Elevated circulating Netrin-4 levels in women with polycystic ovary syndrome: a cross-sectional study and multiple intervention studies

Although previous studies have reported some association between Netrin-4 (NTN4) and obesity, its association with other metabolic disorders remains unknown. The aim of this study was to explore the associations of Netrin-4 with insulin resistance (IR) and metabolic disorders in polycystic ovary syndrome (PCOS) women and the normal population. The current study was comprised of a cross-sectional study and a series of interventional studies. Circulating NTN4 and adiponectin levels were determined using ELISA kits. Hyperinsulinemic-euglycemic clamps and oral glucose tolerance tests were conducted in all subjects. 137 PCOS women were given anti-insulin resistance treatment for 24 weeks. Transcriptome sequencing data of abdominal subcutaneous adipose stem cells in PCOS women were downloaded for differentially expressed gene (DEG) analysis. Bioinformatics analysis found that genes and signaling pathways related to NTN4 were mainly associated with fatty acid metabolism. Circulating NTN4 levels were elevated in PCOS and IR subjects and exhibited a significant correlation with various metabolic and androgen indices. Among the three treatment groups, only GLP‑1RA reduced circulating NTN4 levels, and this effect appeared to be independent of its insulin‑sensitizing effect. Our results have reinforced the hypothesis that NTN4 may be a biomarker and potential pharmacological target in the management and understanding of IR and PCOS. ChiCTR-OOC-14,005,314. Date of registration: September 16, 2014.