Local glucose elevation activates pyroptosis via NLRP3 inflammasome in ovarian granulosa cells of overweight patients

Overweight, with an increasing prevalence worldwide, significantly impairs the clinical outcomes following in vitro fertilization (IVF). Hyperglycemia, hyperlipidemia, and metabolic disorders are always accompanied by the majority of overweight patients. The association between granulosa cell function and metabolic alterations in follicular fluid including lipids, proteins, and growth factors has been extensively documented. However, the effects of higher glucose level on ovarian granulosa cells (GCs), remain largely unknown. In this study, we identified that overweight women had elevated follicular glucose level which profoundly activated NLRP3 inflammasome and pyroptosis. An in vitro correlation between follicular high glucose, NLRP3 inflammasome and pyroptosis was also established. More importantly, in granulosa cells of overweight patients, the activation of the NLRP3 inflammasome and pyroptosis induced by high glucose was involved in the dysregulation of estradiol synthesis. Our study may provide new options to interpretate and improve IVF outcomes in overweight women.

Automated summary

Overweight significantly impairs IVF outcomes and is often accompanied by hyperglycemia, hyperlipidemia, and metabolic disorders. The relationship between granulosa cell function and metabolic alterations in follicular fluid has been extensively studied. However, the effects of high glucose levels on ovarian granulosa cells are not well understood. This study found that overweight women have elevated follicular glucose levels which activate the NLRP3 inflammasome and pyroptosis. The dysregulation of estradiol synthesis in granulosa cells of overweight patients was also attributed to the activation of the NLRP3 inflammasome and pyroptosis induced by high glucose. This study provides new insights for interpreting and improving IVF outcomes in overweight women.