Spexin role in human granulosa cells physiology and PCOS: expression and negative impact on steroidogenesis and proliferation

Abstract

Spexin (SPX) is a novel neuropeptide and adipokine negatively correlated with obesity and insulin resistance. A recent study investigated expression and regulatory function of SPX in the hypothalamus and pituitary; however, the effect on ovarian function is still unknown. The aim of this study was to characterize the expression of SPX and its receptors, galanin receptors 2 and 3 (GALR2/3) in the human ovary and to study its in vitro effect on granulosa cells (GC) function. Follicular fluid (FF) and GC were obtained from normal weight and obese healthy and diagnosed with polycystic ovarian syndrome (PCOS) women. Expression of SPX and GALR2/3 in the ovary was studied by qPCR, western blot, and immunohistochemistry. The level of SPX in FF was assessed by ELISA. The in vitro effect of recombinant human SPX on GC proliferation, steroidogenesis, and signaling pathways (MAP3/1, STAT3, AKT, PKA) was analyzed. Moreover, GC proliferation and estradiol (E2) secretion were measured with and without an siRNA against GALR2/3 and pharmacological inhibition of the above kinases. The results showed that both the SPX concentration in FF and its gene expression were decreased in GC of obese and PCOS women, while the protein expression of GALR2/3 was increased. We noted that SPX reduced GC proliferation and steroidogenesis; these effects were mediated by GALR2/3 and kinases MAP3/1, AKT and STAT3 for proliferation or kinases MAP3/1 and PKA for E2 secretion. The obtained data clearly documented that SPX is a novel regulator of human ovarian physiology and possibly plays a role in PCOS pathogenesis.

Deciphering The Transcriptional Activities of Genes Coding For Adipokines and Their Receptors in Porcine Ex Situ-Protected Mesenchymal Stem Cells Undergoing Adipogenic Differentiation

“…Similarly, another member of the adipokine family, designated as vaspin, also contributes to the decrease in the expression of its 78-kDa receptor, termed glucose-regulated protein 78 (GRP78), in porcine ovarian follicles (Kurowska et al, 2020). Spexin acts differently depending on the receptor type, i.e., it leads to either an increase in the expression of galanin receptor 2, or a decrease in the expression of galanin receptor 3 in human granulosa cells (Kurowska et al, 2023).…”

Advances in research on spexin-mediated regulation of reproductive function in vertebrates

“…Spexin inhibited granulosa cells (GCs) proliferation and E2 release. Kurowska et al (32)observed immunolocalization of spexin and GALR2/3 in human ovaries, including GCs, oocytes, theca, and cumulus cells. This finding aligns with previous data describing the expression of spx in rat ovaries (4).…”

“…This finding aligns with previous data describing the expression of spx in rat ovaries ( 4 ). Studies on the molecular mechanism of spexin in the KGN cell line showed that the peptide negatively influenced GCs function by inhibiting cell proliferation via GALR2/3, MAP3/1, STAT3, and AKT and E2 secretion via GALR2/3, MAP3/1, and PKA ( 32 ). In summary, there is currently no direct evidence to suggest that spexin mediates E2 regulation of the reproductive axis, but limited research suggests that E2 regulates spx expression in the hypothalamus.…”