Quantitative Trait Loci for Obesity- and Diabetes-Related Traits and Their Dietary Responses to High-Fat Feeding in LGXSM Recombinant Inbred Mouse Strains

• Published in: Diabetes (New York, N.Y.) Vol. 53; no. 12; pp. 3328 - 3336
• Main Authors: CHEVERUD, James M, EHRICH, Thomas H, HRBEK, Tomas, KENNEY, Jane P, PLETSCHER, L. Susan, SEMENKOVICH, Clay F
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.12.2004
• Subjects: Animals; Biological and medical sciences; Chromosome Mapping; Crosses, Genetic; Diabetes; Diabetes Mellitus - genetics; Diabetes research; Diabetes. Impaired glucose tolerance; Diet; Dietary Fats; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Genetic Markers; Genomes; Glucose; Laboratory animals; Male; Medical sciences; Metabolic diseases; Mice; Mice, Inbred Strains; Nutrition research; Obesity; Obesity - complications; Obesity - genetics; Oils & fats; Quantitative Trait Loci; Recombination, Genetic; Risk factors; United States; Endocrinopathy; Obesity; Vertebrata; Mammalia; Feeding behavior; Mouse; Animal; Diabetes mellitus; Rodentia; Nutrition disorder; Nutritional status; Feeding
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.53.12.3328

Quantitative Trait Loci for Obesity- and Diabetes-Related Traits and Their Dietary Responses to High-Fat Feeding in LGXSM Recombinant Inbred Mouse Strains James M. Cheverud 1 , Thomas H. Ehrich 1 , Tomas Hrbek 1 , Jane P. Kenney 1 , L. Susan Pletscher 1 and Clay F. Semenkovich 2 1 Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 2 Department of Medicine, Washington University School of Medicine, St. Louis, Missouri Address correspondence and reprint requests to James M. Cheverud, Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110. E-mail: cheverud{at}pcg.wustl.edu Abstract Genetic variation in response to high-fat diets is important in understanding the recent secular trends that have led to increases in obesity and type 2 diabetes. The examination of quantitative trait loci (QTLs) for both obesity- and diabetes-related traits and their responses to a high-fat diet can be effectively addressed in mouse model systems, including LGXSM recombinant inbred (RI) mouse strains. A wide range of obesity- and diabetes-related traits were measured in animals from 16 RI strains with 8 animals of each sex fed a high- or low-fat diet from each strain. Marker associations were measured at 506 microsatellite markers spread throughout the mouse genome using a nested ANOVA. Locations with significant effects on the traits themselves and/or trait dietary responses were identified after correction for multiple comparisons by limiting the false detection rate. Nonsyntenic associations of marker genotypes were common at QTL locations so that the significant results were limited to loci still significant in multiple QTL models. We discovered 91 QTLs at 39 locations. Many of these locations ( n = 31) also showed genetic effects on dietary response, typically because the loci produced significantly larger effects on the high-fat diet. Fat depot weights, leptin levels, and body weight at necropsy tended to map to the same locations and were responsible for a majority of the dietary response QTLs. Basal glucose levels and the response to glucose challenge mapped together in locations distinct from those affecting obesity. These QTL locations form a panel for further research and fine mapping of loci affecting obesity- and diabetes-related traits and their responses to high-fat feeding. FDR, false discovery rate FPR, false-positive rate QTL, quantitative trait locus Footnotes Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . Accepted August 25, 2004. Received July 23, 2004. DIABETES