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Science 5 March 1999:
Vol. 283. no. 5407, pp. 1544 - 1548
DOI: 10.1126/science.283.5407.1544
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Reports

Increased Insulin Sensitivity and Obesity Resistance in Mice Lacking the Protein Tyrosine Phosphatase-1B Gene

Mounib Elchebly, 1 Paul Payette, 2 Eva Michaliszyn, 1 Wanda Cromlish, 2 Susan Collins, 2 Ailsa Lee Loy, 1 Denis Normandin, 2 Alan Cheng, 1 Jean Himms-Hagen, 3 Chi-Chung Chan, 2 Chidambaram Ramachandran, 2 Michael J. Gresser, 2 Michel L. Tremblay, 1 Brian P. Kennedy 2*

Protein tyrosine phosphatase-1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B+/+ littermates. The enhanced insulin sensitivity of the PTP-1B-/- mice was also evident in glucose and insulin tolerance tests. The PTP-1B-/- mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B+/+ mice. On a high-fat diet, the PTP-1B-/- and PTP-1B+/- mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B+/+ mice rapidly gained weight and became insulin resistant. These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity.

1 Department of Biochemistry, McGill University, 3655 Drummond Street, Montreal, Quebec, Canada, H3G 1Y6.
2 Department of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, Post Office Box 1005, Pointe Claire-Dorval, Quebec, Canada, H9R 4P8.
3 Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada, K1H 8M5.
*   To whom correspondence should be addressed. E-mail: brian_kennedy{at}merck.com

