Mitochondrial and glucose metabolic dysfunctions in granulosa cells induce impaired oocytes of polycystic ovary syndrome through Sirtuin 3.
Free radical biology & medicine
Mitochondrial function and glucose metabolism play important roles in bidirectional signaling between granulosa cells (GCs) and oocytes. However, the factors associated with mitochondrial function and glucose metabolism of GCs in polycystic ovary syndrome (PCOS) are poorly understood, and their potential downstream effects on oocyte quality are still unknown. The aim of this study was to investigate whether there are alterations in mitochondrial-related functions and glucose metabolism in ovarian GCs of women with PCOS and the role of Sirtuin 3 (SIRT3) in this process. Here, we demonstrated that women with PCOS undergoing in vitro fertilization and embryo transfer had significantly lower rates of metaphase II oocytes, two-pronuclear fertilization, cleavage, and day 3 good-quality embryos. Germinal vesicle- and metaphase I-stage oocytes from women with PCOS exhibited increased mitochondrial reactive oxygen species (ROS), decreased mitochondrial membrane potential, and downregulation of glucose-6-phosphate dehydrogenase. GCs from women with PCOS presented significant alterations in mitochondrial morphology, amount, and localization, decreased membrane potential, reduced adenosine triphosphate (ATP) synthesis, increased mitochondrial ROS and oxidative stress, and insufficient oxidative phosphorylation (OXPHOS) together with decreased glycolysis. SIRT3 expression was significantly decreased in GCs of PCOS patients, and knockdown of SIRT3 in KGN cells could mimic the alterations in mitochondrial functions and glucose metabolism in PCOS GCs. SIRT3 knockdown changed the acetylation status of NDUFS1, which might induce altered mitochondrial OXPHOS, the generation of mitochondrial ROS, and eventually defects in the cellular insulin signaling pathway. These findings suggest that SIRT3 deficiency in GCs of PCOS patients may contribute to mitochondrial dysfunction, elevated oxidative stress, and defects in glucose metabolism, which potentially induce impaired oocytes in PCOS.
10.1016/j.freeradbiomed.2022.05.010
Novel PGK1 determines SKP2-dependent AR stability and reprograms granular cell glucose metabolism facilitating ovulation dysfunction.
Liu Xia,Sun Changfa,Zou Kexin,Li Cheng,Chen Xiaojun,Gu Hangchao,Zhou Zhiyang,Yang Zuwei,Tu Yaoyao,Qin Ningxin,Zhao Yiran,Wu Yimei,Meng Yicong,Ding Guolian,Liu Xinmei,Sheng Jianzhong,Yu Chuanjin,Huang Hefeng
EBioMedicine
BACKGROUND:Disordered folliculogenesis is a core characteristic of polycystic ovary syndrome (PCOS) and androgen receptors (ARs) are closely associated with hyperandrogenism and abnormalities in folliculogenesis in PCOS. However, whether the new AR binding partner phosphoglycerate kinase 1 (PGK1) in granulosa cells (GCs) plays a key role in the pathogenesis of PCOS remains unclear. METHODS:We identified the new AR binding partner PGK1 by co-IP (co-immunoprecipitation) in luteinized GCs, and reconfirmed by co-IP, co-localization and GST pull down assay, and checked PGK1 expression levels with qRT-PCR and western blotting. Pharmaceuticals rescue assays in mice, and metabolism assay, AR protein stability and RNA-seq of PGK1 targets in cells proved the function in PCOS. FINDINGS:PGK1 and AR are highly expressed in PCOS luteinized GCs and PCOS-like mouse ovarian tissues. PGK1 regulated glucose metabolism and deteriorated PCOS-like mouse metabolic disorder, and paclitaxel rescued the phenotype of PCOS-like mice and reduced ovarian PGK1 and AR protein levels. PGK1 inhibited AR ubiquitination levels and increased AR stability in an E3 ligase SKP2-dependent manner. Additionally, PGK1 promoted AR nuclear translocation, and RNA-seq data showed that critical ovulation-related genes were regulated by the PGK1-AR axis. INTERPRETATION:PGK1 regulated GCs metabolism and interacted with AR to regulate the expression of key ovulation genes, and also mediated cell proliferation and apoptosis, which resulted in the etiology of PCOS. This work highlights the pathogenic mechanism and represents a novel therapeutic target for PCOS. FUNDING:National Key Research and Development Program of China; National Natural Science Foundation of China grant.
