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J. Biol. Chem., Vol. 279, Issue 43, 45155-45161, October 22, 2004

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Interaction between Altered Insulin and Lipid Metabolism in CEACAM1-inactive Transgenic Mice^*

Tong Dai, George A. Abou-Rjaily, Qusai Y. Al-Share', Yan Yang, Mats A. Fernström, Anthony M. DeAngelis, Abraham D. Lee¶, Lawrence Sweetman||, Antonino Amato**, Marzia Pasquali, Gary D. Lopaschuk, Sandra K. Erickson¶¶, and Sonia M. Najjar||||

From the Departments of Pharmacology and Therapeutics and ^¶Physical Therapy at the Medical College of Ohio, Toledo, Ohio 43614, the ^||Institute of Metabolic Disease, Baylor University Medical Center, Dallas, Texas 75246, ^**Sigma Tau Research Inc., Gaithersburg, Maryland 20877, the Department of Pathology, University of Utah, Salt Lake City, Utah 84132, Cardiovascular Research Group, University of Alberta, Edmonton T6G 2S2, Canada, and the ^¶¶Department of Medicine, University of California, San Francisco and Veterans Affairs Medical Center, San Francisco, California 94121

Inactivation of CEACAM1 in L-SACC1 mice by a dominant-negative transgene in liver impairs insulin clearance and increases serum free fatty acid (FFA) levels, resulting in insulin resistance. The contribution of elevated FFAs in the pathogenesis of insulin resistance is herein investigated. Treatment of L-SACC1 female mice with carnitine restored plasma FFA content. Concomitantly, it normalized insulin levels without directly regulating receptor-mediated insulin internalization and prevented glucose tolerance in these mice. Similarly, treatment with nicotinic acid, a lipolysis inhibitor, restored insulin-stimulated receptor uptake in L-SACC1 mice. Taken together, these data suggest that chronic elevation in plasma FFAs levels contributes to the regulation of insulin metabolism and action in L-SACC1 mice.

Received for publication, April 29, 2004 , and in revised form, August 9, 2004.

^* This work was supported by National Institutes of Health Grants DK 54254 and DK 57497, by an American Diabetes Association Research award, and by Sigma Tau Research Inc. (to S. M. N.). This work was also supported by a Merit Award from the Department of Veterans Affairs (to S. K. E.) and by a research grant from the Canadian Institutes for Health Research (to G. D. L.). 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.

These authors contributed equally to this work.

^|||| To whom correspondence should be addressed: Medical College of Ohio, 3035 Arlington Ave., HSci Bldg., Rm. 270, Toledo, OH 43614. Tel.: 419-383-4059; Fax: 419-383-2871; E-mail: snajjar{at}mco.edu.

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