Genetic background shapes phenotypic response to diet for adiposity in the Collaborative Cross

Authors: YAM, PHOEBE - University Of California, Davis; ALBRIGHT, JODY - University Of North Carolina; VERHAGUE, MELISSA - University Of North Carolina; Gertz, Erik; PARDO-MANUEL DE VILL, VILLENAFERNANDO - University Of North Carolina; Bennett, Brian

Submitted to: Frontiers in Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/15/2020
Publication Date: 2/11/2021
Citation: Yam, P., Albright, J., Verhague, M., Gertz, E.R., Pardo-Manuel De Vill, V., Bennett, B.J. 2021. Genetic background shapes phenotypic response to diet for adiposity in the Collaborative Cross. Frontiers in Genetics. 11. Article 615012. https://doi.org/10.3389/fgene.2020.615012.
DOI: https://doi.org/10.3389/fgene.2020.615012

Interpretive Summary: Obesity has become a health care crisis in the United States and results from an imbalance between energy expenditure and levels of dietary intake. Much research has been directed to understanding the factors affecting obesity at a population level and we are now embracing the inter-individual variation that affects susceptibility to obesity. In the current study we use 22 strains of mice from the Collaborative Cross (CC), a highly diverse recombinant inbred mouse population, to model the individual response to diets enriched in sucrose or protein. We identify that diet-induced changes in adiposity and other traits also depend largely on CC strain.

Technical 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.