Autophagy in ovary and polycystic ovary syndrome: role, dispute and future perspective

Kumariya, Sanjana; Ubba, Vaibhave; Jha, Rajesh Kumar; Gayen, Jiaur R.

doi:10.1080/15548627.2021.1938914

Cited by 122 publications

(85 citation statements)

References 218 publications

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“…16 However, the cellular response in the ovary may be the initial pathological mechanism of PCOS, and recent studies found that LC3 protein was mainly expressed in follicular granulosa cells, and that excessive autophagy in ovarian granulosa cells may lead to the occurrence of PCOS. 17 The newly identified adipocytokine chemerin plays an important role in lipid formation and blood glucose regulation. 18 Patients with PCOS had abnormally high serum levels of chemerin, which were reduced by the use of metformin for symptom relief.…”

Section: Discussionmentioning

confidence: 99%

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Chemerin regulates autophagy to participate in polycystic ovary syndrome

et al. 2021

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Objective Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age. Chemerin has recently been discovered as a novel adipokine associated with obesity and metabolic syndrome. Excessive autophagy activity and overexpression of autophagy-related genes in follicular granulosa cells are important mechanisms of PCOS. This study aimed to investigate the effect of chemerin on autophagy in PCOS. Methods A rat model of PCOS was established by subcutaneous injection of testosterone propionate under a high-fat diet. Expression levels of chemerin and its receptor CMKLR1 were determined by real-time polymerase chain reaction and western blot. Proliferation and apoptosis of human granulosa cells in vitro and expression of autophagy-related genes were examined using bafilomycin A1 (autophagy inhibitor) and Torin1 (autophagy inducer). Results Chemerin and CMKLR1 expression were significantly increased in the ovary in a rat model of PCOS. Ectopic expression of chemerin promoted the proliferation and inhibited the apoptosis of COV434 cells. Ectopic expression of chemerin also induced autophagy by inhibiting the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Conclusions Chemerin and CMKLR1 were overexpressed in PCOS rats. Chemerin promoted autophagy through inhibiting the PI3K/Akt/mTOR pathway, and may provide a potential target and biomarker of PCOS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chemerin regulates autophagy to participate in polycystic ovary syndrome

et al. 2021

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“…Jin et al further explored the effect of androgen exposure on the function of granulosa cells and found that testosterone significantly induced ER stress and apoptosis of ovarian granulosa cells in vitro, indicating the negative effect of androgen-induced ER stress on follicle development (8). In addition, Li et al revealed a positive correlation between serum testosterone levels and the expression of autophagy-related genes, suggesting that androgen excess contributed to the activation of autophagy and apoptosis in granulosa cells, which subsequently impairs ovarian function (9,10). Combined, these results suggested androgens promote apoptosis of granulosa cells in PCOS, while the specific role and mechanism of androgens in regulating follicular growth and ovulation remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, Li et al. revealed a positive correlation between serum testosterone levels and the expression of autophagy-related genes, suggesting that androgen excess contributed to the activation of autophagy and apoptosis in granulosa cells, which subsequently impairs ovarian function ( 9 , 10 ). Combined, these results suggested androgens promote apoptosis of granulosa cells in PCOS, while the specific role and mechanism of androgens in regulating follicular growth and ovulation remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Effects of Androgen Excess-Related Metabolic Disturbances on Granulosa Cell Function and Follicular Development

Liao

Yun

et al. 2022

Front. Endocrinol.

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Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease in women of reproductive age. Ovarian dysfunction including abnormal steroid hormone synthesis and follicular arrest play a vital role in PCOS pathogenesis. Hyperandrogenemia is one of the important characteristics of PCOS. However, the mechanism of regulation and interaction between hyperandrogenism and ovulation abnormalities are not clear. To investigate androgen-related metabolic state in granulosa cells of PCOS patients, we identified the transcriptome characteristics of PCOS granulosa cells by RNA-seq. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes (DEGs) revealed that genes enriched in lipid metabolism pathway, fatty acid biosynthetic process and ovarian steroidogenesis pathway were abnormally expressed in PCOS granulosa cells in comparison with that in control. There are close interactions among these three pathways as identified by analysis of the protein-protein interaction (PPI) network of DEGs. Furthermore, in vitro mouse follicle culture system was established to explore the effect of high androgen and its related metabolic dysfunction on follicular growth and ovulation. RT-qPCR results showed that follicles cultured with dehydroepiandrosterone (DHEA) exhibited decreased expression levels of cumulus expansion-related genes (Has2, Ptx3, Tnfaip6 and Adamts1) and oocyte maturation-related genes (Gdf9 and Bmp15), which may be caused by impaired steroid hormone synthesis and lipid metabolism, thus inhibited follicular development and ovulation. Furthermore, the inhibition effect of DHEA on follicle development and ovulation was ameliorated by flutamide, an androgen receptor (AR) antagonist, suggesting the involvement of AR signaling. In summary, our study offers new insights into understanding the role of androgen excess induced granulosa cell metabolic disorder in ovarian dysfunction of PCOS patients.

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“…Moreover, considering that ovarian autophagy is critical for follicular development [ 83 ], the genes involved in these mechanisms were investigated. In PNA mice, a global hypomethylation is detected, resulting in an overexpression of genes involved in the mitogen-activated protein kinase (MAPK)/p53 pathway ( Mapk14, Mapkapk3 and Trp53 ) and autophagy (Becn1) [ 63 ].…”

Section: Mechanisms Involved In Pcos Pathogenesismentioning

confidence: 99%

Metabolic and Molecular Mechanisms of Diet and Physical Exercise in the Management of Polycystic Ovarian Syndrome

et al. 2022

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Polycystic ovary syndrome (PCOS) is an endocrine systemic disorder mainly characterized by a hormonal and metabolic disbalance that leads to oligo/anovulation, hyperandrogenism and the formation of ovarian cysts. Despite the progress that has been reached in its diagnosis and management, little is known about the molecular mechanisms and signaling pathways underlying the pathogenic mechanisms. In this sense, recent research has suggested that the influence of multiple factors, including age, environment, lifestyle and the disease state environment can change the clinical presentation of PCOS via epigenetic modifications. Variants in the genes encoding for proteins involved in steroidogenesis and glucose homeostasis play a crucial role in the development of the disease. Other genes involved in inflammation and cell proliferation seem to undergo an epigenetic control. Moreover, lifestyle factors influence the PCOS course and prognosis, including diet and physical activity, which are fundamental in reducing oxidative stress, inflammation and in improving metabolic and hormonal parameters. In the present review, literature evidence on molecular and epigenetic mechanisms related to PCOS etiology will be discussed, with a particular attention on the positive influence of diet and physical activity as nonpharmacological ways of intervention in the management of the disease.

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Autophagy in ovary and polycystic ovary syndrome: role, dispute and future perspective

Cited by 122 publications

References 218 publications

Chemerin regulates autophagy to participate in polycystic ovary syndrome

Chemerin regulates autophagy to participate in polycystic ovary syndrome

Effects of Androgen Excess-Related Metabolic Disturbances on Granulosa Cell Function and Follicular Development

Metabolic and Molecular Mechanisms of Diet and Physical Exercise in the Management of Polycystic Ovarian Syndrome

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