Improved ovarian adiponectin system expression in polycystic ovary syndrome treated with exenatide

Asma Vatankhah; Mohabbat Jamhiri; Sima Vatankhah; Keivan Lorian; Mohammad Ebrahim Rezvani; Mahin Izadi

doi:10.5653/cerm.2024.06912

Brief Communication

Clinical and Experimental Reproductive Medicine 2025;52(1):98-100.

Published online: August 1, 2024

DOI: https://doi.org/10.5653/cerm.2024.06912

Improved ovarian adiponectin system expression in polycystic ovary syndrome treated with exenatide

Asma Vatankhah¹

, Mohabbat Jamhiri², Sima Vatankhah³, Keivan Lorian⁴, Mohammad Ebrahim Rezvani¹

, Mahin Izadi⁴

¹Department of Physiology, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran

²Department of Physiology, Medical School, Shahid Beheshti University of Medical Sciences, Tehran, Iran

³Schools of Medicine, Kashan University of Medical Sciences, Kashan, Iran

⁴Research and Clinical Center for Infertility, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

Corresponding author: Mahin Izadi Research and Clinical Center for Infertility, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
Tel: +98-9177521021 Fax: +98-89137-84891 E-mail: Mizadi890112@gmail.com

Co-corresponding author: Mohammad Ebrahim Rezvani Department of Physiology, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
Tel: +98-38203414 Fax: +98-38203414 E-mail: merezvani@gmail.com

Received February 1, 2024 Revised April 29, 2024 Accepted June 9, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder that can cause infertility. This experimental study was conducted to elucidate the role of adiponectin signaling in rats with PCOS treated with exenatide. Twenty-eight adult female Wistar rats were divided into four groups of seven. The normal group did not receive any drug. The PCOS+vehicle (Veh) group received estradiol valerate to induce PCOS, then was divided into PCOS+E50 and PCOS+E100 groups and treated with 50 or 100 mg/kg doses of exenatide, respectively. The mRNA expression of adiponectin and adiponectin receptor 1 (Adipo-R1) was evaluated using a semi-quantitative real-time polymerase chain reaction. The results indicated that the level of adiponectin diminished in the PCOS rats while exenatide increased adiponectin expression at both doses. Adiponectin receptor mRNA levels were higher in the PCOS rats than in the normal rats (p<0.05). In addition, exenatide decreased the levels of Adipo-R1 expression. Taken together, our results showed that exenatide may improve PCOS characteristics in rats through the molecular regulation of adiponectin and its receptor.

Keywords: Adiponectin; Exenatide; Polycystic ovary syndrome

Introduction

Polycystic ovary syndrome (PCOS) is a common multifaceted and intricate endocrine disorder that affects 5% to 10% of women of reproductive age and likely leads to infertility, hirsutism, menstrual irregularities, hyperandrogenism, and insulin resistance [1]. A previous study reported low levels of serum adiponectin in women with PCOS [2]. Adiponectin is a peptide secreted by fat cells, which regulates glucose levels, lipid metabolism, and insulin sensitivity through its anti-fibrotic and antioxidant effects [3]. There are two types of membrane receptors for adiponectin, including adiponectin receptor 1 (Adipo-R1) and adiponectin receptor 2 (Adipo-R2), which improve the metabolism of glucose [4]. The mRNA expression of Adipo-R1 is positively related to insulin, triglyceride, cholesterol [5], and testosterone [6] levels. It has been found that tissues treated with testosterone and estradiol increase the expression of these receptors [7]. An increase in adiponectin receptors has also been reported in PCOS [8]. To alleviate the metabolic complications of PCOS, an effective and accurate intervention should be considered. Exenatide is a synthetic glucagon-like peptide 1 (GLP-1) agonist [9]. Various GLP-1 analogs improve the menstrual cycle in women with PCOS [10]. The specific mechanism by which exenatide improves the complications of PCOS has yet to be determined. Therefore, this study investigated the impact of exenatide on the expression of mRNA levels in the ovarian adiponectin system in the rat model of PCOS.

Methods

1. Animals

Twenty-eight Wistar female rats weighing 175 to 200 g were distributed into four groups. Seven rats per cage were maintained in the animal house at a temperature of 20±2 °C, with 12/12 hours of light/dark conditions and free access to water and food. Ethical approval was received from the Animal Ethics Committee of the Yazd University of Medical Sciences (IR.SSU.medicine.REC.1394. 240).

According to accepted protocols, normal estrous cycles were identified and included in this study [11]. Estradiol valerate (4 mg/kg) (Aburaihan Pharmaceutical Co.) was injected intramuscularly in each rat [12]. Abnormal estrous cyclicity and disturbances in the cycle indicated the development of PCOS in the rats, as described in the study by Asadi et al. [13]. The rats in the normal group remained without intervention (control). Rats in the second group became polycystic and received the vehicle (PCOS+Veh). The groups 3 (PCOS+Exe 50) and 4 (PCOS+Exe 100) rats with PCOS received an intraperitoneal injection of exenatide at doses of 50 or 100 µg/kg, respectively, for 30 days.

Under anesthesia, the bilateral ovaries were removed and freshly frozen at –70 °C for molecular assays. Total RNA was extracted for the molecular assays (RNX-plus solution; CinnaGen). Next, cDNA was synthesized (Thermo Fisher Scientific Inc.) and the cDNA underwent real-time polymerase chain reaction using SYBR Green MasterMix (Takara Holdings Inc.). The ribosomal protein L13a gene was used as the reference. The relative comparison of gene expression was done with the 2^-∆∆Ct method. The obtained data were analyzed using one-way analysis of variance and Tukey′s multiple comparison post hoc test. Statistical significance was set at p<0.05.

