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J. Biol. Chem., Vol. 280, Issue 36, 31679-31685, September 9, 2005

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Mouse and Human Resistins Impair Glucose Transport in Primary Mouse Cardiomyocytes, and Oligomerization Is Required for This Biological Action^*

Christophe Graveleau, Vlad G. Zaha, Arash Mohajer¶, Ronadip R. Banerjee||, Nicole Dudley-Rucker||, Claire M. Steppan||**, Michael W. Rajala, Philipp E. Scherer, Rexford S. Ahima||, Mitchell A. Lazar||, and E. Dale Abel, Established Investigator of the American Heart Association

From the Division of Endocrinology, Metabolism, and Diabetes and the Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah 84112, the ^||Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and the Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461

The adipocytokine resistin impairs glucose tolerance and insulin sensitivity in rodents. Here, we examined the effect of resistin on glucose uptake in isolated adult mouse cardiomyocytes. Murine resistin reduced insulin-stimulated glucose uptake, establishing the heart as a resistin target tissue. Notably, human resistin also impaired insulin action in mouse cardiomyocytes, providing the first evidence that human and mouse resistin homologs have similar functions. Resistin is a cysteinerich molecule that circulates as a multimer of a dimeric form dependent upon a single intermolecular disulfide bond, which, in the mouse, involves Cys²⁶; mutation of this residue to alanine (C26A) produces a monomeric molecule that appears to be bioactive in the liver. Remarkably, unlike native resistin, monomeric C26A resistin had no effect on basal or insulin-stimulated glucose uptake in mouse cardiomyocytes. Resistin impairs glucose uptake in cardiomyocytes by mechanisms that involve altered vesicle trafficking. Thus, in cardiomyocytes, both mouse and human resistins directly impair glucose transport; and in contrast to effects on the liver, these actions of resistin require oligomerization.

Received for publication, April 13, 2005

^* This work was supported in part by National Institutes of Health Grant DK58073 (to E. D. A.), Grants DK49210 and DK49780 (to M. A. L.), Medical Scientist Training Grant T32-GM07288 (to M. W. R.), and Grant DK55758 (to P. E. S.) and by research grants from the American Diabetes Association and the Ben and Iris Margolis Foundation (to E. D. A.). 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.

Both authors contributed equally to this work.

^¶ Supported by the Bioscience Undergraduate Research Program of the University of Utah.

^** Present address: Pfizer Global Research and Development, Groton, CT 06340.

To whom correspondence should be addressed: Div. of Endocrinology, Metabolism, and Diabetes and Program in Human Molecular Biology and Genetics, University of Utah School of Medicine, 15 North 2030 East, Bldg. 533, Rm. 3410B, Salt Lake City, UT 84112. Tel.: 801-585-0727; Fax: 801-585-0701; E-mail: dale.abel{at}hmbg.utah.edu.

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