Sam68 mediates leptin signaling and action in human granulosa cells: possible role in leptin resistance in PCOS

Abstract

Introduction Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, obesity, and insulin resistance, that leads to subfertility. Sam68 is an RNA-binding protein with signaling functions that is ubiquitously expressed, including gonads. Sam68 is recruited to leptin signaling, mediating different leptin actions. Objective We aimed to investigate the role of Sam68 in leptin signaling, mediating the effect on aromatase expression in granulosa cells and the posible implication of Sam68 in the leptin resistance in PCOS. Materials and methods Granulosa cells were from healthy donors (n = 25) and women with PCOS (n = 25), within the age range of 20 to 40 years, from Valencian Infertility Institute (IVI), Seville, Spain. Sam68 expression was inhibited by siRNA method and overexpressed by expression vector. Expression level was analysed by qPCR and immunoblot. Statistical significance was assessed by ANOVA followed by different post-hoc tests. A P value of <0.05 was considered statistically significant. Results We have found that leptin stimulation increases phosphorylation and expression level of Sam68 and aromatase in granulosa cells from normal donors. Downregulation of Sam68 expression resulted in a lower activation of MAPK and PI3K pathways in response to leptin, whereas overexpression of Sam68 increased leptin stimulation of signaling, enhancing aromatase expression. Granulosa cells from women with PCOS presented lower expression of Sam68 and were resistant to the leptin effect on aromatase expression. Conclusions These results suggest the participation of Sam68 in leptin receptor signaling, mediating the leptin effect on aromatase expression in granulosa cells, and point to a new target in leptin resistance in PCOS.

Decreased Expression of Sam68 Is Associated with Insulin Resistance in Granulosa Cells from PCOS Patients

“…Next, the possible participation of Sam68 in insulin receptor signaling and the regulation of Sam68 expression by insulin in GCs from healthy donors were also investigated. In this context, we also found that the insulin stimulation of GCs increased the expression of Sam68 in a similar way to that previously observed with leptin in GCs from healthy donors [ 36 ] and other systems [ 9 ]. Therefore, this result further supports the possible role of Sam68 in the signaling of insulin in GCs.…”

Progress of Adipokines in the Female Reproductive System: A Focus on Polycystic Ovary Syndrome

“…Studies have shown that Leptin enhanced the expression of aromatase genes by activating classic signal transduction pathways MAPK and PI3K, whereas this phenomenon was significantly attenuated in granulosa cells of PCOS patients, together with significantly increased plasma Leptin and decreased soluble Leptin receptor (s OB-R) in PCOS patients ( 80 ). This may suggest that Leptin resistance in PCOS patients may be possibly mediated by Sam68, an RNA-binding protein that is widely expressed in the body and has signaling functions ( 81 ). A study aiming to illustrate the effects of aerobic exercise on PCOS rats with HA showed the effect of Leptin on inflammation in PCOS ( 82 ).…”

Elevated Serum Leptin Levels as a Predictive Marker for Polycystic Ovary Syndrome

“…This study indicated that serum leptin levels were elevated in patients with PCOS compared with the non-PCOS control group, supporting the previous studies. It has been suggested that high leptin in PCOS may interfere with the development of the mature oocyte and ovarian steroidogenesis, contributing to ovulatory dysfunction and infertility ( 20 , 21 ). Moreover, hyperleptinemia may interact with hyperandrogenemia and chronic low-grade inflammation in PCOS, forming a vicious circle in PCOS ( 22 ).…”