Results

1. Effects of exenatide on the mRNAs of adiponectin and Adipo-R1

Our results indicated that, in the PCOS+Veh group, the mRNA levels of adiponectin decreased significantly when compared with the normal group (p<0.05). In both exenatide-treated groups, the mRNA level of adiponectin was significantly higher than the PCOS+Veh group (p<0.05). The expression level of Adipo-R1 was also higher in the PCOS+Veh group than in the normal group (p<0.05). The expression level of Adipo-R1 decreased in the PCOS+E50 and PCOS+E100 groups when compared to the PCOS+Veh groups (Figure 1).

Discussion

In this study, the effects of different doses of exenatide on ovarian adiponectin system expression in a rat model of PCOS were investigated. Our study showed that both 50 and 100 µg/kg doses of exenatide significantly increased the mRNA expression of adiponectin and reduced the expression of Adipo-R1 in ovarian tissue. In line with our results, other studies revealed that exenatide can decrease the complications of PCOS [14,15]. However, the exact mechanism of exenatide on PCOS improvement is still not fully understood. According to the present study, exenatide probably exerts its protective effects by increasing adiponectin levels. In conclusion, this study revealed that adiponectin may play a partial but important role in the effect of exenatide on improving PCOS.

Conflict of interest

No potential conflict of interest relevant to this article was reported.

Author contributions

Conceptualization: MER, MI. Methodology: AV, MER, MI. Formal analysis: MER. Data curation: MER. Funding acquisition: AV. Project administration: MER, MI. Visualization: MER, MI. Software: MER, MI. Validation: MER, MI. Investigation: AV. Writing-original draft: AV, MJ. Writing-review & editing: MER, MI. Approval of final manuscript: AV, MJ, SV, KL, MER, MI.

Figure 1.

The effect of exenatide (Exe) on the mRNA levels of (A) adiponectin and (B) adiponectin receptor 1. Normal: no intervention; polycystic ovary syndrome (PCOS)+vehicle (Veh): PCOS rats; PCOS+Exe 50: PCOS rats received Exe at dose of 50 μg/kg; PCOS+Exe 100: PCOS rats received Exe at dose of 100 μg/kg. ^a)p<0.05: when compared to the normal group; ^b)p<0.05: when compared to PCOS group.

References

1. Maqbool M, Gani I, Geer MI. Polycystic ovarian syndrome-a multifaceted disease: a review. Int J Pharm Sci Res 2019;10:1072-79.

2. Mirza SS, Shafique K, Shaikh AR, Khan NA, Anwar Qureshi M. Association between circulating adiponectin levels and polycystic ovarian syndrome. J Ovarian Res 2014;7:18.

3. Yamauchi T, Iwabu M, Okada-Iwabu M, Kadowaki T. Adiponectin receptors: a review of their structure, function and how they work. Best Pract Res Clin Endocrinol Metab 2014;28:15-23.

4. Nguyen TM. Adiponectin: role in physiology and pathophysiology. Int J Prev Med 2020;11:136.

5. Akingbemi BT. Adiponectin receptors in energy homeostasis and obesity pathogenesis. Prog Mol Biol Transl Sci 2013;114:317-42.

6. Garcia V, Orostica L, Poblete C, Rosas C, Astorga I, Romero C, et al. Endometria from obese PCOS women with hyperinsulinemia exhibit altered adiponectin signaling. Horm Metab Res 2015;47:901-9.

7. Capllonch-Amer G, Sbert-Roig M, Galmes-Pascual BM, Proenza AM, Llado I, Gianotti M, et al. Estradiol stimulates mitochondrial biogenesis and adiponectin expression in skeletal muscle. J Endocrinol 2014;221:391-403.

8. Tan BK, Chen J, Digby JE, Keay SD, Kennedy CR, Randeva HS. Upregulation of adiponectin receptor 1 and 2 mRNA and protein in adipose tissue and adipocytes in insulin-resistant women with polycystic ovary syndrome. Diabetologia 2006;49:2723-8.

9. Tzotzas T, Karras SN, Katsiki N. Glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of obese women with polycystic ovary syndrome. Curr Vasc Pharmacol 2017;15:218-29.

10. Elkind-Hirsch K, Marrioneaux O, Bhushan M, Vernor D, Bhushan R. Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93:2670-8.

11. Ahren B. Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes. Expert Opin Emerg Drugs 2008;13:593-607.

12. Chapman JC, Min SH, Freeh SM, Michael SD. The estrogen-injected female mouse: new insight into the etiology of PCOS. Reprod Biol Endocrinol 2009;7:47.

13. Asadi N, Izadi M, Aflatounian A, Esmaeili-Dehaj M, Rezvani ME, Hafizi Z. Chronic niacin administration ameliorates ovulation, histological changes in the ovary and adiponectin concentrations in a rat model of polycystic ovary syndrome. Reprod Fertil Dev 2021;33:447-54.

14. Liu X, Zhang Y, Zheng SY, Lin R, Xie YJ, Chen H, et al. Efficacy of exenatide on weight loss, metabolic parameters and pregnancy in overweight/obese polycystic ovary syndrome. Clin Endocrinol (Oxf) 2017;87:767-74.

15. Tang L, Yuan L, Yang G, Wang F, Fu M, Chen M, et al. Changes in whole metabolites after exenatide treatment in overweight/obese polycystic ovary syndrome patients. Clin Endocrinol (Oxf) 2019;91:508-16.