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

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. Diabetes 53: 3328 -3336, 2004 T he prevalence of obesity and its correlates, such as type 2 diabetes, has increased greatly over the last 20 years (1). There has also been a concomitant change in the age of onset for type 2 diabetes, with increasing diagnoses of this disease in children, adolescents, and young adults (2). These secular changes in obesity and diabetes are not due to genetic changes in populations (3), rather they are due to environmental changes in nutrition and activity over time. Even so, there is genetic variation in humans in the response to dietary and activity factors. Some individuals respond strongly to an obesogenic environment by becoming obese, while other individuals remain lean when challenged by the same environment (4). These variations in response to environmental stimuli are, in part, due to genetic variations between people.Study of differential response to dietary factors in human populations can be challenging because of the difficulty in controlling or accurately recording diet over an extended period of time. Animal studies of the genetic basis for differential response to dietary factors can play an important role in attempts to understand the genetics involved in recent increases in obesity and type 2 diabetes. We have used the cross of inbred mouse strains LG/J and SM/J over the past y...

Fine-mapping quantitative trait loci affecting murine external ear tissue regeneration in the LG/J by SM/J advanced intercross line

“…Animals were reared by their mothers for 3 weeks after which half of each litter was weaned onto a high-or low-fat diet (Cheverud et al, 2004). The diets are isocaloric, but the low-fat diet has 15% of its calories from fat while the high-fat diet has 42% of its calories from fat.…”

Genetic, epigenetic, and gene-by-diet interaction effects underlie variation in serum lipids in a LG/J×SM/J murine model

“…The LG/J×SM/J cross has proven to be an excellent system for identifying QTL associated with variation in serum lipid levels and with variation in other metabolic traits, such as obesity and glucose tolerance ( 11,12 ). Genetic responses to high-and low-fat diets between these two strains, as well as trait heritabilities, have been reported elsewhere (13)(14)(15). Here we utilize the LG/J×SM/J cross to dissect the complex interactions of genetic effects, environmental factors, and the interplay between them by examining genome-wide genetic and, for the fi rst time, genomic imprinting effects on serum lipids among different sex, diet, and sex-by-diet cohorts.…”

Quantitative trait loci linked to thalamus and cortex gray matter volumes in BXD recombinant inbred mice

“…After adjusting cortex gray matter volume for 'total brain volume minus cortex gray matter volume', all QTLs remained. We examined the correlations between QTL markers for each variable to detect genomic locations spuriously correlated by non-syntenic association (Williams et al, QTLs Cheverud et al, 2004). Non-syntenic association may occur when unlinked regions of the genome are associated with one another by chance in a limited sample of RI strains.…”