Dapagliflozin alleviated obesity-related follicular development dysfunction by regulating glucose metabolism and mitochondria function in granulosa cells.

Abstract

Dapagliflozin (DAPA), an inhibitor of the sodium-glucose cotransporter 2 (SGLT2), modulates intracellular glucose homeostasis. Previous studies have demonstrated that DAPA can improve body composition and metabolic disorders in obese women. However, whether DAPA could ameliorate high-fat diets (HFD)-induced female ovarian dysfunction and the precise molecular mechanisms remain unclear. The primary objective of this study is to investigate the effects of DAPA on ovarian and granulosa cells (GCs) function under high-fat conditions, as well as to elucidate the underlying mechanisms. Mice were fed an HFD to establish obesity models. After successful obesity modeling, mice were fed a diet supplemented with DAPA. KGN cells were exposed to palmitic acid (PA) and treated with DAPA. We identified that SGLT2 was expressed in ovaries. DAPA treatment resulted in reduced body weight and adiposity, as well as improvements in glucose metabolism and the normalization of estrous cycles in HFD mice. Furthermore, DAPA promoted ovarian follicle development by inhibiting the reactive oxygen species (ROS)/NOD-like receptor protein 3 (NLRP3) inflammasome pathway. In vitro, DAPA downregulated SGLT2 expression, reduced intracellular glucose overload and actic acid accumulation in PA-treated KGN cells. DAPA also mitigated mitochondrial dysfunction, enhances adenosine triphosphate production and inhibits ROS/NLRP3 pathway activation in PA-treated KGN cells. What's more, DAPA reduced the accumulation of intracellular lipid droplets and restored the expression of steroid hormone biosynthesis enzymes and after PA treatment. In conclusion, these results indicated that DAPA may attenuate glucose accumulation and enhance mitochondrial function in GCs under high-fat conditions, potentially through suppression of SGLT2 expression, ultimately reducing pyroptosis and improving follicular development in obesity.