Polikistik over sendromu oluşturulmuş sıçanlarda irisinin metabolik yolaklar ve bu yolaklarda görevli gen ifadeleri üzerine etkileri

Öz

Amaç: Pkos sıklıkla obezitenin eşlik ettiği endokrin ve metabolik bir bozukluktur. Mevcut çalışmamızda obez pkos sıçan modelinde egzersizin etkilerinin biyokimyasal ve moleküler düzeyde araştırılması amaçlanmıştır. Yöntem: 21 günlük, 24 Wistar albino dişi sıçan Kontrol, Pkos, Pkos+Egzersiz, Egzersiz olmak üzere 4 gruba ayrıldı (n=6). Obez pkos modeli 50 günlük deney süresince yüksek yağlı diyetle beslenme ve deneyin 1.-28. günler arasında subkutan 10mg/kg/gün Testosteron Propiyonat uygulamasıyla oluşturuldu. Egzersiz grupları 29.-50. günler arasında günlük 1 saat silindir tankta yüzdürüldü. Sıçanlara günlük vajinal simear yapılarak menstrueal siklus takibi yapıldı. Serumda LH, FSH ve İrisin seviyeleri Elisa ile ölçüldü. Over, beyaz yağ (Bat), kahverengi yağ ve kas dokularında UCP2, UCP3, FNDC5 genlerinin ve over dokusunda apoptoz ve otofaji ile ilişkili genlerin ifadeleri qRT-PCR ile belirlendi. Bulgular: Kas ve Bat dokusunda kontrole göre Pkos ve Pkos+egzersiz gruplarında UCP2 (p=0.01 ve p=0.01) ve UCP3 (p=0.004 ve p=0.04) ifadesi anlamlı olarak artarken Egzersiz grubunda Bat dokusunda UCP2 azalmıştır (p=0.01 ve p=0.01). Kasda FNDC5 ifadesi Pkos (p=0.01), Pkos+Egzersiz (p=0.0007) ve Egzersiz (p=0.02) gruplarında anlamlı olarak azalırken, bat’da artmıştır. Serum irisin düzeylerinin Pkos ve Pkos+Egzersiz gruplarında anlamlı olarak daha düşük olduğu (p=0.001), Overde ise apoptozis ve otofaji ilişkili gen ifadelerinin Pkos ve Pkos+egzersiz gruplarında anlamlı arttığı gözlenmiştir (p<0.05). Sonuç: Çalışmamız Pkos’ta egzersizin hormonal ve metabolik düzenlemeler üzerinde önemli etkilerini göstermektedir. Ancak egzersiz, Pkos’un neden olduğu bazı bozuklukları iyileştirse de, irisin üretimi ve over dokusundaki hücresel mekanizmalar üzerindeki etkileri sınırlı kalmaktadır. Bu bulgular, Pkos tedavisinde egzersizin tek başına yeterli olmayabileceğini ve farklı egzersiz, beslenme ve farmakolojik yaklaşımlarla desteklenmesi gerektiğini ortaya koymaktadır.

Anahtar Kelimeler

• FNDC5
• PCOS
• UCP2/UCP3
• irisin
• obezite

Effects of irisin on metabolic pathways and gene expressions functioning in these pathways in rats with polycystic ovary syndrome

