Overweight/Obesity and Hyperinsulinemia Impair Oocyte Developmental Competence via Cumulus Cell Dysfunction and Oxidative Stress-Mediated Follicular Microenvironment Remodeling

Abstract

Overweight and obesity, frequently accompanied by hyperinsulinemia, are established risk factors for female infertility. Cumulus cells (CCs) are hypothesized to play a crucial role in this etiology, yet the underlying mechanisms remain largely elusive. In the current study, we investigated the impact of hyperinsulinemic overweight/obesity on the follicular niche using integrated clinical analysis and in vitro maturation (IVM) assays. Follicular fluid and CCs from patients stratified by body mass index (BMI) and fasting insulin levels were evaluated. Immature oocytes, including oocytes at the metaphase I (MI) and germinal vesicle (GV) stages, underwent IVM using conditioned media or co-culture with autologous or allogeneic CCs. Additionally, CC transcriptomic profiling was performed using RNA-seq. We found that overweight/obesity, particularly when accompanied by hyperinsulinemia, induced CC immune activation, characterized by elevated follicular IgG, IgM, and pro-inflammatory cytokines. This pathological niche significantly compromised oocyte maturation. Notably, co-culture with CCs from normal-weight patients or supplementation with the antioxidant N-acetyl-L-cysteine (NAC) effectively reversed these defects. In conclusion, hyperinsulinemic obesity impairs oocyte competence through CC dysfunction and follicular remodeling. Restoring the CC-oocyte microenvironment via co-culture with healthy CCs or antioxidant therapy represents a promising strategy to alleviate this impairment and improve IVM efficiency in clinical practice.