Haj

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

The SH2 domain-containing protein-tyrosine phosphatase Shp2 has been implicated in a variety of growth factor signaling pathways, but its role in insulin signaling has remained unresolved. In vitro studies suggest that Shp2 is both a negative and positive regulator of insulin signaling, while its physiological function in a number of peripheral insulin-responsive tissues remains unknown. To address the metabolic role of Shp2 in the liver, we generated mice with either chronic or acute hepatic Shp2 deletion using tissue-specific Cre-LoxP and adenoviral Cre approaches, respectively. We then analyzed insulin sensitivity, glucose tolerance, and insulin signaling in liver-specific Shp2-deficient and control mice. Mice with chronic Shp2 deletion exhibited improved insulin sensitivity and increased glucose tolerance compared with controls. Acute Shp2 deletion yielded comparable results, indicating that the observed metabolic effects are directly caused by the lack of Shp2 in the liver. These findings correlated with, and were most likely caused by, direct dephosphorylation of IRS1/IRS2 in the liver, accompanied by increased PI3K/Akt signaling. In contrast, insulin-induced Erk activation was dramatically attenuated, yet there was no effect on the putative Erk site on IRS1 (Ser612) or on S6K1 activity. These studies show that Shp2 is a negative regulator of hepatic insulin action, and its deletion enhances the activation of PI3K/Akt pathway downstream of the insulin receptor.
Original languageEnglish
Pages (from-to)39750-39758
Number of pages9
JournalThe Journal of Biological Chemistry
Volume285
Issue number51
Early online date14 Sep 2010
DOIs
Publication statusPublished - 17 Dec 2010

Fingerprint

Phosphoric Monoester Hydrolases
Liver
Homeostasis
Insulin
Glucose
Phosphatidylinositol 3-Kinases
Insulin Resistance
SH2 Domain-Containing Protein Tyrosine Phosphatases
Chemical activation
Insulin Receptor
Tissue
Intercellular Signaling Peptides and Proteins

Keywords

  • adenoviruses
  • glucose
  • liver
  • metabolic regulation
  • signal transduction
  • protein-tyrosine phosphatase (Tyrosine Phosphatase)

Cite this

Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase 2. / Matsuo, Kosuke; Delibegovic, Mirela; Matsuo, Izumi; Nagata, Naoto; Liu, Siming; Bettaieb, Ahmed ; Xi, Yannan ; Araki, Kazushi ; Young, Wentian; Kahn, Barbara B.; Neel, Benjamin G.; Haj, Fawaz G.

In: The Journal of Biological Chemistry, Vol. 285, No. 51, 17.12.2010, p. 39750-39758.

Research output: Contribution to journalArticle

Matsuo, K, Delibegovic, M, Matsuo, I, Nagata, N, Liu, S, Bettaieb, A, Xi, Y, Araki, K, Young, W, Kahn, BB, Neel, BG & Haj, FG 2010, 'Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase 2', The Journal of Biological Chemistry, vol. 285, no. 51, pp. 39750-39758. https://doi.org/10.1074/jbc.M110.153734
Matsuo, Kosuke ; Delibegovic, Mirela ; Matsuo, Izumi ; Nagata, Naoto ; Liu, Siming ; Bettaieb, Ahmed ; Xi, Yannan ; Araki, Kazushi ; Young, Wentian ; Kahn, Barbara B. ; Neel, Benjamin G. ; Haj, Fawaz G. / Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase 2. In: The Journal of Biological Chemistry. 2010 ; Vol. 285, No. 51. pp. 39750-39758.
@article{00a365ec87b3471e81f20ff7e31d7068,
title = "Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase 2",
abstract = "The SH2 domain-containing protein-tyrosine phosphatase Shp2 has been implicated in a variety of growth factor signaling pathways, but its role in insulin signaling has remained unresolved. In vitro studies suggest that Shp2 is both a negative and positive regulator of insulin signaling, while its physiological function in a number of peripheral insulin-responsive tissues remains unknown. To address the metabolic role of Shp2 in the liver, we generated mice with either chronic or acute hepatic Shp2 deletion using tissue-specific Cre-LoxP and adenoviral Cre approaches, respectively. We then analyzed insulin sensitivity, glucose tolerance, and insulin signaling in liver-specific Shp2-deficient and control mice. Mice with chronic Shp2 deletion exhibited improved insulin sensitivity and increased glucose tolerance compared with controls. Acute Shp2 deletion yielded comparable results, indicating that the observed metabolic effects are directly caused by the lack of Shp2 in the liver. These findings correlated with, and were most likely caused by, direct dephosphorylation of IRS1/IRS2 in the liver, accompanied by increased PI3K/Akt signaling. In contrast, insulin-induced Erk activation was dramatically attenuated, yet there was no effect on the putative Erk site on IRS1 (Ser612) or on S6K1 activity. These studies show that Shp2 is a negative regulator of hepatic insulin action, and its deletion enhances the activation of PI3K/Akt pathway downstream of the insulin receptor.",
keywords = "adenoviruses, glucose, liver, metabolic regulation, signal transduction, protein-tyrosine phosphatase (Tyrosine Phosphatase)",
author = "Kosuke Matsuo and Mirela Delibegovic and Izumi Matsuo and Naoto Nagata and Siming Liu and Ahmed Bettaieb and Yannan Xi and Kazushi Araki and Wentian Young and Kahn, {Barbara B.} and Neel, {Benjamin G.} and Haj, {Fawaz G.}",
year = "2010",
month = "12",
day = "17",
doi = "10.1074/jbc.M110.153734",
language = "English",
volume = "285",
pages = "39750--39758",
journal = "The Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC",
number = "51",