Öz

Aim: Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder frequently associated with obesity. This study aimed to evaluate the biochemical and molecular effects of exercise in an obese PCOS rat model. Method: Twenty-four 21-day-old female Wistar albino rats were divided into four groups: Control, PCOS, PCOS+Exercise, and Exercise (n=6 each). The obese PCOS model was established over 50 days by high-fat diet feeding combined with subcutaneous testosterone propionate (10 mg/kg/day) from day 1 to 28. Exercise groups underwent swimming in a cylindrical tank for 1 hour daily between days 29 and 50. Estrous cycles were tracked by vaginal smear. Serum LH, FSH, and irisin were measured with ELISA. Expression of UCP2, UCP3, and FNDC5 genes in ovary, brown adipose tissue (BAT), white adipose tissue, and muscle, , as well as genes associated with apoptosis and autophagy in ovarian tissue, was quantified by qRT-PCR. Ovarian apoptotic and autophagy-related genes were also assessed. Results: Compared to the control group, UCP2 (p=0.01) and UCP3 (p=0.004, p=0.04) expression were significantly increased in muscle and BAT of PCOS and PCOS+Exercise groups, whereas BAT UCP2 was decreased in the Exercise group (p=0.01). FNDC5 expression was significantly reduced in muscle of PCOS (p=0.01), PCOS+Exercise (p=0.0007), and Exercise (p=0.02) groups, but increased in BAT. Serum irisin levels were lower in PCOS and PCOS+Exercise groups (p=0.001). Ovarian apoptotic and autophagy-related genes were significantly elevated in PCOS and PCOS+Exercise groups (p<0.05). Conclusion: : Exercise exerts beneficial metabolic and hormonal effects in PCOS but shows limited ability to restore ovarian molecular homeostasis, particularly irisin signaling. These findings suggest that combining exercise with dietary or pharmacological approaches may be required for effective PCOS management.

Anahtar Kelimeler

• FNDC5
• PCOS
• UCP2/UCP3
• irisin
• obesity

Kaynakça

1. Barber TM, Franks S. Obesity and polycystic ovary syndrome. Clinical endocrinology. 2021;95(4):531-541.
2. Taher MA, Hasseb MT, Abd Elneam AI. Mitochondrial uncoupling carrier protein-2 DNA polymorphism (− 866 G/A) as a risk for polycystic ovary syndrome in Saudi Arabian females. Eur Chem Bull. 2016;5(11):483-486.
3. Boström P, Wu J, Jedrychowski MP, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463-468.
4. Börzsei D, Szabó R, Hoffmann A, et al. Multiple applications of different exercise modalities with rodents. Oxid Med Cell Longev. 2021;2021(1):3898710.
5. Phaneuf S, Leeuwenburgh C. Apoptosis and exercise. Medicine & Science in Sports & Exercise. 2001;33(3):393-396.
6. Das M, Djahanbakhch O, Hacihanefioglu B, et al. Granulosa cell survival and proliferation are altered in polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism. 2008;93(3):881-887.
7. Bas D, Abramovich D, Hernandez F, Tesone M. Altered expression of Bcl‐2 and Bax in follicles within dehydroepiandrosterone‐induced polycystic ovaries in rats. Cell biology international. 2011;35(5):423-429.
8. Honnma H, Endo T, Henmi H, et al. Altered expression of Fas/Fas ligand/caspase 8 and membrane type 1-matrix metalloproteinase in atretic follicles within dehydroepiandrosterone-induced polycystic ovaries in rats. Apoptosis. 2006;11:1525-1533.

