P-668 Effects of the active site domain of visfatin on the improvement of ovarian function in 4-vinylcyclohexene diepoxide-induced ovarian failure mice
Authors: Kim C W , Park M J , Choi J M , Baek J , Yoou C H , Joo B S 
Published: June 2023

Abstract

Study question
Can only the active site of domain of visfatin improve ovarian function in mice with 4-vinylcyclohexene diepoxide (VCD)-induced ovarian failure?

Summary answer
The active site domain of visfatin improves ovarian function and fertility potential in VCD-induced mice by stimulating the ovarian angiogenesis and early follicular development.

What is known already
Ovarian aging is a representative unmet need in infertility treatment and many studies have attempted to improve oocytes quality by activating ovarian angiogenesis. Visfatin has been reported to have angiogenic activity. Our previous study reported that visfatin improved ovarian function and fertility potential in aged female mice. However, visfatin has many limitations in developing as a drug due to large molecular weight. Visfatin is composed of two structural domains, and the active site is located in the second structural domain (amino acid residues 181 to 390), which were defined as the active site domain (hereafter A-domain peptide) in this study.

Study design, size, duration
This is a controlled experimental study using a total of mice with 60 VCD-induced ovarian failure. The duration of this study was from January to November 2022.

Participants/materials, setting, methods
C57BL/6 female mice were randomly divided into six groups: Five groups received 160mg/kg VCD and one group received an equal volume of vehicle. Four VCD groups were intraperitoneally injected three times at intervals of 2 days with 500 and 1000 ng/ml of full-size visfatin and A-domain peptide, respectively. The remaining one group served as a negative control. After final treatment, follicular development, gene expression, AMH level, and fertility potential were examined.

Main results and the role of chance
In hematoxylin and eosin (H&E) staining, numbers of functional follicles including primordial, primary, secondary, and antral follicles were significantly decreased in the VCD-vehicle group compared to the control. However, treatment of full-size visfatin and A-domain peptide increased the number of primordial and primary follicle. On immnohistochemistry (IHC), expression of BMP15, C-KIT, VEGF, and visfatin in ovarian tissues were significantly reduced in the VCD-vehicle group, but immunoreactivity of these factors strongly stained in the treatment of full-size visfatin and A-domain peptide. This effect was more remarkable in 500 ng/ml of A-domain peptide compared to other treatments. The serum AMH level was significantly lower in the VCD-vehicle group compared to the control group, but it was increased after the treatment with A-domain peptide and full-size visfatin.

Limitations, reasons for caution
This study does not elucidate a clear mechanism how A-domain peptide increases the ovarian function and fertility of VCD-induced ovarian failure mice although it stimulated the expression of genes associated with early follicular development and angiogenesis. Also, generalizability to humans may be limited because the study was conducted in mice.

Wider implications of the findings
This study suggests that administration of A-domain peptide could be applied as a new treatment strategy for ovarian aging, presumably by activating ovarian angiogenesis and dormant primordial follicles.

Trial registration number
Not applicable