High-fat and high-sucrose diet impairs female reproduction by altering ovarian transcriptomic and metabolic signatures

Excessive energy intake in modern society has led to an epidemic surge in metabolic diseases, such as obesity and type 2 diabetes. These disorders pose profound threats to women's reproductive health. However, the precise impact and underlying pathogenesis of energy excess on female reproduction remain unclear. In this study, we established an obese and hyperglycemic female mouse model induced by a high-fat and high-sucrose (HFHS) diet, mimicking the modern lifestyle of overnutrition. These mice displayed marked reproductive dysfunction, including elevated serum testosterone levels, irregular estrous cycles, and impaired folliculogenesis. Analysis of the ovarian metabolome of the HFHS mice revealed a pronounced disturbance in amino acid metabolism. Transcriptomic profiling of these ovaries identified dysregulated genes involved in steroid hormone biosynthesis and glucolipid metabolism. Further multi-omic analysis unveils aberrations in ovarian arginine biosynthesis metabolism induced by HFHS diet. Notably, comparisons between HFHS mice and a cohort of women with polycystic ovary syndrome (PCOS) identified analogous reproductive and metabolic signatures. Therefore, our results provide direct in vivo evidence for the detrimental effects of overnutrition on female reproduction and offer insights into the metabolic underpinnings of PCOS. Overall design: Comparative gene expression profiling analysis of RNA-seq data for ovarians of HFHS mice and its NCD controls