9. Sumarac-Dumanovic M, Apostolovic M, Janjetovic K, et al. Downregulation of autophagy gene expression in endometria from women with polycystic ovary syndrome. Molecular and cellular endocrinology. 2017;440:116-124.
10. Bhuvaneshwari S, Poornima R, Averal HI. Detection of polycystic ovary syndrome and its treatment with Pergulariadaemia in rat models. IOSR J Pharm. 2015;5(5):42-49.
11. Qin L, Yao Z-q, Chang Q, et al. Swimming attenuates inflammation, oxidative stress, and apoptosis in a rat model of dextran sulfate sodium-induced chronic colitis. Oncotarget. 2016;8(5):7391.
12. Bostanci M, Akdemir N, Cinemre B, Cevrioglu A, Özden S, Ünal O. Serum irisin levels in patients with polycystic ovary syndrome. European Review for Medical & Pharmacological Sciences. 2015;19(23)
13. Ali SH, Al-Nuaimi A, Al-Musawi BJ. Serum irisin and leptin levels in obese and non-obese women with polycystic ovary syndrome with reference to glucose homeostasis. Int J Pharm Pharm Sci. 2016;8(10):276-283.
14. Abali R, Temel Yuksel I, Yuksel MA, et al. Implications of circulating irisin and Fabp4 levels in patients with polycystic ovary syndrome. Journal of obstetrics and gynaecology. 2016;36(7):897-901.
15. Majeed AA, Al-Qaisi AHJ, Ahmed WA. The Comparison of Irisin, Subfatin, and Adropin in Normal-Weight and Obese Polycystic Ovary Syndrome Patients. Iranian Journal of Medical Sciences. 2024;49(6):350.
16. Zhang H-J, Zhang X-F, Ma Z-M, et al. Irisin is inversely associated with intrahepatic triglyceride contents in obese adults. Journal of hepatology. 2013;59(3):557-562.
17. Erickson HP. Irisin and FNDC5 in retrospect: an exercise hormone or a transmembrane receptor? Adipocyte. 2013;2(4):289-293.
18. Pedersen SB, Lund S, Buhl ES, Richelsen B. Insulin and contraction directly stimulate UCP2 and UCP3 mRNA expression in rat skeletal muscle in vitro. Biochemical and Biophysical Research Communications. 2001;283(1):19-25.
19. Cortright RN, Zheng D, Jones JP, et al. Regulation of skeletal muscle UCP-2 and UCP-3 gene expression by exercise and denervation. American Journal of Physiology-Endocrinology and Metabolism. 1999;276(1):E217-E221.
20. Villarroya F, Iglesias R, Giralt M. PPARs in the control of uncoupling proteins gene expression. PPAR research. 2007;2007(1):074364.
21. Tsuboyama-Kasaoka N, Tsunoda N, Maruyama K, et al. Up-regulation of uncoupling protein 3 (UCP3) mRNA by exercise training and down-regulation of UCP3 by denervation in skeletal muscles. Biochemical and Biophysical Research Communications. 1998;247(2):498-503.
22. Hoeks J, Hesselink MK, Sluiter W, et al. The effect of high‐fat feeding on intramuscular lipid and lipid peroxidation levels in UCP3‐ablated mice. FEBS letters. 2006;580(5):1371-1375.
23. Salvetti NR, Panzani CG, Gimeno EJ, Neme LG, Alfaro NS, Ortega HH. An imbalance between apoptosis and proliferation contributes to follicular persistence in polycystic ovaries in rats. Reproductive Biology and Endocrinology. 2009;7:1-10.
24. Chi X-X, Zhang T, Chu X-L, Zhen J-L, Zhang D-J. The regulatory effect of Genistein on granulosa cell in ovary of rat with PCOS through Bcl-2 and Bax signaling pathways. Journal of Veterinary Medical Science. 2018;80(8):1348-1355.
25. Nagata S. Apoptosis by death factor. cell. 1997;88(3):355-365.
26. Roughton SA, Lareu RR, Bittles AH, Dharmarajan AM. Fas and Fas ligand messenger ribonucleic acid and protein expression in the rat corpus luteum during apoptosis-mediated luteolysis. Biology of Reproduction. 1999;60(4):797-804.
27. Li D, You Y, Bi F-F, et al. Autophagy is activated in the ovarian tissue of polycystic ovary syndrome. Reproduction. 2018;155(1):85-92.
28. Feng J, Fu S, Cao X, et al. Synaptonemal complex protein 2 (SYCP2) mediates the association of the centromere with the synaptonemal complex. Protein & cell. 2017;8(7):538-543.
29. Skov V, Glintborg D, Knudsen S, et al. Pioglitazone enhances mitochondrial biogenesis and ribosomal protein biosynthesis in skeletal muscle in polycystic ovary syndrome. PloS one. 2008;3(6):e2466.
30. Xu Q, Cai J, Cong Y-B, et al. A Comparative Transcriptome and Proteome Analysis in Rat Models Reveals Effects of Aging and Diabetes on Expression of Neuronal Genes. International Journal of Gerontology. 2016;10(4):212-217.