}

TY - JOUR

T1 - Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase 2

AU - Matsuo, Kosuke

AU - Delibegovic, Mirela

AU - Matsuo, Izumi

AU - Nagata, Naoto

AU - Liu, Siming

AU - Bettaieb, Ahmed

AU - Xi, Yannan

AU - Araki, Kazushi

AU - Young, Wentian

AU - Kahn, Barbara B.

AU - Neel, Benjamin G.

AU - Haj, Fawaz G.

PY - 2010/12/17

Y1 - 2010/12/17

N2 - The SH2 domain-containing protein-tyrosine phosphatase Shp2 has been implicated in a variety of growth factor signaling pathways, but its role in insulin signaling has remained unresolved. In vitro studies suggest that Shp2 is both a negative and positive regulator of insulin signaling, while its physiological function in a number of peripheral insulin-responsive tissues remains unknown. To address the metabolic role of Shp2 in the liver, we generated mice with either chronic or acute hepatic Shp2 deletion using tissue-specific Cre-LoxP and adenoviral Cre approaches, respectively. We then analyzed insulin sensitivity, glucose tolerance, and insulin signaling in liver-specific Shp2-deficient and control mice. Mice with chronic Shp2 deletion exhibited improved insulin sensitivity and increased glucose tolerance compared with controls. Acute Shp2 deletion yielded comparable results, indicating that the observed metabolic effects are directly caused by the lack of Shp2 in the liver. These findings correlated with, and were most likely caused by, direct dephosphorylation of IRS1/IRS2 in the liver, accompanied by increased PI3K/Akt signaling. In contrast, insulin-induced Erk activation was dramatically attenuated, yet there was no effect on the putative Erk site on IRS1 (Ser612) or on S6K1 activity. These studies show that Shp2 is a negative regulator of hepatic insulin action, and its deletion enhances the activation of PI3K/Akt pathway downstream of the insulin receptor.

AB - The SH2 domain-containing protein-tyrosine phosphatase Shp2 has been implicated in a variety of growth factor signaling pathways, but its role in insulin signaling has remained unresolved. In vitro studies suggest that Shp2 is both a negative and positive regulator of insulin signaling, while its physiological function in a number of peripheral insulin-responsive tissues remains unknown. To address the metabolic role of Shp2 in the liver, we generated mice with either chronic or acute hepatic Shp2 deletion using tissue-specific Cre-LoxP and adenoviral Cre approaches, respectively. We then analyzed insulin sensitivity, glucose tolerance, and insulin signaling in liver-specific Shp2-deficient and control mice. Mice with chronic Shp2 deletion exhibited improved insulin sensitivity and increased glucose tolerance compared with controls. Acute Shp2 deletion yielded comparable results, indicating that the observed metabolic effects are directly caused by the lack of Shp2 in the liver. These findings correlated with, and were most likely caused by, direct dephosphorylation of IRS1/IRS2 in the liver, accompanied by increased PI3K/Akt signaling. In contrast, insulin-induced Erk activation was dramatically attenuated, yet there was no effect on the putative Erk site on IRS1 (Ser612) or on S6K1 activity. These studies show that Shp2 is a negative regulator of hepatic insulin action, and its deletion enhances the activation of PI3K/Akt pathway downstream of the insulin receptor.

KW - adenoviruses

KW - glucose

KW - liver

KW - metabolic regulation

KW - signal transduction

KW - protein-tyrosine phosphatase (Tyrosine Phosphatase)

U2 - 10.1074/jbc.M110.153734

DO - 10.1074/jbc.M110.153734

M3 - Article

VL - 285

SP - 39750

EP - 39758

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

SN - 0021-9258

IS - 51

ER -