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J. Biol. Chem., Vol. 282, Issue 19, 14291-14299, May 11, 2007

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Reduction of Low Molecular Weight Protein-tyrosine Phosphatase Expression Improves Hyperglycemia and Insulin Sensitivity in Obese Mice^*

Sanjay K. Pandey¹, Xing Xian Yu, Lynnetta M. Watts, M. Dodson Michael, Kyle W. Sloop, Amber R. Rivard, Thomas A. Leedom, Vara Prasad Manchem, Laura Samadzadeh, Robert A. McKay, Brett P. Monia, and Sanjay Bhanot

From the Metabolic Disease Program, Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, CA 92008, and Endocrine Discovery, Lilly Research Laboratories, Indianapolis, Indiana 46285

To investigate the role of low molecular weight protein-tyrosine phosphatase (LMW-PTP) in glucose metabolism and insulin action, a specific antisense oligonucleotide (ASO) was used to reduce its expression both in vitro and in vivo. Reduction of LMW-PTP expression with the ASO in cultured mouse hepatocytes and in liver and fat tissues of diet-induced obese (DIO) mice and ob/ob mice led to increased phosphorylation and activity of key insulin signaling intermediates, including insulin receptor- subunit, phosphatidylinositol 3-kinase, and Akt in response to insulin stimulation. The ASO-treated DIO and ob/ob animals showed improved insulin sensitivity, which was reflected by a lowering of both plasma insulin and glucose levels and improved glucose and insulin tolerance in DIO mice. The treatment did not decrease body weight or increase metabolic rate. These data demonstrate that LMW-PTP is a key negative regulator of insulin action and a potential novel target for the treatment of insulin resistance and type 2 diabetes.

Received for publication, October 12, 2006 , and in revised form, March 9, 2007.

^* 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 To whom correspondence should be addressed: Metabolic Disease Program, Antisense Drug Discovery, Isis Pharmaceuticals, 1896 Rutherford Rd., Carlsbad, CA 92008. Tel.: 760-603-2361; Fax: 760-603-3862; E-mail: spandey{at}isisph.com.

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