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

Abstract

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.

ACKNOWLEDGMENTS

We thank Bruce M. Spiegelman, Bradford B. Lowell, Jeffrey S. Flier, and Thomas McGarry for comments on the manuscript, William G. Tsiaras for technical help, and Lena Du and Joel Lawitts for blastocyst injections.

This work was supported by grants from the Human Frontier Science Program (LT0020/1999 to O.B.) and the National Institutes of Health (NRSA-AI09815 to L.D.K.; NRSA-DK09903 to J.M.Z.; P01 DK 56116, P30-DK46200, and RO1-DK-43051 to B.B.K.; PO1-DK50654 and RO1-CA49152 to B.G.N.; and P30-DK45735 and RO1-DK40936 to G.I.S.). G.I.S. is an investigator and J.K.K. is a research associate of the Howard Hughes Medical Institute. O.D.P. was supported by an ADA mentor-based fellowship (to B.B.K.).