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Pharmacological Targeting of Adipocytes/Fat Metabolism for Treatment of Obesity and Diabetes.
P. F. Pilch and N. Bergenhem (2006)
Mol. Pharmacol. 70, 779-785
   Abstract »    Full Text »    PDF »
Photoperiodic regulation of insulin receptor mRNA and intracellular insulin signaling in the arcuate nucleus of the Siberian hamster, Phodopus sungorus.
A. Tups, M. Helwig, S. Stohr, P. Barrett, J. G. Mercer, and M. Klingenspor (2006)
Am J Physiol Regulatory Integrative Comp Physiol 291, R643-R650
   Abstract »    Full Text »    PDF »
Targeted disruption of iNOS prevents LPS-induced S-nitrosation of IRbeta/IRS-1 and Akt and insulin resistance in muscle of mice.
M. A. Carvalho-Filho, M. Ueno, J. B. C. Carvalheira, L. A. Velloso, and M. J. A. Saad (2006)
Am J Physiol Endocrinol Metab 291, E476-E482
   Abstract »    Full Text »    PDF »
A Naphthoquinone Derivative, Shikonin, Has Insulin-Like Actions by Inhibiting Both Phosphatase and Tensin Homolog Deleted on Chromosome 10 and Tyrosine Phosphatases.
K. Nigorikawa, K. Yoshikawa, T. Sasaki, E. Iida, M. Tsukamoto, H. Murakami, T. Maehama, K. Hazeki, and O. Hazeki (2006)
Mol. Pharmacol. 70, 1143-1149
   Abstract »    Full Text »    PDF »
Diet-induced Obesity Alters AMP Kinase Activity in Hypothalamus and Skeletal Muscle.
T. L. Martin, T. Alquier, K. Asakura, N. Furukawa, F. Preitner, and B. B. Kahn (2006)
J. Biol. Chem. 281, 18933-18941
   Abstract »    Full Text »    PDF »
Insulin Resistance and Atherosclerosis.
J. Nigro, N. Osman, A. M. Dart, and P. J. Little (2006)
Endocr. Rev. 27, 242-259
   Abstract »    Full Text »    PDF »
Conformation-assisted Inhibition of Protein-tyrosine Phosphatase-1B Elicits Inhibitor Selectivity over T-cell Protein-tyrosine Phosphatase.
E. Asante-Appiah, S. Patel, C. Desponts, J. M. Taylor, C. Lau, C. Dufresne, M. Therien, R. Friesen, J. W. Becker, Y. Leblanc, et al. (2006)
J. Biol. Chem. 281, 8010-8015
   Abstract »    Full Text »    PDF »
Association of Protein Tyrosine Phosphatase-N1 Polymorphisms With Coronary Calcified Plaque in the Diabetes Heart Study.
K. P. Burdon, J. L. Bento, C. D. Langefeld, J. K. Campbell, J. J. Carr, L. M. Wagenknecht, D. M. Herrington, B. I. Freedman, S. S. Rich, and D. W. Bowden (2006)
Diabetes 55, 651-658
   Abstract »    Full Text »    PDF »
Casitas b-Lineage Lymphoma-Deficient Mice Are Protected Against High-Fat Diet-Induced Obesity and Insulin Resistance.
J. C. Molero, S. G. Waring, A. Cooper, N. Turner, R. Laybutt, G. J. Cooney, and D. E. James (2006)
Diabetes 55, 708-715
   Abstract »    Full Text »    PDF »
Counter-Regulatory Function of Protein Tyrosine Phosphatase 1B in Platelet-Derived Growth Factor- or Fibroblast Growth Factor-Induced Motility and Proliferation of Cultured Smooth Muscle Cells and in Neointima Formation.
Y. Chang, B. Ceacareanu, D. Zhuang, C. Zhang, Q. Pu, A. C. Ceacareanu, and A. Hassid (2006)
Arterioscler Thromb Vasc Biol 26, 501-507
   Abstract »    Full Text »    PDF »
Protein tyrosine phosphatase 1B negatively regulates macrophage development through CSF-1 signaling.
K. M. Heinonen, N. Dube, A. Bourdeau, W. S. Lapp, and M. L. Tremblay (2006)
PNAS 103, 2776-2781
   Abstract »    Full Text »    PDF »
Leptin resistance following over-expression of protein tyrosine phosphatase 1B in liver.
N T Lam, S D Covey, J T Lewis, S Oosman, T Webber, E C Hsu, A T Cheung, and T J Kieffer (2006)
J. Mol. Endocrinol. 36, 163-174
   Abstract »    Full Text »    PDF »
Insulin Receptor Kinase-Associated Phosphotyrosine Phosphatases in Hepatic Endosomes: Assessing the Role of Phosphotyrosine Phosphatase-1B.
C. Li, G. Baquiran, F. Gu, M. L. Tremblay, A. Fazel, J. J. M. Bergeron, and B. I. Posner (2006)
Endocrinology 147, 912-918
   Abstract »    Full Text »    PDF »
Chromium Picolinate Enhances Skeletal Muscle Cellular Insulin Signaling In Vivo in Obese, Insulin-Resistant JCR:LA-cp Rats.
Z. Q. Wang, X. H. Zhang, J. C. Russell, M. Hulver, and W. T. Cefalu (2006)
J. Nutr. 136, 415-420
   Abstract »    Full Text »    PDF »
Protein-tyrosine Phosphatase 1B Deficiency Protects against Fas-induced Hepatic Failure.
V. Sangwan, G. N. Paliouras, A. Cheng, N. Dube, M. L. Tremblay, and M. Park (2006)
J. Biol. Chem. 281, 221-228
   Abstract »    Full Text »    PDF »
Oral Vanadium Enhances the Catabolic Effects of Central Leptin in Young Adult Rats.
J. Wilsey, M. K. Matheny, and P. J. Scarpace (2006)
Endocrinology 147, 493-501
   Abstract »    Full Text »    PDF »
Genetic Ablation of Protein Tyrosine Phosphatase 1B Accelerates Lymphomagenesis of p53-Null Mice through the Regulation of B-Cell Development.
N. Dube, A. Bourdeau, K. M. Heinonen, A. Cheng, A. Lee Loy, and M. L. Tremblay (2005)
Cancer Res. 65, 10088-10095
   Abstract »    Full Text »    PDF »
Protein Tyrosine Phosphatase-1B Gene PTPN1: Selection of Tagging Single Nucleotide Polymorphisms and Association With Body Fat, Insulin Sensitivity, and the Metabolic Syndrome in a Normal Female Population.
N. J. Spencer-Jones, X. Wang, H. Snieder, T. D. Spector, N. D. Carter, and S. D. O'Dell (2005)
Diabetes 54, 3296-3304
   Abstract »    Full Text »    PDF »
Monitoring the Activation State of the Insulin-Like Growth Factor-1 Receptor and Its Interaction with Protein Tyrosine Phosphatase 1B Using Bioluminescence Resonance Energy Transfer.
C. Blanquart, N. Boute, D. Lacasa, and T. Issad (2005)
Mol. Pharmacol. 68, 885-894
   Abstract »    Full Text »    PDF »
PTP-1B is an essential positive regulator of platelet integrin signaling.
E. G. Arias-Salgado, F. Haj, C. Dubois, B. Moran, A. Kasirer-Friede, B. C. Furie, B. Furie, B. G. Neel, and S. J. Shattil (2005)
J. Cell Biol. 170, 837-845
   Abstract »    Full Text »    PDF »
The Role of Protein-tyrosine Phosphatase 1B in Integrin Signaling.
F. Liang, S.-Y. Lee, J. Liang, D. S. Lawrence, and Z.-Y. Zhang (2005)
J. Biol. Chem. 280, 24857-24863
   Abstract »    Full Text »    PDF »
Association Testing of the Protein Tyrosine Phosphatase 1B Gene (PTPN1) With Type 2 Diabetes in 7,883 People.
J. C. Florez, C. M. Agapakis, N. P. Burtt, M. Sun, P. Almgren, L. Rastam, T. Tuomi, D. Gaudet, T. J. Hudson, M. J. Daly, et al. (2005)
Diabetes 54, 1884-1891
   Abstract »    Full Text »    PDF »
The C. elegans homolog of the mammalian tumor suppressor Dep-1/Scc1 inhibits EGFR signaling to regulate binary cell fate decisions.
T. A. Berset, E. F. Hoier, and A. Hajnal (2005)
Genes & Dev. 19, 1328-1340
   Abstract »    Full Text »    PDF »
Liver-specific Protein-tyrosine Phosphatase 1B (PTP1B) Re-expression Alters Glucose Homeostasis of PTP1B-/-Mice.
F. G. Haj, J. M. Zabolotny, Y.-B. Kim, B. B. Kahn, and B. G. Neel (2005)
J. Biol. Chem. 280, 15038-15046
   Abstract »    Full Text »    PDF »
Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling.
I K Lund, J A Hansen, H S Andersen, N P H Moller, and N Billestrup (2005)
J. Mol. Endocrinol. 34, 339-351
   Abstract »    Full Text »    PDF »


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