Unveiling ODP4: A breakthrough in PCOS treatment via BAT transplantation

Women with polycystic ovary syndrome (PCOS) often face infertility due to endocrine disorders affecting their reproductive, metabolic, and endocrine systems. Although brown adipose tissue (BAT) transplantation has been established to treat polycystic ovaries and hyperandrogenism in PCOS rats, the underlying mechanism is still largely unclear owing to lacking effective clinical treatment. Peptides are believed to significantly contribute to PCOS pathogenesis, however, the specific effects of active peptides released by BAT on PCOS remain largely unexplored. This study sought to identify active peptides secreted in the recipient's BAT and investigate their potential biological functions in PCOS. We validated the impact of BAT transplantation and found that an overexpressed ovary derived peptide 4 (ODP4) in BAT transplantation rats could potentiate the inhibitory effect of dehydroepiandrosterone (DHEA) on granulosa cell (GC) development, yield a stimulatory effect on cell apoptosis and regulate ovulation genes and hormone synthesis. In DHEA-induced PCOS rats, ODP4 restored the estrous cycle and reduced cystic follicles, indicating its potential in PCOS treatment. Furthermore, transcriptomic analysis of KGN cells treated with ODP4 and DHEA showed changes in genes related to mitochondrial activity and oxidative damage. The mechanism results showed that ODP4 enhanced mitochondrial functionality, elevated ATP production, and decreased oxidative damage in KGN cells treatment with DHEA, suggesting its preventive role in mitochondrial malfunction and oxidative damage. These findings reveal unrecognized roles of ODP4 in PCOS pathogenesis. Our study substantiates that the connection between BAT transplantation and PCOS is related to peptidomics. Additionally, ODP4 has prospects for clinical application as an innovative therapeutic PCOS target.