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Molecular and Cellular Biology, November 2007, p. 7727-7734, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00959-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Improved Glucose Homeostasis in Mice with Muscle-Specific Deletion of Protein-Tyrosine Phosphatase 1B

Mirela Delibegovic,^1* Kendra K. Bence,^1, Nimesh Mody,² Eun-Gyoung Hong,³ Hwi Jin Ko,³ Jason K. Kim,³ Barbara B. Kahn,^2* and Benjamin G. Neel^1,

Cancer Biology Program,¹ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts,² Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania³

Received 30 May 2007/ Returned for modification 12 July 2007/ Accepted 13 August 2007

Obesity and type 2 diabetes are characterized by insulin resistance. Mice lacking the protein-tyrosine phosphatase PTP1B in all tissues are hypersensitive to insulin but also have diminished fat stores. Because adiposity affects insulin sensitivity, the extent to which PTP1B directly regulates glucose homeostasis has been unclear. We report that mice lacking PTP1B only in muscle have body weight and adiposity comparable to those of controls on either chow or a high-fat diet (HFD). Muscle triglycerides and serum adipokines are also affected similarly by HFD in both groups. Nevertheless, muscle-specific PTP1B^–/– mice exhibit increased muscle glucose uptake, improved systemic insulin sensitivity, and enhanced glucose tolerance. These findings correlate with and are most likely caused by increased phosphorylation of the insulin receptor and its downstream signaling components. Thus, muscle PTP1B plays a major role in regulating insulin action and glucose homeostasis, independent of adiposity. In addition, rosiglitazone treatment of HFD-fed control and muscle-specific PTP1B^–/– mice revealed that rosiglitazone acts additively with PTP1B deletion. Therefore, combining PTP1B inhibition with thiazolidinediones should be more effective than either alone for treating insulin-resistant states.

Published ahead of print on 27 August 2007.

Present address: Department of Animal Biology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA.

Present address: Ontario Cancer Institute and Princess Margaret Hospital, Department of Medical Biophysics, University of Toronto, 610 Univ. Ave., Rm. 7-504, Toronto, ON M5G 2M9, Canada.

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