Advertisement

Role of Visfatin in Restoration of Ovarian Aging and Fertility in the Mouse Aged 18 Months

  • 2 Accesses

Abstract

The activation of dormant primordial follicles and ovarian angiogenesis has been attempted as a new treatment strategy for age-related ovarian aging. This study examined whether visfatin rescues age-related fertility decline in female mice aged 18 months, and whether this effect relates to the mTOR/PI3K signaling pathways for activation of primordial follicles and ovarian angiogenesis. Female mice were intraperitoneally injected with 0.1 ml of 500 ng/ml or 1000 ng/ml of visfatin three times at intervals of 2 days, and both ovaries were provided for H&E staining. In another experiment, the mice were superovulated with pregnant mare’s serum gonadotropin and human chorionic gonadotropin, and were mated with males. After 18 h, zygotes were collected and cultured for 4 days, and numbers and embryo developmental competency of zygotes retrieved were evaluated. The expression of mTOR/PI3K signaling pathway regulated genes (4EBP1, S6K1, and RPS6) and angiogenic factors (VEGF, visfatin, and SDF-1α) in the ovary were examined. As well, visfatin-treated mice were mated with male mice for 2 weeks, and the pregnancy outcome was monitored up to 3 weeks. Visfatin significantly increased the total numbers of follicles compared with control. Numbers of zygotes retrieved, blastocyst formation rate, and pregnancy rate were significantly increased at 500 ng/ml of visfatin (2.83%, 40.0%, and 80%, respectively) compared with control (0, 0, and no pregnancy). Ovarian expressions of S6K1, RPS6, VEGF, visfatin, and SDF-1α were significantly stimulated at 500 ng/ml of visfatin. These results show that visfatin treatment of an optimal dose rescues age-related decline in fertility, possibly by stimulating mTOR/PI3K signaling.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 510

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Broekmans FJ, Knauff EA, te Velde ER, Macklon NS, Fauser BC. Female reproductive ageing: current knowledge and future trends. Trends Endocrinol Metab. 2007;18:58–65.

  2. 2.

    Navot D, Drews MR, Bergh PA, Guzman I, Karstaedt A, Scott RT Jr, et al. Age-related decline in female fertility is not due to diminished capacity of the uterus to sustain embryo implantation. Fertil Steril. 1994;61:97–101.

  3. 3.

    Simpson JL. Lobo RA, Kelsey J, Marcus R, eds. Genetic programming in ovarian development and oogenesis. Menopause: biology and pathobiology. San Diego: Academic Press; 2000: 77–94.

  4. 4.

    Keefe DL, Niven-Fairchild T, Powell S, Buradagunta S. Mitochondrial deoxyribonucleic acid deletions in oocytes and reproductive aging in women. Fertil Steril. 1995;64:577–83.

  5. 5.

    Thouas GA, Trounson AO, Jones GM. Effect of female age on mouse oocyte developmental competence following mitochondrial injury. Biol Reprod. 2005;73:366–673.

  6. 6.

    Bentov Y, Casper RF. The aging oocyte--can mitochondrial function be improved? Fertil Steril. 2013;99:18–22.

  7. 7.

    te Velde ER, Peasron PL. The variability of female reproductive aging. Hum Reprod Update. 2002;8:141–54.

  8. 8.

    Tatone C, Amicarelli F, Carbone MC, Monteleone P, Caserta D, Marci R, et al. Cellular and molecular aspects of ovarian follicle ageing. Hum Reprod Update. 2008;14:131–42.

  9. 9.

    Redmer CA, Reynolds LP. Angiogenesis in the ovary. Rev Reprod. 1996;1:182–92.

  10. 10.

    Lee DH, Joo BS, Suh DS, Park JH, Choi YM, Lee KS. Sodium nitroprusside treatment during the superovulation process improves ovarian response and ovarian expression of vascular endothelial growth factor in aged female mice. Fertil Steril. 2008;89:1514–21.

  11. 11.

    Ha CS, Joo BS, Kim SC, Joo JK, Kim HG, Lee KS. Estrogen administration during superovulation increases oocyte quality and expressions of vascular endothelial growth factor and nitric oxide synthase in the ovary. J Obstet Gynaecol Res. 2010;36:789–95.

  12. 12.

    Choi KH, Joo BS, Sun ST, et al. Administration of visfatin during superovulation improves developmental competency of oocytes and fertility potential in aged female mice. Fertil Steril. 2012;97:1234–41.

  13. 13.

    Geva E, Jaffe RB. Role of vascular endothelial growth factor in ovarian physiology and pathology. Fertil Steril. 2000;74:429–38.

  14. 14.

    Fraser HM. Regulation of the ovarian follicular vasculature. Reprod Biol Endocrinol. 2006;4:18–26.

  15. 15.

    McGee EA, Hsueh AJ. Initial and cyclic recruitment of ovarian follicles. Endocr Rev. 2000;21:200–14.

  16. 16.

    Adhikari D, Liu K. Molecular mechanisms underlying the activation of mammalian primordial follicles. Endocr Rev. 2009;30:438–64.

  17. 17.

    Hsueh AJ, Kawamura K, Cheng Y, Fauser BC. Intraovarian control of early folliculogenesis. Endocr Rev. 2015;36:1–24.

  18. 18.

    Shea LD, Woodruff TK, Shikanov A. Bioengineering the ovarian follicle microenvironment. Annu Rev Biomed Eng. 2014;16:29–52.

  19. 19.

