View Program - 2022 Population, Evolutionary, and Quantitative Genetics Conference

Type II Diabetes (T2D) is a systemic inflammatory disease characterized by progressive insulin resistance. The development of T2D is associated with the consumption of food with high contents of fat and sugar, i.e., a western diet. Hundreds of genetic loci have been associated with T2D susceptibility, revealing that the underlying mechanisms of the disease are complex. Distinct isogenic mouse models provide an opportunity to study the development of T2D in different genetic backgrounds with multiple environmental exposures, including diets. In this study, we generated bulk RNA sequencing data from eight tissues (adipose, islet, liver, kidney, heart, skeletal muscle, hypothalamus, and dorsal vagal complex) from mice from three isogenic strains, C57BL/6J (B6), CAST/EiJ (CAST), and NZO/HlLtJ (NZO). The study included female and male mice raised on either low-fat/low-sugar or high-fat/high-sugar diets. These strains, the “Three Bears”, represent a range of T2D susceptibilities. The CAST strain is highly resistant to diet effects and T2D; the NZO strain presents spontaneous obesity and high incidence of T2D, especially in males, which is exacerbated by the western diet; and the B6 strain presents moderate resistance, with T2D and obesity emerging only after long-term exposure to the western diet. By quantifying differences in gene expression in response to diet across these strains, we aim to illuminate molecular mechanisms related to variation in metabolic responses to the western diet and their relationship to T2D. We found that islet, adipose, and hypothalamus present the strongest strain-specific gene expression responses to diet. In the islets, we see activation of immune response and depletion of beta cells, especially in male NZO mice. In contrast, CAST mice show adaptive responses to western diet with increased cellular respiration and fatty acid oxidation across multiple tissues. Differences in metabolic efficiency across these strains are associated with differential levels of circulating erythropoietin and the activation of mitochondrial uncoupling proteins (UCP2 and UCP3) in multiple tissues. These findings suggest that higher rates of energy expenditure and fatty acid oxidation contribute to the robust T2D resistance of the CAST strain while on a western diet.

Genotype-by-diet interactions regulate gene expression across multiple tissues in the “Three Bears” mouse models of type II diabetes