Acute and long-term transcriptomic responses of granulosa cells to obesogenic diet and concomitant effects on oocyte quality: insight from an outbred mouse model†.

Abstract

Diet-induced obesity can cause long-term alterations in ovarian functions, but the acute effects of obesogenic diets on the follicular cells and their progression over time, when intake is continued and obesity develops, remain unclear. We aimed to determine the onset and progression of changes in the granulosa cell transcriptomic profile after starting a high-fat/high sugar (HFHS)-diet feeding in mice. We also examined the changes in oocyte lipid droplet content and mitochondrial ultrastructural abnormalities. Swiss (outbred) mice were sacrificed at 24 h, 3 days, and at 1, 4, 8, 12, and 16 weeks of feeding HFHS and control diets. Lipid droplet content significantly increased in the HFHS oocytes within 24 h compared to controls (P < 0.05). Oocyte mitochondrial abnormalities only increased starting from 8 weeks. Granulosa RNA-seq revealed altered transcriptomic gene-set enrichments (GO terms and KEGG pathways, Padj < 0.05) already at 3 days and 1 week indicating acute endoplasmic reticulum unfolded protein responses, with concomitant fluctuations in several cellular metabolic pathways and gene sets related to mitochondrial bioenergetic functions, some of which persisted after 8 weeks. Interestingly, the short- and long-term patterns of changes in cytochrome P450, steroid hormone biosynthesis, retinol metabolism, bile acid metabolism, fatty acid metabolism, and Pi3K/Akt signaling pathways were most prominent and highly correlated; all being acutely upregulated, then chronically downregulated. These results show that the impact of obesogenic diet on the oocyte and granulosa cells is prompt, while the response depends on the duration of feeding and occurs in a multiphasic cascade together with a progressive deterioration in oocyte quality.