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Molecular and Cellular Biology, March 2005, p. 2498-2510, Vol. 25, No. 6
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.6.2498-2510.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Insulin Hypersensitivity and Resistance to Streptozotocin-Induced Diabetes in Mice Lacking PTEN in Adipose Tissue

Christine Kurlawalla-Martinez,1 Bangyan Stiles,2* Ying Wang,2 Sherin U. Devaskar,1 Barbara B. Kahn,3 and Hong Wu2*

Department of Pediatrics, Division of Neonatology,1 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California,2 Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts3

Received 17 August 2004/ Returned for modification 15 September 2004/ Accepted 1 December 2004

In adipose tissue, insulin controls glucose and lipid metabolism through the intracellular mediators phosphatidylinositol 3-kinase and serine-threonine kinase AKT. Phosphatase and a tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/AKT pathway, is hypothesized to inhibit the metabolic effects of insulin. Here we report the generation of mice lacking PTEN in adipose tissue. Loss of Pten results in improved systemic glucose tolerance and insulin sensitivity, associated with decreased fasting insulin levels, increased recruitment of the glucose transporter isoform 4 to the cell surface in adipose tissue, and decreased serum resistin levels. Mutant animals also exhibit increased insulin signaling and AMP kinase activity in the liver. Pten mutant mice are resistant to developing streptozotocin-induced diabetes. Adipose-specific Pten deletion, however, does not alter adiposity or plasma fatty acids. Our results demonstrate that in vivo PTEN is a potent negative regulator of insulin signaling and insulin sensitivity in adipose tissue. Furthermore, PTEN may be a promising target for nutritional and/or pharmacological interventions aimed at reversing insulin resistance.

* Corresponding author. Mailing address: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 23-234 CHS, 650 Charles E. Young Dr. South, Los Angeles, California, 90095. Phone: (310) 825-5160. Fax: (310) 267-0242. E-mail for Hong Wu: hwu{at}mednet.ucla.edu. E-mail for Bangyan Stiles: bstiles{at}mednet.ucla.edu.

Molecular and Cellular Biology, March 2005, p. 2498-2510, Vol. 25, No. 6
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.6.2498-2510.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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