10.1016/j.ebiom.2020.103058
Oxidative stress and energy metabolism abnormalities in polycystic ovary syndrome: from mechanisms to therapeutic strategies.
Reproductive biology and endocrinology : RB&E
Polycystic ovary syndrome (PCOS), as a common endocrine and metabolic disorder, is often regarded as a primary cause of anovulatory infertility in women. The pathogenesis of PCOS is complex and influenced by multiple factors. Emerging evidence highlights that energy metabolism dysfunction and oxidative stress in granulosa cells (GCs) are pivotal contributors to aberrant follicular development and impaired fertility in PCOS patients. Mitochondrial dysfunction, increased oxidative stress, and disrupted glucose metabolism are frequently observed in individuals with PCOS, collectively leading to compromised oocyte quality. This review delves into the mechanisms linking oxidative stress and energy metabolism abnormalities in PCOS, analyzing their adverse effects on reproductive function. Furthermore, potential therapeutic strategies to mitigate oxidative stress and metabolic disturbances are proposed, providing a theoretical basis for advancing clinical management of PCOS.
10.1186/s12958-024-01337-0
Disclosing α-lactalbumin impact on the intestinal and vaginal microbiota of women suffering from polycystic ovary syndrome.
Microbial biotechnology
Polycystic ovary syndrome (PCOS) is one of the most widespread endocrinopathy affecting women of reproductive age with detrimental effects on life quality and health. Among several mechanisms involved in its aetiopathogenesis, recent studies have also postulated the involvement of the vaginal and intestinal microbiota in the development of this disorder. In this study, an accurate insight into the microbial changes associated with PCOS was performed through a pooled-analysis highlighting that this syndrome is characterized by intestinal and vaginal dysbiosis with a reduction of beneficial microorganisms and a higher proportion of potential pathogens. Based on this observation, we evaluated the ability of a milk-derived protein exerting positive outcomes in the management of PCOS, that is, α-lactalbumin (α-LA), to recover PCOS-related dysbiosis. In vitro experiments revealed that this protein improved the growth performances of members of two health-promoting bacterial genera, that is, Bifidobacterium and Lactobacillus, depleted in both intestinal and vaginal microbiota of PCOS-affected women. In addition, α-LA modulated the taxonomic composition and growth performances of the microbial players of the complex intestinal and vaginal microbiota. Finally, an in vivo pilot study further corroborated these observations. The oral administration of α-LA for 30 days to women with PCOS revealed that this protein may have a role in favouring the growth of health-promoting bacteria yet limiting the proliferation of potential pathogens. Overall, our results could pave the way to the use of α-LA as a valid compound with 'prebiotic effects' to limit/restore the PCOS-related intestinal and vaginal dysbiosis.
10.1111/1751-7915.14540
Gut and Vaginal Microbiomes in PCOS: Implications for Women's Health.
Gu Yuanyuan,Zhou Guannan,Zhou Fangyue,Li Yao,Wu Qiongwei,He Hongyu,Zhang Yi,Ma Chengbin,Ding Jingxin,Hua Keqin
Frontiers in endocrinology
PCOS is defined as a kind of endocrine and metabolic disorder which affects females at reproductive ages, is becoming much more common, nowadays. Microbiomes are known as microorganisms that inhabit the body to play a vital role in human health. In recent years, several basic and clinical studies have tried to investigate the correlation between the reproductive health/disorder and microbiomes (gut microbiomes and vaginal microbiomes). However, the mechanism is still unclear. In this review, we reviewed the relationship between PCOS and microbiomes, including gut/vaginal microbiomes compositions in PCOS, mechanism of microbiomes and PCOS, and then collectively focused on the recent findings on the influence of microbiomes on the novel insight regarding the therapeutic strategies for PCOS in the future clinical practice.
10.3389/fendo.2022.808508
Effects of Metformin on Reproductive, Endocrine, and Metabolic Characteristics of Female Offspring in a Rat Model of Letrozole-Induced Polycystic Ovarian Syndrome With Insulin Resistance.
