Originally published In Press as doi:10.1074/jbc.M310688200 on March 18, 2004
J. Biol. Chem., Vol. 279, Issue 23, 24844-24851, June 4, 2004
Transgenic Overexpression of Protein-tyrosine Phosphatase 1B in Muscle Causes Insulin Resistance, but Overexpression with Leukocyte Antigen-related Phosphatase Does Not Additively Impair Insulin Action*
Janice M. Zabolotny
,
Fawaz G. Haj¶,
Young-Bum Kim||,
Hyo-Jeong Kim**,
Gerald I. Shulman**,
Jason K. Kim||**,
Benjamin G. Neel¶
, and
Barbara B. Kahn
From the
Division of Endocrinology, Diabetes, and Metabolism and ¶Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts 02215 and the **Department of Internal Medicine, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520
Previous studies implicate protein-tyrosine phosphatase 1B (PTP1B) and leukocyte antigen-related phosphatase (LAR) as negative regulators of insulin signaling. The expression and/or activity of PTP1B and LAR are increased in muscle of insulin-resistant rodents and humans. Overexpression of LAR selectively in muscle of transgenic mice causes whole body insulin resistance. To determine whether overexpression of PTP1B also causes insulin resistance, we generated transgenic mice overexpressing human PTP1B selectively in muscle at levels similar to those observed in insulin-resistant humans. Insulin-stimulated insulin receptor (IR) tyrosyl phosphorylation and phosphatidylinositol 3'-kinase activity were impaired by 35% and 40-60% in muscle of PTP1B-overexpressing mice compared with controls. Insulin stimulation of protein kinase C (PKC)
/
activity, which is required for glucose transport, was impaired in muscle of PTP1B-overexpressing mice compared with controls, showing that PTP1B overexpression impairs activation of these PKC isoforms. Furthermore, hyperinsulinemic-euglycemic clamp studies revealed that whole body glucose disposal and muscle glucose uptake were decreased by 40-50% in PTP1B-overexpressing mice. Overexpression of PTP1B or LAR alone in muscle caused similar impairments in insulin action; however, compound overexpression achieved by crossing PTP1B- and LAR-overexpressing mice was not additive. Antibodies against specific IR phosphotyrosines indicated overlapping sites of action of PTP1B and LAR. Thus, overexpression of PTP1B in vivo impairs insulin sensitivity, suggesting that overexpression of PTP1B in muscle of obese humans and rodents may contribute to their insulin resistance. Lack of additive impairment of insulin signaling by PTP1B and LAR suggests that these PTPs have overlapping actions in causing insulin resistance in vivo.
Received for publication, September 26, 2003
, and in revised form, March 18, 2004.
* This work was supported in part by National Institutes of Health Grants R01 DK060839 (to B. B. K.), R01 DK060838 and R01 CA049152 (to B. G. N.), a pilot grant from P30 DK046200 (to J. M. Z.), and U24 DK059635 (to G. I. S. and J. K. K.) and by American Diabetes Association Grants (to B. B. K and B. G. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Supported by an Individual National Research Service Award DK09903 and a Research Career Development Award K01 DK62212 from the National Institutes of Health.
|| Supported by American Diabetes Association Junior Faculty Awards.
To whom correspondence may be addressed: Harvard Institutes of Medicine 1043, 77 Ave. Louis Pasteur, Boston, MA 02115. Tel.: 617-667-2823; Fax: 617-667-0610; E-mail: bneel{at}bidmc.harvard.edu.
To whom correspondence may be addressed: Endocrine Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Research North 325E, Boston, MA 02215. Tel.: 617-667-5422; Fax: 617-667-2927; E-mail: bkahn{at}bidmc.harvard.edu.
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Copyright © 2004 by the American Society for Biochemistry and Molecular Biology.
