This project is designed to identify the genetic basis for variation in obesity and diabetes-associated traits and the development of obesity and diabetes in response to a high-fat diet. Obesity has reached very high levels in the US and other developed
countries and is beginning to increase in frequency even in countries with less developed economies. There are a variety of causes of obesity, including genes, environments, and their interactions but the dramatic secular trend towards obesity is most likely due to dietary and lifestyle changes associated with a developed economy, not to genetic changes in the population at large. The ‘obesity epidemic’ is of environmental origin. Even so, some individuals respond to the high-fat “Western” diet by becoming obese while others exposed to the same diet do not. This individual variation in response to dietary fat is, in part, due to genetic differences. We are examining the genetic basis for variation in response to a high-fat diet in mice by following up on our discovery of several dietary-obesity quantitative trait loci (QTLs) in the LGXSM Recombinant Inbred (RI) mice. We are fine-mapping these QTLs down to a sub-cM interval in an Advanced Intercross (AI) Line to identify a set of 5-20 positional candidate loci for each QTL and evaluating the positional candidate genes for sequence and expression polymorphism between the LG/J and SM/J mouse strains. These studies will enhance our understanding of the physiological bases of dietary obesity and diabetes and identify genes affecting response to a high-fat diet.

Collaborators

Dr. Clay Semenkovich, Washington University

Grant Funding

Supported by a grant from NIDDK DK055736

Publications on the Topic

Pasricha, S., J. Kenney-Hunt, K. Anderson, N. Jafari, R. A. Hall, F. Lammert, J. M. Cheverud, and R. M. Green. 2015. Identification of eQTLs for Hepatic Xbp1s and Socs3 Gene Expression in Mice fed a High-Fat, High Caloric Diet. G3: Genes, Genomes, Genetics, 5:487-496.

Partridge, C, G. L. Fawcett, B. Wang, C. F. Semenkovich, and J. M. Cheverud. 2014. The effect of dietary fat intake on hepatic gene expression in LG/J AND SM/J mice. BMC Genomics 15:99.

Maxwell, T. J., C. M. Ballantyne, J. M. Cheverud, C. S. Guild, C. E. Ndumele and E. Boerwinkle. 2013. APOE modulates the correlation between triglycerides, cholesterol, and CHD through pleiotropy and gene-by-gene interactions. Genetics 195:1397-1405.

Minkina, O., Cheverud, J. M., Fawcett, G. L., Semenkovich, C. F. and J. P. Kenney-Hunt. 2012. Quantitative trait loci affecting liver fat content in mice. G3: Genes, Genomes, Genetics 2: 1019-1025.

Kraja, A. T., H. A. Lawson, D. K. Arnett, I. B. Borecki, U. Broeckel, L. de las Fuentes, S. C. Hunt, M. A. Province, J. M. Cheverud and D.C. Rao. 2012.  Obesity-insulin targeted genes in the 3p26-25 region in human studies and LG/J and SM/J mice. Metabolism 61:1129-1141.

Lawson, H. A., J. E. Cady, C. Partridge, J.B. Wolf, C. F. Semenkovich, and J. M. Cheverud. 2011. Genetic effects at pleiotropic loci are context-dependent with consequences for the maintenance of genetic variation in populations. PLoS Genetics 7(9): e1002256.

Lawson, H. A., A. Lee, G. L. Fawcett, B. Wang, L. S. Pletscher, T. J. Maxwell, T. H. Ehrich, J. P. Kenney-Hunt, J. B. Wolf, C. F. Semenkovich and J. M. Cheverud. 2011. The importance of context to the genetic architecture of diabetes-related traits is revealed in a genome-wide scan of a LG/J x SM/J murine model. Mammalian Genome 22: 197-208.

Jarvis, J. P. and J. M. Cheverud. 2011.  Mapping the epistatic network underlying murine reproductive fatpad variation, Genetics 187: 597-610.

Cheverud, J. M., H. A. Lawson, G. L. Fawcett, B. Wang, L. S. Pletscher, A. Fox, T. J. Maxwell, T. H. Ehrich, J. P. Kenney-Hunt, J. B. Wolf  and C. F. Semenkovich. 2011. Diet-dependent genetic and genomic imprinting effects on obesity in mice. Obesity 19: 160-170; doi:10.1038/oby.2010.141.

Lawson, H. A., K. M. Zelle, G. L. Fawcett, B. Wang, L. S. Pletscher, T. J. Maxwell, T. H. Ehrich, J. P. Kenney‐Hunt, J. B. Wolf, C. F. Semenkovich, and J. M. Cheverud. 2010. Genetic, epigenetic, and gene‐by‐diet interaction effects underlie variation in serum lipids in a LG/J x SM/J murine model. Journal of Lipid Research 51: 2976-2984 ; doi:10.1194/jlr.M006957.

Lawson, H. A. and J. M. Cheverud. 2010. Metabolic syndrome components in murine models. Endocrine, Metabolic & Immune Disorders – Drug Targets 10: 25-40.

Fawcett, G. L., J. P. Jarvis, C. C. Roseman, B. Wang, J. B. Wolf and J. M. Cheverud. 2010. Fine-mapping of adiposity quantitative trait loci in an F_9/10 advanced intercross line. Obesity 18: 1383-1392.

Cheverud, J. M., G. L. Fawcett, J. P. Jarvis, E. A. Norgard, M. Pavlicev, L. S. Pletscher, K. S. Polonsky, H. Ye, G. I. Bell and C. F. Semenkovich. 2010. Calpain-10 is a component of the obesity-related quantitative trait locus, Adip1. Journal of Lipid Research, 51: 907-913.