Xie Yidong,Xiao Li,Li Shangwei
Frontiers in endocrinology
The beneficial effects of metformin, especially its capacity to ameliorate insulin resistance (IR) in polycystic ovary syndrome (PCOS), explains why it is widely prescribed. However, its effect on the offspring of patients with PCOS remains uncertain. This study investigated the impact of metformin treatment on the first- and second-generation female offspring born to letrozole-induced PCOS-IR rats. Forty-five female Wistar rats were implanted with continuous-release letrozole pellets or placebo and treated with metformin or vehicle control. Rats exposed to letrozole showed PCOS-like reproductive, endocrine, and metabolic phenotypes in contrast to the controls. Metformin significantly decreased the risk of body weight gain and increased expression in F1 female offspring in PCOS-IR rats, contributing to the improvement in obesity, hyperinsulinemia, and IR. Decreased expression and increased expression were observed in F1 female rats of the PCOS-IR and PCOS-IR+Metformin groups, suggesting that and dysfunction might promote the development of PCOS. Nevertheless, we found no significant differences in , , and expression or other PCOS phenotypes in F2 female offspring of PCOS-IR rats. These findings indicated widespread reproductive, endocrine, and metabolic changes in the PCOS-IR rat model, but the PCOS phenotypes could not be stably inherited by the next generations. Metformin might have contributed to the improvement in obesity, hyperinsulinemia, and IR in F1 female offspring. The results of this study could be used as a theoretical basis in support of using metformin in the treatment of PCOS-IR patients.
10.3389/fendo.2021.701590
Vaginal microbiome in obesity and its impact on reproduction.
Best practice & research. Clinical obstetrics & gynaecology
A number of reproductive outcomes have been increasingly found to be affected by the vaginal microbiota. Obesity has become a global epidemic, affecting increasing numbers of reproductive-age women, and has been shown to be a risk factor for a number of adverse female health outcomes. A healthy vaginal microbiome is characterized by Lactobacillus-dominance, in particular Lactobacillus crispatus; obesity has been found to be associated with higher diversity and a lower likelihood of Lactobacillus-dominance. In this review, we summarize the evidence on the vaginal microbiome in obese women and the impact on reproductive outcomes such as conception rates, early pregnancy, and preterm birth. We further explore the mechanisms by which obesity may result in an altered microbial composition and highlight future avenues for therapeutic targeting of the vaginal microbiota.
10.1016/j.bpobgyn.2023.102365
Metformin ameliorates polycystic ovary syndrome in a rat model by decreasing excessive autophagy in ovarian granulosa cells via the PI3K/AKT/mTOR pathway.
Endocrine journal
Polycystic ovary syndrome (PCOS) is a common gynecological disease accompanied by a variety of clinical features, including anovulation, hyperandrogenism, and ovarian abnormalities, resulting in infertility. PCOS affects approximately 6%-15% of all reproductive-age women worldwide. Metformin, a popular drug used to treat PCOS in patients, has beneficial effects in reducing hyperandrogenism and inducing ovulation; however, the mechanisms by which metformin ameliorates PCOS are not clear. Hence, we aimed to explore the mechanisms of metformin in treating PCOS. In the present study, we first treated a letrozole-induced PCOS rat model with metformin, detected the pathological recovery of PCOS, and then assessed the effects of metformin on HO-induced autophagy in ovarian granulosa cells (GCs) by detecting the level of oxidative stress and the expression of autophagy-associated proteins and key proteins in the PI3K/AKT/mTOR pathway. We demonstrated that metformin ameliorated PCOS in a rat model by downregulating autophagy in GCs, and metformin decreased the levels of oxidative stress and autophagy in HO-induced GCs and affected the PI3K/AKT/mTOR signaling pathway. Taken together, our results indicate that metformin ameliorates PCOS in a rat model by decreasing excessive autophagy in GCs via the PI3K/AKT/mTOR pathway, and this study provides evidence for targeted reduction of excessive autophagy of ovarian granulosa cells and improvement of PCOS.
10.1507/endocrj.EJ21-0480
Impact of high-fructose diet and metformin on histomorphological and molecular parameters of reproductive organs and vaginal microbiota of female rat.
