Impact of Chromosome 2 Obesity Loci on Cardiovascular Complications of Insulin Resistance in LDL Receptor–Deficient C57BL/6 Mice
- Daria Estrada-Smith1,
- Alan R. Collins2,
- Xuping Wang3,
- Craig Crockett1,
- Lawrence Castellani3,
- Aldons J. Lusis13 and
- Richard C. Davis3
- 1Department of Human Genetics, University of California Los Angeles, Los Angeles, California
- 2Department of Medicine/Division of Endocrinology, Diabetes and Hypertension, University of California Los Angeles, Los Angeles, California
- 3Department of Medicine, Division of Cardiology, University of California Los Angeles, Los Angeles, California
- Address correspondence and reprint requests to Daria Estrada-Smith, Box 957088, 6524 Gonda, Los Angeles, CA 90095-7088. E-mail: destrada{at}mednet.ucla.edu
Abstract
Previous characterization of mouse chromosome 2 identified genomic intervals that influence obesity, insulin resistance, and dyslipidemia. For this, resistant CAST/Ei (CAST) alleles were introgressed onto a susceptible C57BL/6J background to generate congenic strains with CAST alleles encompassing 67–162 Mb (multigenic obesity 6 [MOB6]) and 84–180 Mb (MOB5) from mouse chromosome 2. To examine the effects of each congenic locus on atherosclerosis and glucose disposal, we bred each strain onto a sensitizing LDL receptor–null (LDLR−/−) C57BL/6J background to predispose them to hypercholesterolemia and insulin resistance. LDLR−/− congenics and controls were characterized for measures of atherogenesis, insulin sensitivity, and obesity. We identified a genomic interval unique to the MOB6 congenic (72–84 Mb) that dramatically decreased atherosclerosis by approximately threefold and decreased insulin resistance. This region also reduced adiposity twofold. Conversely, the congenic region unique to MOB5 (162–180 Mb) increased insulin resistance but had little effect on atherosclerosis and adiposity. The MOB congenic intervals are concordant to human and rat quantitative trait loci influencing diabetes and atherosclerosis traits. Thus, our results define a strategy for studying the poorly understood interactions between diabetes and atherosclerosis and for identifying genes underlying the cardiovascular complications of insulin resistance.
Footnotes
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Additional information can be found in an online appendix at http://diabetes.diabetesjournals.org.
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted May 15, 2006.
- Received March 21, 2006.
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