PPARγ modulation enhances ovarian function and oocyte competence in aged mice

Abstract

Although anti-Müllerian hormone (AMH) is a key regulator of primordial follicle activation and ovarian reserve maintenance, the upstream pathways linking metabolic signaling to AMH regulation are unclear. Peroxisome Proliferator-activated receptor gamma (PPARγ), implicated in follicle development, is expressed in ovarian granulosa cells. The study determined whether PPARγ activation regulated AMH expression and primordial follicle regulation in the ovary. Ex vivo neonatal ovary culture, in vivo neonatal and aged mouse models, and in vitro human granulosa-like cell analyses were combined. Ovaries from 2-day-old neonatal mice were cultured ex vivo for up to 96 h under control or rosiglitazone-treated conditions. In vivo 1-day-old neonatal mice (PD1) were analyzed 7 days after treatment. To assess age-dependent effects, young adult (7–8 weeks) and aged (56–62 weeks) female mice received repeated treatment over a 21-day period, followed by ovulation induction, oocyte retrieval, and in vitro fertilization. Molecular biological, histological, and functional outcomes were assessed at predefined time points. PPARγ activation increased Amh expression together with the expression of AMH-associated transcription factors, including Sf1 , Gata4 , and Foxl2 , without altering PPARγ mRNA levels ( P  < 0.05). STAT3 phosphorylation at Ser727 was selectively enhanced in both mouse ovaries and human granulosa-like cells ( P  < 0.01), whereas total STAT3 abundance and Tyr705 phosphorylation remained unchanged. These molecular responses were consistently observed across independent biological replicates, supporting the robustness and reproducibility of the signaling effects. Concomitant with these molecular alterations, treatment of aged mice resulted in increased primordial follicle numbers, reduced zona pellucida remnants, and improvements in oocyte quality and blastocyst development ( P  < 0.05). Treatment effects in young mice were minimal, indicating an age-dependent responsiveness to PPARγ activation. Mice and a human granulosa-like cell lines were studied, without any genetic manipulation of PPARγ. Therefore, caution is warranted when extrapolating the results to clinical contexts. The findings support the regulatory role of PPARγ in linking metabolic signaling to AMH regulation and early follicle dynamics, providing mechanistic insights into age-dependent changes in ovarian function.