Gene expression in normal-weight mice offspring from parents on Western Diets suggests altered risk for obesity and metabolic disease

The influence of parental obesity on a child's likelihood of becoming an obese adult remains uncertain. Concurrently, the Western diet is deemed a significant factor in obesity prevalence. Hence, we investigated how parents' Western diet impacts offspring's obesity risk. Recent rodent studies indicate males are more susceptible to inheriting obesity than females. Therefore, we focused on whether exposure to maternal, paternal, or parental obesogenic diet during early development stages might program long-term overweight in males. We randomly assigned three-week-old C57BL6/N mice to two diet groups: a Western diet (WD) and a control diet (CD). From 6 to 14 weeks of age, mice in both groups received their assigned diets. Adult females from both diet groups were mated with males from both diet groups, resulting in four breeding cage combinations: CD/CD (parental control diet), CD/WD (maternal Western diet), WD/CD (paternal Western diet), and WD/WD (parental Western diet). We analyzed weight gain trajectories of parental (P) and filial (F1) individuals based on animal sex, litter size, and parental diets. F1 transcriptome assays were conducted on four tissues: interscapular brown adipose (IBAT), epididymal white adipose (EWAT), subcutaneous inguinal white adipose (INGWAT), and liver (LIV) of male offspring. q-mode PCA was used to evaluate the effects of sex, litter size, and parental diet on the transcriptomes. We then examined the influence of parental dietary combinations, focusing on 27 obesity-related genes to describe transcriptome changes. Differentially expressed genes (DEGs) between dietary contrasts were identified and described using Gene Ontology terms. Filial weight gain was primarily influenced by sex and litter size, with no significant effect from parental diet. Transcriptome data showed no clustering by sex or litter size. Most DEGs (FDR-adjusted p < 0.05, log2-fold change = 1) were found between offspring of parents on the Western diet (WD/WD) and control diet (CD/CD): 46 in INGWAT, 44 in BAT, 33 in LIV, and 11 in EWAT. GO terms for these genes were linked to regulatory processes associated with high energy intake and Western diets, such as inflammation and cell death in INGWAT, regulatory processes counteracting weight gain and inflammation in IBAT and EWAT, and increased cellular stress in LIV. We provide new transcriptomic support for the hypothesis that having two obese parents, rather than having only one obese parent, alters the risks of obesity and metabolic disease, likely for the worse.