Scientific reports
There are limited data on the effects of a high-fructose diet on the female reproductive system. Although metformin has some functional effects on female fertility, its reproductive outcome on high fructose diet-induced metabolic syndrome is unclear. The aim of the present study is to evaluate the impact of a high fructose diet on histomorphological and molecular parameters of the reproductive organs and vaginal microbiota as well as the treatment potential of metformin. Wistar albino rats were used in the study. The metabolic syndrome model was induced by a high-fructose diet in rats for 15 weeks. Metformin was orally administered once a day for the last 6 weeks. The high-fructose diet increased blood glucose, triglycerides, insulin, and ovarian testosterone levels; however, it reduced ovarian aromatase levels and follicle numbers and caused uterine inflammation. The high-fructose diet-induced molecular abnormalities on ovarian tissue were demonstrated by the downregulation of ovarian insulin signaling pathway proteins and dysregulation of ovarian mitogenic and apoptotic pathway proteins. A high-fructose diet caused vaginal dysbiosis, metformin increased probiotic bacteria in the vaginal microbiota. Our results revealed that metformin improves ovarian impairments by modulating hormonal balance, insulin level, mapk, and apoptotic signaling molecules, as well as regulating the vaginal microbiota.
10.1038/s41598-024-76211-5
PHLPP1 inhibits the growth and aerobic glycolysis activity of human ovarian granular cells through inactivating AKT pathway.
BMC women's health
BACKGROUND:Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphologic features, and PCOS is associated with infertility. PH domain Leucine-rich repeat Protein Phosphatase 1 (PHLPP1) has been shown to regulate AKT. The aim of present study is to investigate the role of PHLPP1 in PCOS. METHODS:The expression levels of PHLPP1 in dihydrotestosterone (DHT)-treated human ovarian granular KGN cells were determined by qRT-PCR and Western blot. PHLPP1 was silenced or overexpressed using lentivirus. Cell proliferation was detected by CCK-8. Apoptosis and ROS generation were analyzed by flow cytometry. Glycolysis was analyzed by measuring extracellular acidification rate (ECAR). RESULTS:DHT treatment suppressed proliferation, promoted apoptosis, enhanced ROS, and inhibited glycolysis in KGN cells. PHLPP1 silencing alleviated the DHT-induced suppression of proliferation and glycolysis, and promotion of apoptosis and ROS in KGN cells. PHLPP1 regulated cell proliferation and glycolysis in human KGN cells via the AKT signaling pathway. CONCLUSIONS:Our results showed that PHLPP1 mediates the proliferation and aerobic glycolysis activity of human ovarian granular cells through regulating AKT signaling.
10.1186/s12905-023-02872-5
Metformin inhibits ovarian granular cell pyroptosis through the miR-670-3p/NOX2/ROS pathway.
Aging
Recent studies have demonstrated that ovarian granular cells (OGCs) pyroptosis is present in the ovaries of polycystic ovary syndrome (PCOS) mice and that NLRP3 activation destroys follicular functions. Metformin has been shown to protect against PCOS by reducing insulin resistance in women, whereas its role in OGC pyroptosis is unknown. This study aimed to investigate the impact of metformin on OGC pyroptosis and the underlying mechanisms. The results showed that treating a human granulosa-like tumor cell line (KGN) with metformin significantly decreased LPS-induced expression of miR-670-3p, NOX2, NLRP3, ASC, cleaved caspase-1, and GSDMD-N. Cellular caspase-1 activity; ROS production; oxidative stress; and the secretion of IL-1β, IL-6, IL-18, and TNF-α were also diminished. These effects were amplified by adding N-acetyl-L-cysteine (NAC), a pharmacological inhibitor of ROS. In contrast, metformin's anti-pyroptosis and anti-inflammatory effects were robustly ameliorated by NOX2 overexpression in KGN cells. Moreover, bioinformatic analyses, RT-PCR, and Western blotting showed that miR-670-3p could directly bind to the NOX2 (encoded by the CYBB gene in humans) 3'UTR and decrease NOX2 expression. Metformin-induced suppression of NOX2 expression, ROS production, oxidative stress, and pyroptosis was significantly alleviated by transfection with the miR-670-3p inhibitor. These findings suggest that metformin inhibits KGN cell pyroptosis via the miR-670-3p/NOX2/ROS pathway.
10.18632/aging.204745