GLP-1/GLP-1R Signaling Regulates Ovarian PCOS-Associated Granulosa Cells Proliferation and Antiapoptosis by Modification of Forkhead Box Protein O1 Phosphorylation Sites

Sun, Zhihua; Li, Peiyi; Wang, Xiao; Lai, Shuchang; Qiu, Hong; Chen, Zhi; Hu, Shengqiang; Yao, Jie; Shen, Jie

doi:10.1155/2020/1484321

Cited by 13 publications

(6 citation statements)

References 41 publications

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“…After 6 weeks, liraglutide induced granulosa cell proliferation and promoted their viability in DHEA-induced PCOS mice by modifying the forkhead box protein O1 (FOXO1) phosphorylation site. 62 In another study of 20 Parkes strain mice, PCOS was induced using DHEA at a dose of 6 mg/100 g of body weight per day. The PCOS-induced mice then received liraglutide, either 100 or 200 µg/day twice a day for 14 days.…”

Section: Evidence For the Therapeutic Potentials Of Glp-1 Ra In Pcosmentioning

confidence: 99%

The potential role of incretin-based therapies for polycystic ovary syndrome: a narrative review of the current evidence

Abdalla

Deshmukh

Atkin

et al. 2021

Therapeutic Advances in Endocrinology

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Introduction: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age. Metabolic consequences associated with PCOS include, but are not limited to, insulin resistance (IR), type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). This narrative review aims to provide a comprehensive overview of the potential therapeutic roles of the incretin-based therapies in the management of PCOS. Methods: We performed a systematic search of databases including PubMed, MEDLINE and EMBASE up to 1 October 2020. We developed a search string of medical subject headings (MeSH) including the terms PCOS, incretin mimetics, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-1 receptor antagonists (GLP-1 RAs), liraglutide, exenatide, semaglutide, dipeptidyl peptidase-4 (DPP-4) inhibitors, combined with IR, testosterone and sex hormone-binding globulin (SHBG). Results: We identified 854 relevant articles and, after the initial screening, eight interventional animal studies, one observational animal study, 14 interventional human studies, two case–control studies and one systematic review were included. These studies showed the potential significant roles of GLP-1 RAs and DPP-4 inhibitors in the management of PCOS, with significant improvements in the metabolic parameters, including substantial weight reduction and improved insulin sensitivity. These agents also improved the hormonal parameters through decreased free androgen and increased SHBG. Moreover, they improved menstrual regularity, increased fertility with enhanced ovulation and pregnancy in obese women with PCOS. Conclusion: GLP-1 RAs and DPP-4 inhibitors have a promising therapeutic role in PCOS; however, larger clinical trials are needed to establish the role of incretin-based therapies in the management of PCOS.

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Section: Evidence For the Therapeutic Potentials Of Glp-1 Ra In Pcosmentioning

confidence: 99%

The potential role of incretin-based therapies for polycystic ovary syndrome: a narrative review of the current evidence

Abdalla

Deshmukh

Atkin

et al. 2021

Therapeutic Advances in Endocrinology

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“…Indeed, we found that both GIP and GLP-1 receptors were present in the ovaries and uterine horn, suggesting their involvement in important aspects of female reproductive function. Previous studies have also demonstrated GLP-1Rs in mouse ovarian granulosa cells [ 39 ].…”

Section: Discussionmentioning

confidence: 98%

Evidence for Involvement of GIP and GLP-1 Receptors and the Gut-Gonadal Axis in Regulating Female Reproductive Function in Mice

et al. 2022

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Substantial evidence suggests crosstalk between reproductive and gut-axis but mechanisms linking metabolism and reproduction are still unclear. The present study evaluated the possible role of glucose-dependent-insulinotropic-polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) in reproductive function by examining receptor distribution and the effects of global GIPR and GLP-1R deletion on estrous cycling and reproductive outcomes in mice. GIPR and GLP-1R gene expression were readily detected by PCR in female reproductive tissues including pituitary, ovaries and uterine horn. Protein expression was confirmed with histological visualisation of incretin receptors using GIPR-Cre and GLP1R-Cre mice in which the incretin receptor expressing cells were fluorescently tagged. Functional studies revealed that female GIPR−/− and GLP-1R−/− null mice exhibited significantly (p < 0.05 and p < 0.01) deranged estrous cycling compared to wild-type controls, indicative of reduced fertility. Furthermore, only 50% and 16% of female GIPR−/− and GLP-1R−/− mice, respectively produced litters with wild-type males across three breeding cycles. Consistent with a physiological role of incretin receptors in pregnancy outcome, litter size was significantly (p < 0.001–p < 0.05) decreased in GIPR−/− and GLP-1R−/− mice. Treatment with oral metformin (300 mg/kg body-weight), an agent used clinically for treatment of PCOS, for a further two breeding periods showed no amelioration of pregnancy outcome except that litter size in the GIPR−/− group was approximately 2 times greater in the second breeding cycle. These data highlight the significance of incretin receptors in modulation of female reproductive function which may provide future targets for pharmacological intervention in reproductive disorders.

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“…Some studies have suggested that the proliferation and apoptosis of granulosa cells (GCs) are the root causes of follicular development and atresia, with forkhead box protein O1 (FoxO1) playing an important role in promoting PCOS follicular atresia and GCs apoptosis ( 162 , 163 ). The GLP-1/GLP-1R axis was demonstrated to enhance the activity of PCOS ovarian granulosa cells by partially modifying the FoxO1 phosphorylation sites, thereby promoting oocyte maturation ( 164 ). In addition, liraglutide was found to repair the cognitive impairment in a rat model of PCOS by inhibiting the overexpression of the Notch signaling pathway ( 165 ).…”

Section: Effects On Polycystic Ovary Syndromementioning

confidence: 99%

GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

et al. 2021

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Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection of islet β cells, promotion of islet β cell proliferation and minimal side effects. Studies have found that GLP-1R is widely distributed on pancreatic and other tissues and has multiple biological effects, such as reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism and reducing fat deposition. Moreover, GLP-1RAs have neuroprotective, anti-infectious, cardiovascular protective, and metabolic regulatory effects, exhibiting good application prospects. Growing attention has been paid to the relationship between GLP-1RAs and tumorigenesis, development and prognosis in patient with T2DM. Here, we reviewed the therapeutic effects and possible mechanisms of action of GLP-1RAs in the nervous, cardiovascular, and endocrine systems and their correlation with metabolism, tumours and other diseases.

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GLP-1/GLP-1R Signaling Regulates Ovarian PCOS-Associated Granulosa Cells Proliferation and Antiapoptosis by Modification of Forkhead Box Protein O1 Phosphorylation Sites

Cited by 13 publications

References 41 publications

The potential role of incretin-based therapies for polycystic ovary syndrome: a narrative review of the current evidence

The potential role of incretin-based therapies for polycystic ovary syndrome: a narrative review of the current evidence

Evidence for Involvement of GIP and GLP-1 Receptors and the Gut-Gonadal Axis in Regulating Female Reproductive Function in Mice

GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

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