Genetic Background Shapes Phenotypic Response to Diet for Adiposity in the Collaborative Cross

Abstract

Defined as chronic excessive accumulation of adiposity, obesity results from long-term imbalance between energy intake and expenditure. The mechanisms behind how caloric imbalance occurs are complex and influenced by numerous biological and environmental factors, especially genetics, and diet. Population-based diet recommendations have had limited success partly due to the wide variation in physiological responses across individuals when they consume the same diet. Thus, it is necessary to broaden our understanding of how individual genetics and diet interact relative to the development of obesity for improving weight loss treatment. To determine how consumption of diets with different macronutrient composition alter adiposity and other obesity-related traits in a genetically diverse population, we analyzed body composition, metabolic rate, clinical blood chemistries, and circulating metabolites in 22 strains of mice from the Collaborative Cross (CC), a highly diverse recombinant inbred mouse population, before and after 8 weeks of feeding either a high protein or high fat high sucrose diet. At both baseline and post-diet, adiposity and other obesity-related traits exhibited a broad range of phenotypic variation based on CC strain; diet-induced changes in adiposity and other traits also depended largely on CC strain. In addition to estimating heritability at baseline, we also quantified the effect size of diet for each trait, which varied by trait and experimental diet. Our findings identified CC strains prone to developing obesity, demonstrate the genotypic and phenotypic diversity of the CC for studying complex traits, and highlight the importance of accounting for genetic differences when making dietary recommendations.

Altered macronutrient composition and genetics influence the complex transcriptional network associated with adiposity in the Collaborative Cross

“…After confirming the relationship between expression of genes related to obesity and body fat % in the CC, we investigated the effects of genetic background (strain) and diet on hepatic gene expression levels. Similar to adiposity and the obesity-related traits examined in our previous study [101], genetic background had a far stronger effect on hepatic gene expression than diet, as shown by the overwhelmingly larger number of significant DEGs by strain (9436) compared to the number of DEGs by diet (1344). Interestingly, gene expression of 28.9% of diet DEGs was significantly correlated with adiposity (389/1344) compared to 25% of strain DEGs (2367/9436).…”

“…Details on the origin, housing, husbandry, treatment of the CC mice, diet compositions, and phenotyping have been described previously [ 101 ]. Briefly, female mice from 22 CC strains (total n = 204) were obtained from the UNC Systems Genetics Core Facility in 2016 and put on either a high-protein ( n = 102) or high-fat high-sucrose ( n = 102) diet for 8 weeks followed by analysis of body composition, metabolic rate, and physical activity.…”

“…Broad-sense heritability ( H 2 ) estimates and the intraclass correlations (ICC) for diet were calculated as described previously [ 101 ] for the 11,542 genes used in limma analysis to assess the degree of influence on gene expression variation from genetics (strain) and diet, respectively. H 2 was estimated by calculating the intraclass correlation ( r I ) and the coefficient of genetic determination ( g 2 ) using mean square between (MSB) strains and mean square within (MSW) strains values derived from linear regression analysis [ 20 ].…”

“…Trimethylamine N-oxide (TMAO), choline, betaine, and carnitine were quantified using liquid chromatography-mass spectrometry (LC-MS) methods as described with modifications [95]. Metabolic health scores were calculated using measurements of several metabolic risk factors (circulating glucose, insulin, glucose/insulin ratio, cholesterol, triglycerides, and body fat %) to approximate overall metabolic health [101].…”

“…Previously, we examined the effects of diet and genetic background on adiposity and other obesity-related traits [ 101 ]. In the current study, we focus on the effects of macronutrient composition and strain (genetic background) on hepatic gene expression and relate these to phenotypic traits and biological functions.…”