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Molecular and Cellular Biology, August 2000, p. 5479-5489, Vol. 20, No. 15
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice

Lori D. Klaman,1 Olivier Boss,2 Odile D. Peroni,2 Jason K. Kim,3 Jennifer L. Martino,1 Janice M. Zabolotny,2 Nadeem Moghal,1 Margaret Lubkin,4 Young-Bum Kim,2 Arlene H. Sharpe,5 Alain Stricker-Krongrad,4 Gerald I. Shulman,3 Benjamin G. Neel,1,* and Barbara B. Kahn2,*

Cancer Biology Program, Division of Hematology-Oncology,1 and Division of Endocrinology,2 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, and Division of Immunology, Brigham and Women's Hospital,5 Boston, Massachusetts 02215; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 065363; and Metabolic Diseases Physiology, Millennium Pharmaceuticals, Cambridge, Massachusetts 021394

Received 15 March 2000/Accepted 24 April 2000

Protein-tyrosine phosphatase 1B (PTP-1B) is a major protein-tyrosine phosphatase that has been implicated in the regulation of insulin action, as well as in other signal transduction pathways. To investigate the role of PTP-1B in vivo, we generated homozygotic PTP-1B-null mice by targeted gene disruption. PTP-1B-deficient mice have remarkably low adiposity and are protected from diet-induced obesity. Decreased adiposity is due to a marked reduction in fat cell mass without a decrease in adipocyte number. Leanness in PTP-1B-deficient mice is accompanied by increased basal metabolic rate and total energy expenditure, without marked alteration of uncoupling protein mRNA expression. In addition, insulin-stimulated whole-body glucose disposal is enhanced significantly in PTP-1B-deficient animals, as shown by hyperinsulinemic-euglycemic clamp studies. Remarkably, increased insulin sensitivity in PTP-1B-deficient mice is tissue specific, as insulin-stimulated glucose uptake is elevated in skeletal muscle, whereas adipose tissue is unaffected. Our results identify PTP-1B as a major regulator of energy balance, insulin sensitivity, and body fat stores in vivo.


* Corresponding author. Mailing address for Benjamin G. Neel: Cancer Biology Program, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. Phone: (617) 667-2823. Fax: (617) 667-0610. E-mail: bneel{at}caregroup.harvard.edu. Mailing address for Barbara B. Kahn: Diabetes Unit, Beth Israel Deaconess Medical Center, 99 Brookline Ave., Boston, MA 02215. Phone: (617) 667-5422. Fax: (617) 667-2927.


Molecular and Cellular Biology, August 2000, p. 5479-5489, Vol. 20, No. 15
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.



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