In the present study, we have made use of a well-established model of PCOS-implanted with letrozole pellets-to study its effects on insulin resistance, as we reported previously(19). We have evaluated that ABA treatment resulted in decreased testosterone concentration, body weight, and improvement of insulin resistance in PCOS rats induced by letrozole. Our further study revealed that ABA reversed H2O2-induced cell apoptosis in KGNs, and also mitigated ROS activity in H2O2-induced KGNs, which may be closely associated with the alteration of ovary hormone release and IR. Therefore, the present results indicated that gained bodyweight, impaired insulin resistance, and higher T levels were significantly improved after ABA treatment in PCOS rats, suggesting that it may facilitate the treatment of PCOS. ABA significantly reduced cell apoptosis and ROS levels and increased cell viability. To our knowledge, these findings provided the first evidence dressing the role of ABA in maintaining KGNs survival and protecting against cell damage and oxidative stress in granulosa cells around oocytes.
In the present study, PCOS rats induced by letrozole in our study did not exhibit any significant changes in IPGTT, but induced insulin resistance with abnormal insulin levels and increased T levels, consistent with our previous study(19). These phenotypes are more similar to PCOS patients. ABA naturally originates from different dietary sources but also is endogenously produced by the carotenoid biosynthesis pathway. It has been demonstrated that chronic consumption of a supplement containing a low dose of ABA ameliorates the prediabetes markers. Moreover, it has also been proven that the improvement was greater in these subjects than in healthy ones, suggesting the beneficial influence of low-dose ABA supplementation in prediabetics(7). As PCOS is considered as a condition at a high risk of developing into prediabetes, or even diabetes, it reminds us that ABA may be a potential treatment for PCOS. In this paper, dietary ABA was displayed to possess the capacity to alleviate PCOS throughout a series of routine indicators, including reduced body weights, the rectification of abnormal T, and improved insulin resistance. Our data are consistent with the above results regarding promoting insulin sensitivity. Guri et al (10) showed that the ABA treatment in obese and prediabetic mice in regulating glucose metabolism is owing to its structural similarity to thiazolidinediones and its efficacy similar to that of these antidiabetic oral drugs. ABA may be a potent insulin-sensitizing compound with the ability to control systemic glycemic responses and skeletal muscle metabolism. The treatment of ABA-induced greater insulin sensitivity(12). Nevertheless, unlike thiazolidinediones, ABA exerts its hypoglycemic action, in mammals, by binding lanthionine synthetase C-like 2 (LANCL2) and acting on peroxisome proliferator-activated receptor gamma (PPARγ) (21). The data presented in our study and the published literature on ABA to date highlighted its ability to intersect the pathogenesis of PCOS and insulin resistance in multiple aspects.
Oxidative stress has been proved to be involved in the proliferation, differentiation, and maturation of follicles, which may closely relate to the number of meiotic I(MI) oocytes(14, 22). Oxidant stress has been implicated in many reproductive disorders including PCOS, Primary Ovarian Insufficiency (POI), endometriosis, infertility, and aging. ROS production plays a vital role in the induction of meiosis in the oocyte and higher ROS level has been seemed to impair oocyte maturation, and oxidative stress induces granulosa cell discordant function and impacts oocyte quality(23, 24). Elevated ROS in the ovarian tissues had been found in letrozole-treated PCOS rats(16). In the meanwhile, the antioxidant protective effect of ABA has been extensively studied. Rafiepour et al(25) demonstrated that PPAR γ signaling cascade mediated by reducing ROS levels of ABA’s antioxidant and antiapoptotic properties ABA was able to increase the antioxidant enzymes and peroxidase activities, as well as reduce MDA concentration, H2O2 levels, and body weight in rats(26). As an antioxidant and antiapoptotic agent, ABA may provide a protective role by an endocrine or paracrine mechanism. Thus, the possible function of ABA from human KGNs might be able to provide nutrients and support to the oocytes. Therefore, it prompted us to inquire whether ABA contributes to granulosa cells’ survival. There are many ways to detection of cell death. CCK-8 assay was employed to determine cell viability, annexin V/PI staining was used to measure the cell apoptosis rate. Here, we provided the first evidence demonstrating the role of ABA in inhibiting cell apoptosis, promoting cell viability, and also attenuating the increased expression of ROS levels in H2O2 induced KGNs, suggesting that the level of ABA in follicular fluid might determine the developmental fate of ovarian follicles, and participating in the pathological process of PCOS.
Nevertheless, our study is a preliminary investigation of ABA in the PCOS rat model and ovarian function. Further research is needed to investigate the effects of ABA on ovary function using in vivo and in vitro studies, such as the effects on theca cell, angiogenesis, and folliculogenesis. Further explorations could be clinically relevant for fertility in women, whether ABA could be used as an intervention to treat reproductive disorders.