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J. Biol. Chem., Vol. 282, Issue 31, 22448-22459, August 3, 2007

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Hyperphagia-mediated Obesity in Transgenic Mice Misexpressing the RNA-editing Enzyme ADAR2^*

Minati Singh, Robert A. Kesterson, Michelle M. Jacobs^¶, James M. Joers^||, John C. Gore^||, and Ronald B. Emeson^¶**1

From the Departments of Pharmacology and ^**Molecular Physiology and Biophysics, the ^¶Center for Molecular Neuroscience, and the ^||Institute of Imaging Science, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 and the Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294

ADAR2 is a double-stranded RNA-specific adenosine deaminase involved in the editing of mammalian RNAs by the site-specific conversion of adenosine to inosine. To examine the physiologic consequences resulting from ADAR2 misexpression, we have generated mutant mice expressing either wild-type or deaminase-deficient ADAR2 transgenes under the control of the human cytomegalovirus promoter. Transgenic mice expressing either wild-type or inactive ADAR2 isoforms demonstrated adult onset obesity characterized by hyperglycemia, hyperleptinemia, and increased adiposity. Paired feeding analysis revealed that mutant mice on caloric restriction had a growth rate and body composition indistinguishable from wild-type littermates, indicating that the observed obesity predominantly results from hyperphagia rather than a metabolic derangement. The observation that expression of catalytically inactive ADAR2 also is capable of producing an obese phenotype in mutant animals suggests that ADAR2 may possess additional biological activities beyond those required for the site-selective deamination of adenosine or may interfere with the actions of other double-stranded RNA-specific binding proteins in the cell.

Received for publication, January 10, 2007 , and in revised form, June 11, 2007.

^* This work was supported by National Institutes of Health Grant NS33323 (to R. B. E.) and Vanderbilt Clinical Nutrition Research Unit Grant DK98013. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1–S4.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, Vanderbilt University, 8160 Medical Research Bldg. 3, Nashville, TN 37232-8548. Tel.: 615-936-1688; Fax: 615-936-1689; E-mail: ron.emeson{at}vanderbilt.edu.

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