    Li J, Zhou F, Zheng T, Pan Z, Liang X, Huang J, et al. Ovarian germline stem cells (OGSCs) and the hippo signaling pathway association with physiological and pathological ovarian aging in mice. Cell Physiol Biochem. 2015;36:1712–24.

  20. 20.

    Celik O, Celik N, Gungor S, Haberal ET, Aydin S. Selective regulation of oocyte meiotic events enhances progress in fertility preservation methods. Biochem Insights. 2015;8:11–21.

  21. 21.

    Kawamura K, Cheng Y, Suzuki N, Deguchi M, Sato Y, Takae S, et al. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proc Natl Acad Sci U S A. 2013;10:17474–9.

  22. 22.

    Sun X, Su Y, He Y, Zhang J, Liu W, Zhang H, et al. New strategy for in vitro activation of primordial follicles with mTOR and PI3K stimulators. Cell Cycle. 2015;14:721–31.

  23. 23.

    Zheng W, Nagaraju G, Liu Z, Liu K. Functional roles of the phosphatidylinositol 3-kinases (PI3Ks) signaling in the mammalian ovary. Mol Cell Endocrinol. 2012;356:24–30.

  24. 24.

    Gorre N, Adhikari D, Lindkvist R, et al. mTORC1 signaling in oocytes is dispensable for the survival of primordial follicles and for female fertility. PLoS One. 2014;9:e110491.

  25. 25.

    Li J, Kawamura K, Cheng Y, Liu S, Klein C, Liu S, et al. Activation of dormant ovarian follicles to generate mature eggs. Proc Natl Acad Sci U S A. 2010;107:10280–4.

  26. 26.

    Adhikari D, Gorre N, Risal S, et al. The safe use of a PTEN inhibitor for the activation of dormant mouse primordial follicles and generation of fertilizable eggs. PLoS One. 2012;7:e39034.

  27. 27.

    Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, et al. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science. 2005;307:426–30.

  28. 28.

    Ognjanovic S, Bao S, Yamamoto SY, Garibay-Tupas J, Samal B, Bryant-Greenwood GD. Genomic organization of the gene coding for human pre-B-cell colony enhancing factor and expression in human fetal membranes. J Mol Endocrinol. 2001;26:107–17.

  29. 29.

    Curat CA, Wegner V, Sengenes C, et al. Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin. Diabetologia. 2006;49:744–7.

  30. 30.

    Shen CJ, Tsai EM, Lee JN, Chen YL, Lee CH, Chan TF. The concentrations of visfatin in the follicular fluids of women undergoing controlled ovarian stimulation are correlated to the number of oocytes retrieved. Fertil Steril. 2010;93:1844–50.

  31. 31.

    Xiao J, Xiao ZJ, Liu ZG, et al. Involvement of dimethylarginine dimethylaminohydrolase-2 in visfatin-enhanced angiogenic function of endothelial cells. Diabetes Metab Res. 2009;25:242–9.

  32. 32.

    Bae YH, Bae MK, Kim SR, Lee JH, Wee HJ, Bae SK. Upregulation of fibroblast growth factor-2 by visfatin that promotes endothelial angiogenesis. Biochem Biophys Res Commun. 2009;379:206–11.

  33. 33.

    Adya R, Tan BK, Punn A, Chen J, Randeva HS. Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signaling pathways: novel insights into visfatin-induced angiogenesis. Cardiovasc Res. 2008;78:356–65.

  34. 34.

    Park JW, Kim WH, Shin SH, et al. Visfatin exerts angiogenic effects on human umbilical vein endothelial cells through the mTOR signaling pathway. Biochim Biophys Acta. 1813;2011:763–71.

  35. 35.

    Age Converter; mouse age calculator. Available from: http://www.age-converter.com/mouse-age-calculator.

  36. 36.

    Castellano JM, Mosher KI, Abbey RJ, McBride A, James ML, Berdnik D, et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature. 2017;544:488–92.

  37. 37.

    Duncan FE, Gerton JL. Mammalian oogenesis and female reproductive aging. Aging. 2018;10:162–3.

  38. 38.

    Shimazu T, Jiang JY, Liijima K, et al. Induction of follicular development by direct single injection of vascular endothelial growth factor gene fragments into the ovary of miniature glits. Biol Reprod. 2003;69:1388–93.

  39. 39.

    Danforth DR, Arbogast LK, Ghosh S, Dickerman A, Rofagha R, Friedman CI. Vascular endothelial growth factor stimulates preantral follicle growth in the rat ovary. Biol Reprod. 2003;68:1736–41.

  40. 40.

    Iijima K, Jiang JY, Shimazu T, et al. Acceleration of follicular development by administration of vascular endothelial growth factor in cycling female rats. J Reprod Dev. 2005;51:161–8.

Download references

Author information

Correspondence to Bo Sun Joo or Kyu-Sup Lee.

Ethics declarations

This study was approved by the institutional review board of Pusan National University Hospital, Korea. All animal experiments were conducted under the guidance for the Care and Use of Laboratory Animals of the National Institutes of Health, approved by the Pusan National University Hospital Institutional Animal Care and Use Committee.

Conflict of Interests

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Park, B., Park, M.J., Kim, H.G. et al. Role of Visfatin in Restoration of Ovarian Aging and Fertility in the Mouse Aged 18 Months. Reprod. Sci. (2020) doi:10.1007/s43032-019-00074-9

Download citation

Keywords

  • Visfatin
  • Ovarian aging
  • Fertility
  • Primordial follicle activation
  • mTOR/PI3K