(PTFS05-01-24) Characterization of Global Gene Expression Changes in Response to Diabetogenic Diets in Male and Female TALLYHO/Jng vs. C57BL/6J Mice at 5 and 20 Weeks of Age

Objectives: The TALLYHO/Jng (TH) mouse is an obesity- and type 2 diabetes-prone inbred strain. Diet is an important modulator of genetic susceptibility to diabetes in TH mice. In this study, we evaluated global gene expression changes caused by diabetogenic diets in TH vs normal C57BL/6J (B6) mice.

Methods: At 4 weeks of age (wk), male and female TH and B6 strain of mice were weaned onto either chow or high fat diets and maintained. At 5 and 20 wk, mice were euthanized and tissues including liver, gonadal fat, soleus muscle, and pancreas collected. Six mice per group were used, resulting in 96 samples per tissue. Total RNA was isolated from each tissue and a Poly(A)-based RNAseq library generated and sequenced using paired-end 50 base pair. After trimming and filtering reads to remove low-quality base calls and adapter sequences, a median of 13.5 million reads per sample and a median of 16.8 million read alignments per sample were retained for analysis.

Results: Data were analyzed in 96 single-variable comparisons (between age in each strain, diet, sex, and tissue combination; between strain in each age, diet, sex, and tissue combination; between diet in each strain, age, sex, and tissue combination). The comparisons generated lists of genes which were differentially expressed at a false discovery rate of 10% and by at least two-fold, ranging in length from 43 to 4,596 genes (median 763, interquartile range 1,258). For each of these 96 comparisons, Gene Set Enrichment Analysis was performed against the collection of Reactome pathways to identify pathways dysregulated by the perturbed variable(s). Of the 96 comparisons, 88 identified one or more dysregulated pathways (median 12, interquartile range 19.25). There were 384 unique pathways identified across all comparisons with 21 pathways dysregulated in 20 or more individual comparisons.

Conclusions: Gene expression profiling by RNA-Seq identified genes whose expression is dependent on genotype (TH vs. B6), genes whose expression varies with diet, and genes whose expression variation with diet is dependent on genotype.

Funding Sources: National Institutes of Health