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

Authors: Yam, Phoebe; VERHAGUE, M - University Of North Carolina; ALBRIGHT, JODY - University Of North Carolina; Gertz, Erik; MANUEL-DE-VILLENA, F - University Of North Carolina; Bennett, Brian

Submitted to: Genes and Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/4/2022
Publication Date: 8/10/2022
Citation: Yam, P., VerHague, M., Albright, J., Gertz, E.R., Manuel-de-Villena, F., Bennett, B.J. 2022. Altered macronutrient composition and genetics influence the complex transcriptional network associated with adiposity in the Collaborative Cross. Genes and Nutrition. 17. Article 13. https://doi.org/10.1186/s12263-022-00714-x.
DOI: https://doi.org/10.1186/s12263-022-00714-x

Interpretive Summary: Characterized by excessive accumulation of adiposity resulting in adverse health effects, obesity is a serious disease with a complex etiology. Given the significant role that the liver plays in the biological processes that attenuate adiposity accumulation, expanding the understanding of how genetics and diet influence hepatic gene expression is crucial to improve strategies of obesity prevention and treatment. To examine how genetics and diet impact obesity development, multiple mice from 22 strains of the genetically diverse recombinant inbred Collaborative Cross (CC) mouse panel were challenged to either a high protein or high fat high sucrose diet, followed by extensive phenotyping and microarray analysis of post-diet hepatic gene expression to relate adiposity and obesity-related traits to hepatic gene expression; identify genes, groups of functionally related genes and biological pathways with expression levels influenced by diet or genetic background; and determine which of these genes are also associated with obesity in humans. In this study, we demonstrated that both genetic background and diet influence expression of individual genes as well as the expression for groups of related genes. By integrating phenotype data into our analysis, we found individual genes, groups of genes expressed in the liver, and functional pathways that were related to adiposity and other clinical traits. The identification of genes expressed in the liver related to adiposity provided concrete preliminary suggestions of specific “intermediary” mechanisms that bridge genetics and diet with obesity. Lastly, searching in the genome-wide association studies (GWAS) catalog for obesity genes identified in the CC revealed a list of homologous candidate genes associated with obesity in humans to inform future functional validations studies.

Technical Abstract: Background: Characterized by excessive accumulation of adiposity resulting in adverse health effects, obesity is a serious disease with a complex etiology. Given the significant role that the liver plays in the biological processes that attenuate adiposity accumulation such as lipogenesis and metabolism of dietary macronutrients, expanding the understanding of how genetics and diet influence hepatic gene expression is crucial to improve strategies of obesity prevention and treatment. To determine how genetics and diet impact obesity development, multiple mice from 22 strains of the genetically diverse recombinant inbred Collaborative Cross (CC) mouse panel were challenged to either a high protein or high fat high sucrose diet, followed by extensive phenotyping and microarray analysis of post-diet hepatic gene expression. Results: Genes differentially expressed by diet (1,344) were enriched for biological processes related to metabolic pathways while genes differentially expressed by strain (9,436) were enriched for biological process involved in cell adhesion and signaling. Weighted gene co-expression network analysis identified three biologically relevant gene clusters (modules) whose average expression levels differed by both diet and strain and were significantly correlated with body fat %. Each gene cluster was enriched for distinct types of biological functions. Conclusions: Genetic background affected hepatic gene expression in the CC overall but differences in diet also altered gene expression for a smaller subset of genes. Generally diet alters hepatic gene expression for metabolic processes sensitive to acute environmental changes, while genetic background more heavily influences overall “stable” cellular functions relative to obesity development.