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

BACKGROUND: Obesity is a serious disease with a complex etiology characterized by overaccumulation of adiposity resulting in detrimental health outcomes. Given the liver’s critical role in the biological processes that attenuate adiposity accumulation, elucidating the influence of genetics and dietary patterns on hepatic gene expression is fundamental for improving methods of obesity prevention and treatment. To determine how genetics and diet impact obesity development, 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 analysis of hepatic gene expression. RESULTS: Over 1000 genes differentially expressed by perturbed dietary macronutrient composition were enriched for biological processes related to metabolic pathways. Additionally, over 9000 genes were differentially expressed by strain and enriched for biological process involved in cell adhesion and signaling. Weighted gene co-expression network analysis identified multiple gene clusters (modules) associated with body fat % whose average expression levels were influenced by both dietary macronutrient composition and genetics. Each module was enriched for distinct types of biological functions. CONCLUSIONS: Genetic background affected hepatic gene expression in the CC overall, but diet macronutrient differences also altered expression of a specific subset of genes. Changes in macronutrient composition altered gene expression related to metabolic processes, while genetic background heavily influenced a broad range of cellular functions and processes irrespective of adiposity. Understanding the individual role of macronutrient composition, genetics, and their interaction is critical to developing therapeutic strategies and policy recommendations for precision nutrition. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12263-022-00714-x.