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Genetic determinants of atherosclerosis, obesity, and energy balance in consomic mice

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Abstract

Metabolic diseases such as obesity and atherosclerosis result from complex interactions between environmental factors and genetic variants. A panel of chromosome substitution strains (CSSs) was developed to characterize genetic and dietary factors contributing to metabolic diseases and other biological traits and biomedical conditions. Our goal here was to identify quantitative trait loci (QTLs) contributing to obesity, energy expenditure, and atherosclerosis. Parental strains C57BL/6 and A/J together with a panel of 21 CSSs derived from these progenitors were subjected to chronic feeding of rodent chow and atherosclerotic (females) or diabetogenic (males) test diets, and evaluated for a variety of metabolic phenotypes including several traits unique to this report, namely fat pad weights, energy balance, and atherosclerosis. A total of 297 QTLs across 35 traits were discovered, two of which provided significant protection from atherosclerosis, and several dozen QTLs modulated body weight, body composition, and circulating lipid levels in females and males. While several QTLs confirmed previous reports, most QTLs were novel. Finally, we applied the CSS quantitative genetic approach to energy balance, and identified three novel QTLs controlling energy expenditure and one QTL modulating food intake. Overall, we identified many new QTLs and phenotyped several novel traits in this mouse model of diet-induced metabolic diseases.

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Acknowledgments

We want to thank Annie Hill-Baskin (Case Western Reserve University, Department of Genetics and Genome Sciences, Cleveland, OH, USA) for her generous time and excellent work at supplying breeder mice for this study. This work was supported by the National Institutes of Health Grants RR12305 (JHN), HL055362 and DK094311 (RCL) and by DK DK083042, DK090320, DK 089056 (MWS) and the Nutrition Obesity Research Center (DK035816) (MWS; GJM) and the Diabetes Research Center (P30 DK17047) (MWS).

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Authors and Affiliations

  1. Institute for Systems Biology, 401 North Terry Ave, Seattle, WA, 98109, USA

    Sabrina H. Spiezio

  2. Seattle Biomedical Research Institute, 307 Westlake Avenue North, Seattle, WA, 98109, USA

    Lynn M. Amon

  3. Division of Metabolism, Endocrinology, Nutrition, and Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, WA, 98109, USA

    Timothy S. McMillen, Cynthia M. Vick, Barbara A. Houston, Mark Caldwell, Kayoko Ogimoto, Gregory J. Morton, Michael W. Schwartz & Renée C. LeBoeuf

  4. Bastyr University, 14500 Juanita Drive, Kenmore, WA, 98028, USA

    Elizabeth A. Kirk

  5. Pacific Northwest Research Institute, 720 Broadway, Seattle, WA, 98122, USA

    Joseph H. Nadeau

  6. Department of Medicine, University of Washington, 815 Mercer Street, Seattle, WA, 98109, USA

    Renée C. LeBoeuf

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  1. Sabrina H. Spiezio
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  2. Lynn M. Amon
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  3. Timothy S. McMillen
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  4. Cynthia M. Vick
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  7. Kayoko Ogimoto
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  8. Gregory J. Morton
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  9. Elizabeth A. Kirk
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  10. Michael W. Schwartz
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  12. Renée C. LeBoeuf
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Correspondence to Renée C. LeBoeuf.

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Spiezio, S.H., Amon, L.M., McMillen, T.S. et al. Genetic determinants of atherosclerosis, obesity, and energy balance in consomic mice. Mamm Genome 25, 549–563 (2014). https://doi.org/10.1007/s00335-014-9530-2

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