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Molecular and Cellular Biology, August 2000, p. 5479-5489, Vol. 20, No. 15
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.
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
*
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.
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