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J. Biol. Chem., Vol. 282, Issue 42, 30423-30433, October 19, 2007

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Basal Activation of p70S6K Results in Adipose-specific Insulin Resistance in Protein-tyrosine Phosphatase 1B^–/– Mice^*

Salvatore C. Ruffolo, Pontus K. A. Forsell¹, Xiling Yuan, Sylvie Desmarais, Jean Himms-Hagen^¶, Wanda Cromlish, Kenny K. Wong, and Brian P. Kennedy²

From the Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Quebec, H9R 4P8, Canada, Department of Metabolic Disorders, Merck and Co., Rahway, New Jersey 07065, and ^¶Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada

Although protein-tyrosine phosphatase 1B (PTP-1B) is a negative regulator of insulin action, adipose tissue from PTP-1B^–/– mice does not show enhanced insulin-stimulated insulin receptor phosphorylation. Investigation of glucose uptake in isolated adipocytes revealed that the adipocytes from PTP-1B^–/– mice have a significantly attenuated insulin response as compared with PTP-1B^+/+ adipocytes. This insulin resistance manifests in PTP-1B^–/– animals older than 16 weeks of age and could be partially rescued by adenoviral expression of PTP-1B in null adipocytes. Examination of adipose signaling pathways found that the basal p70S6K activity was at least 50% higher in adipose from PTP-1B^–/– mice compared with wild type animals. The increased basal activity of p70S6K in PTP-1B^–/– adipose correlated with decreases in IR substrate-1 protein levels and insulin-stimulated Akt/protein kinase B activity, explaining the decrease in insulin sensitivity even as insulin receptor phosphorylation was unaffected. The insulin resistance of the of the PTP-1B^–/– adipocytes could also be rescued by treatment with rapamycin, suggesting that in adipose the loss of PTP-1B results in basal activation of mTOR (mammalian target of rapamycin) complex 1 leading to a tissue-specific insulin resistance.

Received for publication, January 24, 2007 , and in revised form, July 9, 2007.

^* This work was supported by Canadian Institute for Health Research Industry-Partnered Fellowship FRN 65497. 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.

¹ Current address: Biolipox AB, Berzelius väg 3, plan 5, 171 65 Solna, Sweden.

² To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, 16711 Trans Canada Hwy., Kirkland, Quebec, H9H 3L1 Canada. Tel.: 514-428-8548; Fax: 514-428-8615; E-mail: Brian_Kennedy{at}merck.com.

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