High-Fat and High-Sugar Diet Induces Murine Premature Ovarian Failure by Promoting Mitochondrial Oxidative Phosphorylation Response

Abstract

The causes of premature ovarian failure (POF) as a result of high-fat and high-sugar (HFHS) diets have not been studied systematically or in depth. In this study, we used single-cell RNA-seq (scRNA-seq) and molecular pathology experimental techniques to systematically analyze the ovarian landscape in HFHS diet-induced POF in mice. An HFHS diet decreased levels of AMH and E2 and induced a significant amount of follicular atresia in mice, according to the enzyme-linked immunosorbent assay (ELISA) and pathology results. The scRNA-seq results also showed that the number of Krt19 + epithelial cell, Csmd1 + cumulus cell, Mgarp + thecal cell, and mt-CO1 + granulosa cell clusters was much higher in the ovarian tissues of HFHS–POF mice than it was in the control group. According to the KEGG analysis, the differentially transcribed genes in these three cell clusters in different groups were chiefly involved in multiple signal transduction pathways, and their overlapping signaling pathways included oxidative phosphorylation. Immunofluorescence staining and qPCR showed that expression levels of the oxidative phosphorylation signaling pathway were significantly lower in the control group than they were in the thecal cell, epithelial cell, and stromal cell clusters of the HFHS–POF mice. To the best of our knowledge, this study is the first to report the application of scRNA-seq to analyze the ovarian landscape of HFHS-fed mice and to verify that the HFHS diet induced POF in mice by activating the oxidative phosphorylation signal transduction pathway in the thecal cell, granulosa cell, and cumulus cell clusters in mouse ovarian tissues.