Downregulation of FASN in granulosa cells and its impact on ovulatory dysfunction in PCOS

Polycystic ovary syndrome (PCOS) is a complicated endocrinological and anovulatory disorder in women. Mice exposed to dihydrotestosterone (DHT) exhibit a PCOS-like phenotype characterized by abnormal steroid hormone production and ovulation dysfunction. The present investigation aims to identify overlapping genes expressed in PCOS patients and a PCOS mouse model induced by DHT and to examine the function of key genes fatty acid synthase (FASN) in hormone production and ovulation dysfunction.

We examined 5 datasets of high-throughput mRNA transcription from the Gene Expression Omnibus (GEO) database, including 4 datasets from individuals with PCOS and 1 dataset from a DHT-induced mouse model. GO and KEGG enrichment analyses revealed these differentially expressed genes (DEGs) are primarily involved in ovarian steroidogenesis and fatty acid metabolism. The PPI network identified 12 hub genes. qRT-PCR verification in human granulosa cells showed differential expression of FASN, SCARB1, FABP5, RIMS2, and RAPGEF4 in PCOS patients (p < 0.05). FASN was downregulated in the granulosa cells (GCs) of PCOS patients (p < 0.05). FASN depletion reduced KGN cell proliferation (p < 0.001), decreased progesterone secretion (p < 0.05), and increased estradiol secretion (p < 0.05). Downregulation of FASN inhibited ovulation by suppressing ERK1/2 phosphorylation and the expression of C/EBPα and C/EBPβ. Lentivirus-mediated FASN downregulation in rat ovaries for one and four weeks impaired the super ovulatory response, reducing oocyte retrieval, estrous cycle, secretion of estrogen and progesterone, and luteinization.

Our results provide new insights into PCOS pathogenesis and suggest that FASN could be a promising target for treating abnormal steroid hormone production and impaired ovulation in PCOS.