Dietary Obesity and Diabetes

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 life-style 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

Fawcett G. L., C. C. Roseman, J. P. Jarvis, B. Wang, and J. M. Cheverud. 2008. Genetic architecture of adiposity and organ weight using combined generation QTL analysis. Obesity (in press).

Kraja A. T., M. A. Province, P. Huang, J. P. Jarvis, T. Rice, J. M. Cheverud and D. C. Rao. 2008. Trends in Metabolic Syndrome and gene networks in human and rodent models. Endocrine, Metabolic & Immune Disorders - Drug Targets (in press).

Schmitt, A. O., H. Al-Hasani, J. M. Cheverud, D. Pomp, L. Bunger and G. A. Brockmann. 2007. Fine mapping of mouse QTLs for fatness using SNP data. OMICS: A Journal of Integrative Biology, 11: 341-350.

Kenney-Hunt, J. P., T. T. Vaughn, L. S. Pletscher, A. Peripato, E. Routman, K. Cothran, D. Durand, E. Norgard, C. Perel, and J. M. Cheverud. 2006. Quantitative trait loci for body size components in mice. Mammalian Genome 17: 526-537.

Wolf, J.B., D. Pomp, E. J. Eisen, J. M. Cheverud and L. J. Leamy. 2006. The contribution of epistatic pleiotropy to the genetic architecture of covariation among organ weights and limb bone lengths in mice. Evolution & Development 8: 468-476.

Kardia, S. L. R., L. F. Bielak, L. A. Langer, J. M. Cheverud, E. Boerwinkle, S. T. Turner, P. F. Sheedy II, P. A. Peyser. 2006. Epistatic effects between two genes in the renin-angiotensis system and systolic blood pressure and coronary artery calcification. Medical Science Monitor 12: CR150-158.

Jarvis , J. P., J. P. Kenney-Hunt, T. H. Ehrich, L. S. Pletscher, C. F. Semenkovich and J. M. Cheverud. 2005. Maternal genotype affects adult offspring lipid, obesity, and diabetes phenotypes in LGXSM recombinant inbred strains. Journal of Lipid Research, 46: 1692-1702.

Ehrich, T. H., J. P. Kenney-Hunt, L. S. Pletscher and J. M. Cheverud. 2005. Genetic variation and correlation of dietary response in an advanced intercross mouse line produced from two divergent growth lines. Genetical Research, Cambridge 85: 211-222.

Ehrich T. H., T. Hrbek, J. P. Kenney-Hunt, L. S. Pletscher, B. Wang, C. F. Semenkovich and J. M. Cheverud. 2005. Fine-mapping gene by diet interactions on chromosome 13 in a LG/J ´SM/J murine model of obesity. Diabetes 54: 1863-1872.

Cheverud, J. M., T. H. Ehrich, T. Hrbek, J. P. Kenney, L. S. Pletscher, and C. F. Semenkovich 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 53: 3328-3336.

Cheverud, J. M., T. H. Ehrich, J. P. Kenney, L. S. Pletscher, and C. F. Semenkovich 2004. Genetic evidence for discordance between obesity and diabetes-related traits in the LGXSM recombinant inbred mouse strains. Diabetes 53: 2700-2708.

Ehrich, T., J. Kenney, T. Vaughn, L. S. Pletscher, and J. Cheverud 2003. Diet, obesity, and hyperglycemia in LG/J and SM/J Mice. Obesity Research 11: 1400-1410.

Leamy, L. J., D. Pomp, E. J. Eisen and J. M. Cheverud 2002. Quantitative trait loci for organ weights and limb bone lengths in mice. Physiological Genomics 10: 21-29.

Cheverud, J., T. Vaughn, L. S. Pletscher, A. Peripato, E. Adams, C. Erickson and K. King-Ellison 2001. Genetic architecture of adiposity in the cross of Large (LG/J) and Small (SM/J) inbred mice, Mammalian Genome, 12: 3-12.

Cheverud, J. M., L. S. Pletscher, T. T. Vaughn, and B. Marhsall 1999. Differential response to dietary fat in Large (LG/J) and Small (SM/J) inbred mouse strains. Physiological Genomics, 1: 33-39.

Vaughn, T. T., L. S. Pletscher, A. Peripato, K. King-Ellison, E. Adams, C. Erikson and J. M. Cheverud 1999. Mapping quantitative trait loci for murine growth – A closer look at genetic architecture. Genetical Research, Camb., 74: 313-322.

Kramer, M. G., T. T. Vaughn, L. S. Pletscher, K. King-Ellison, E. Adams, C. Erickson and J. M. Cheverud 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, 21: 211-218.

Cheverud, J., E. Routman, F. M. Duarte, B. van Swinderen, K. Cothran and C. Perel 1996. Quantitative trait loci for murine growth, Genetics 142: 1305-1319.