Effect of the neuropeptide phoenixin and its receptor GPR173 during folliculogenesis

Abstract

Folliculogenesis is a complex process, defined by the growth and development of follicles from the primordial population. Granulosa cells (GCs) play a vital role in every stage of follicular growth through proliferation, acquisition of gonadotropic responsiveness, steroidogenesis and production of autocrine/paracrine factors. A recently discovered hypothalamic neuropeptide phoenixin is involved in the regulation of the reproductive system. Phoenixin acts through its receptor, G protein-coupled receptor 173 (GPR173), to activate the cAMP/PKA pathway leading to the phosphorylation of CREB (pCREB). Here, we demonstrated the expression patterns of phoenixin and GPR173 in human ovary and explored its role in folliculogenesis. Phoenixin and GPR173 were both expressed in the human ovarian follicle, with increased expression in GCs as the follicle grows. Phoenixin treatment at 100 nM for 24 h induced the proliferation of human non-luteinized granulosa cell line, HGrC1 and significantly increased the expression levels of CYP19A1, FSHR, LHR and KITL, but decreased NPPC expression levels. These effects were suppressed by GPR173 siRNA. The expression level of CREB1, pCREB and estradiol (E2) production in the culture medium was significantly enhanced by phoenixin treatment in a concentration-dependent manner. Phoenixin also significantly increased the follicular area in a murine ovarian tissue culture model, leading to an increased number of ovulated oocytes with a higher level of maturation. Taken together, our data demonstrate that phoenixin is an intraovarian factor that promotes follicular growth through its receptor GPR173 by accelerating proliferation of GCs, inducing E2 production and increasing the expression of genes related to follicle development.

Phoenixin and Its Role in Reproductive Hormone Release

“…While expression of phoenixin and GPR173 was absent in the granulosa cells of primordial follicles, their expression increased with follicle development, with the most intense staining observed in the antral follicle and corpus luteum. 11 Phoenixin and GPR173 immunostaining were also detected in oocytes. Treatment with 100 nM of phoenixin-20 caused an increase in GPR173 expression in human nonluteinized granulosa cells, and at 10 and 100 nM concentrations, phoenixin was observed to increase CREB phosphorylation.…”

“…Importantly, phoenixin induced E2 production in a dose-dependent manner. 11 The authors also demonstrated that phoenixin resulted in an increase in follicle-stimulating hormone receptor and LH receptor in granulosa cells, and thus may contribute to granulosa cell sensitivity to gonadotrophins. 11 Using murine ovarian tissue cultures, phoenixin treatment also increased follicular growth in a dose-dependent manner.…”

“…11 The authors also demonstrated that phoenixin resulted in an increase in follicle-stimulating hormone receptor and LH receptor in granulosa cells, and thus may contribute to granulosa cell sensitivity to gonadotrophins. 11 Using murine ovarian tissue cultures, phoenixin treatment also increased follicular growth in a dose-dependent manner. At 10 and 100 nM, phoenixin induced follicular growth with an increase in the number of ovulated oocytes when compared with control (19.00 AE 1.15 vs. 17.67 AE 1.45 vs. 12.67 AE 1.76, p < 0.05).…”

“…10 Given that phoenixin signaling has been demonstrated at the level of the ovary, and that phoenixin delayed estrus, Nguyen and colleagues investigated the role of phoenixin and its receptor on folliculogenesis. 11 Using human ovarian tissue from women aged 19 to 32 years, undergoing surgery for cervical cancer, they demonstrated expression of phoenixin and its receptor, GPR173, in human ovarian follicles. While expression of phoenixin and GPR173 was absent in the granulosa cells of primordial follicles, their expression increased with follicle development, with the most intense staining observed in the antral follicle and corpus luteum.…”

“…11 Phoenixin-20 at 100 nM additionally resulted in a higher proportion of MI and MII oocytes when compared with control (54.72 vs. 26.32%, p < 0.01). 11 Given that PCOS is a condition associated with disruption in follicular growth, and steroidogenesis, and the observation that women with PCOS have elevated levels of phoenixin, the authors suggested that a further area of interest would be to investigate the effects of phoenixin and its signaling in follicles of women with PCOS. 11…”