Fawcett, G, Roseman, C, Jarvis, J, Wang, B, Wolf, J & Cheverud, J. (2008) 'Genetic architecture of adiposity and organ weight using combined generation QTL analysis', Obesity, vol. 16, no. 8, pp. 1861-1868. doi:10.1038/oby.2008.300 [pdf]

Kraja, A, Province, M, Huang, P, Jarvis, J, Rice, T, Cheverud, J & Rao, D. (2008) 'Trends in Metabolic Syndrome and gene networks in human and rodent models', Endocrine, Metabolic & Immune Disorders - Drug Targets 8:198-207. doi:10.2174/187153008785700145 [pdf]

Schmitt, A, Al-Hasani, H, Cheverud, J, Pomp, D, Bünger, L & Brockmann, G. (2007) 'Fine mapping of mouse QTLs for fatness using SNP data', OMICS: A Journal of Integrative Biology, vol. 11, no. 4, pp. 341-350. doi:10.1089/omi.2007.0015 [pdf]

Kenney-Hunt, J, Vaughn, T, Pletscher, L, Peripato, A, Routman, E, Cothran, K, Durand, D, Norgard, E, Perel, C, & Cheverud, J. (2006) 'Quantitative trait loci for body size components in mice', Mammalian Genome, vol. 17, pp. 526-537. doi:10.1007/s00335-005-0160-6 [pdf]

Wolf, J, Pomp, D, Eisen, E, Cheverud, J & Leamy, L. (2006) 'The contribution of epistatic pleiotropy to the genetic architecture of covariation among organ weights and limb bone lengths in mice', Evolution & Development, vol. 8, pp. 468-476. doi:10.1017/S0016672306008172 [pdf]

Kardia, S, Bielak, L, Langer, L, Cheverud, J, Boerwinkle, E, Turner, S, Sheedy II, P & Peyser, P. (2006) 'Epistatic effects between two genes in the renin-angiotensis system and systolic blood pressure and coronary artery calcification', Medical Science Monitor, vol. 12, pp. CR150-158. pmid:16572049 [pdf]

Jarvis, J, Kenney-Hunt, J, Ehrich, T, Pletscher, L, Semenkovich, C & Cheverud, J. (2005) 'Maternal genotype affects adult offspring lipid, obesity, and diabetes phenotypes in LGXSM recombinant inbred strains', Journal of Lipid Research, vol. 46, pp. 1692-1702. doi:10.1194/jlr.M500073-JLR200 [pdf]

Ehrich, T, Kenney-Hunt, J, Pletscher, L & Cheverud, J. (2005) 'Genetic variation and correlation of dietary response in an advanced intercross mouse line produced from two divergent growth lines', Genetical Research, vol. 85, pp. 211-222. doi:10.1017/S0016672305007603 [pdf]

Ehrich, T, Hrbek, T, Kenney-Hunt, J, Pletscher, L Wang, B, Semenkovich, C & Cheverud, J. (2005) 'Fine-mapping gene by diet interactions on chromosome 13 in a LG/J´SM/J murine model of obesity', Diabetes, vol. 54, pp. 1863-1872. doi:10.2337/diabetes.54.6.1863 [pdf]

Cheverud, J, Ehrich, T, Kenney, J, Pletscher, L & Semenkovich, C. (2004) 'Quantitative trait loci for obesity and diabetes-related traits and their dietary responses to high fat feeding in the LGXSM recombinant inbred mouse strains', Diabetes, vol. 53, pp. 3328-3336. doi:10.2337/diabetes.53.12.3328 [pdf] [Appendix A] [Appendix B]

Ehrich, T, Kenney, J, Vaughn, T, Pletscher, L & Cheverud, J. (2003) 'Diet, obesity, and hyperglycemia in LG/J and SM/J Mice', Obesity Research, vol. 11, pp. 1400-1410. doi:10.1038/oby.2003.189 [pdf]

Leamy, L, Pomp, D, Eisen, E & Cheverud, J. (2002) 'Pleiotropy of quantitative trait loci for organ weights and limb bone lengths in mice', Physiological Genomics, vol. 10, pp. 21-29. doi:10.1152/physiolgenomics.00018.2002 [pdf]

Cheverud, J, Vaughn, T, Pletscher, L, Peripato, A, Adams, E, Erickson, C & King-Ellison, K. (2001) 'Genetic architecture of adiposity in the cross of Large (LG/J) and Small (SM/J) inbred mice', Mammalian Genome, vol. 12, pp. 3-12. doi:10.1007/s003350010218 [pdf]

Cheverud, J, Pletscher, L, Vaughn, T & Marshall, B. (1999) 'Differential response to dietary fat in Large (LG/J) and Small (SM/J) inbred mouse strains', Physiological Genomics, vol. 1, pp. 33-39. pmid:11015559 [pdf]

Vaughn, T, Pletscher, L, Peripato, A, King-Ellison, K, Adams, E, Erikson, C & Cheverud, J. (1999) 'Mapping quantitative trait loci for murine growth - A closer look at genetic architecture', Genetical Research, Cambridge, vol. 74, pp. 313-322. doi:10.1017/S0016672399004103 [pdf]

Kramer, M, Vaughn, T, Pletscher, L, King-Ellison, K, Adams, E, Erickson, C & Cheverud, J. (1998) 'Genetic variation in body weight growth and composition in the intercross of Large (LG/J) and Small (SM/J) inbred strains of mice', Genetics and Molecular Biology, vol. 21, pp. 211-218.

Cheverud, J, Routman, E, Duarte, F, van Swinderen, B, Cothran, K & Perel, C. (1996) 'Quantitative trait loci for murine growth', Genetics, vol. 142, pp. 1305-1319. pmid:8846907 [pdf]