Dietary composition and metabolic stress differentially affect the ovarian microenvironment in mice

The ovarian microenvironment is a dynamic target of aging and highly responsive to metabolic and dietary stressors. Western diets (WD) and high-fat diets (HFD) promote obesity and systemic metabolic dysfunction. However, whether these diets induce remodeling of the ovarian microenvironment remains unclear. In this study, we investigated how distinct dietary patterns influence metabolic homeostasis, estrous cyclicity, ovarian reserve, and stromal remodeling in female mice. Three-month-old C57BL/6 mice (n = 48) were fed a control diet (CTL), low-calorie Western diet (LcWD), WD, or HFD for 17 weeks. WD and HFD were associated with greater progressive weight gain, increased intra-abdominal adiposity, impaired insulin and glucose tolerance, and hepatocellular alterations, whereas LcWD also produced metabolic alterations despite its lower caloric density. WD mice exhibited shorter estrous cycles compared with CTL mice. Despite relatively preserved follicle numbers and no detectable differences in the number of oocytes ovulated, ovarian stromal collagen deposition was increased in WD and HFD mice compared with CTL mice and was intermediate in LcWD mice. Lipofuscin accumulation was higher in WD mice. Collectively, these findings indicate that distinct dietary patterns can promote ovarian stromal remodeling through potentially different metabolic and nutritional contexts, with collagen deposition emerging as a sensitive tissue-level alteration before broad depletion of the ovarian reserve or detectable changes in oocyte-associated parameters. These findings support ovarian stromal fibrosis as a potential early feature of diet-associated ovarian remodeling and reproductive aging.