Impacts of Obesity-Induced Insulin and Leptin Dysregulation on Ovarian Function and Fertility

Introduction: Obesity significantly impacts reproductive health, particularly through disruptions in insulin and leptin signaling which are crucial for ovarian function. This research explores the direct effects of these hormonal disruptions on ovarian tissue from mice fed a high fat diet (HFD) and granulosa cells. Methods: We utilized the steroidogenic human granulosa-like tumor, KGN, cell line to examine ovarian cellular responses to hormonal changes in an obesogenic context. The effects of varying concentrations of insulin and leptin on glucose uptake and lipid metabolism were examined using 14 C 2-deoxyglucose (glucose analog) uptake and cell proliferation assays. Results: Preliminary findings indicate that insulin enhances glucose uptake significantly (p=0.0130), whereas leptin does not affect glucose uptake under similar conditions, suggesting differing roles of these hormones in the metabolic regulation of ovarian cells under obesogenic conditions. Additionally, treatment with NEFA (non-esterified fatty acids) increases KGN cell viability compared to control (p=0.0033), with insulin treatment enhancing cell viability more significantly than NEFA treatment alone. Conversely, leptin treatment markedly reduced cell viability, suggesting potential toxic or inhibitory effects of leptin in the obesogenic context. Furthermore, our triglyceride (TG) analysis revealed that HFD-fed mice exhibited significantly higher TG content in ovarian tissues compared to chow-fed controls (p=0.0095), indicating that lipid accumulation is dynamically regulated within the obesogenic environment. These results highlight the complex interactions between metabolic substrates and hormonal dysregulation in affecting ovarian cell function. Conclusions: Our study provides crucial insights into the metabolic pathways influenced by obesity and highlights potential therapeutic interventions aimed at restoring ovarian function and improving fertility outcomes in women with obesity. Further research is needed to explore the full impact of leptin resistance and its interaction with insulin in the ovarian environment. Yale Liver Center Pilot This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.