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Acetate restores hypothalamic-adipose kisspeptin status in a rat model of PCOS by suppression of NLRP3 immunoreactivity

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Abstract

Purpose

Polycystic ovary syndrome (PCOS) is a complex reproductive event that is delineated by endocrine/metabolic disorders. Alteration of kisspeptin status in the hypothalamus and adipose tissue is critical to increased endocrine/metabolic derangements in PCOS individuals, aggravating the clinical manifestation of PCOS and its complications. Short chain fatty acids (SCFAs) are crucial modulators of metabolic homeostasis. However, the role of SCFAs, particularly acetate on hypothalamic-adipose kisspeptin status (HAKS) in PCOS model is unknown. The present study hypothesized acetate as a key player in restoration of deranged HAKS, associated with experimental PCOS model.

Methods

Three groups (n = 6/group) of female Wistar rats (120–150 g) were used. The groups were treated (po) for 21 days with vehicle, letrozole (1 mg/kg) with/without acetate (200 mg/kg) respectively.

Results

Letrozole-treated animals had impaired glucose homeostasis, elevated testosterone, leptin and LH/FSH ratio and decreased GnRH and adiponectin with ovarian tissues revealing degenerated follicles and disrupted morphology. These animals also showed increased concentration of hypothalamic triglyceride (TG)/total cholesterol (TC), free fatty acid (FFA), and decreased concentration of TG/TC/FFA in visceral adipose tissue (VAT) with an increase in hypothalamic and VAT malondialdehyde, NF-κB/TNF-α and decreased glutathione/G6PD and hypothalamic but not VAT kisspeptin. Immunohistochemical analysis revealed the expression of NLRP3 inflammasome in the hypothalamus and VAT and all these changes were attenuated by acetate.

Conclusions

Altogether, the present results demonstrate that PCOS is characterized with hypothalamic-adipose inflammation, associated with immunohistochemical expression of NLRP3 with significant alteration of hypothalamic but not adipose kisspeptin. The results suggest that acetate restores kisspeptin status in PCOS animals. This beneficial effect is accompanied by repressed NLRP3 immunoreactivity.

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Data availability

The data that support the findings of this study are available on request from the corresponding author.

References

  1. A.S. Melo, R.A. Ferriani, P.A. Navarro, Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice. Clinics 70, 765–769 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  2. A.H. Balen, L.C. Morley, M. Misso, S. Franks, R.S. Legro, C.N. Wijeyaratne, E. Stener-Victorin, B.C. Fauser, R.J. Norman, H. Teede, The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Hum. Reprod. Update 22(6), 687–708 (2016)

    Article  PubMed  Google Scholar 

  3. U. Zafar, Z. Memon, K. Moin, S. Agha, J.A. Hassan, D. Zehra, Prevalence of PCOS with associated symptoms and complications at Tertiary Care Hospital of Karachi. J. Adv. Med. Med. Res. 30(4), 1–9 (2019)

    Article  Google Scholar 

  4. A.Z. Rutkowska, E. Diamanti-Kandarakis, Polycystic ovary syndrome and environmental toxins. Fertil. Steril. 106(4), 948–958 (2016)

    Article  CAS  PubMed  Google Scholar 

  5. Rotterdam ESHRE/ASRM‐Sponsored PCOS Consensus Workshop Group, Revised 2003 consensus on diagnostic criteria and long‐term health risks related to polycystic ovary syndrome (PCOS). Hum. Reprod. 19(1), 41–47 (2004)

    Article  Google Scholar 

  6. J. Liu, Q. Wu, Y. Hao, M. Jiao, X. Wang, S. Jiang, L. Han, Measuring the global disease burden of polycystic ovary syndrome in 194 countries: Global Burden of Disease Study 2017. Hum. Reprod. 36(4), 1108–19. (2021)

    Article  PubMed  PubMed Central  Google Scholar 

  7. M. Peigné, D. Dewailly, Long term complications of polycystic ovary syndrome (PCOS). In Annales d’endocrinologie (2014) (Vol. 75, No. 4, pp. 194–199). Elsevier Masson

  8. R. Azziz, C. Marin, L. Hoq, E. Badamgarav, P. Song, Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span. J. Clin. Endocrinol. Metab. 90(8), 4650–4658 (2005)

    Article  CAS  PubMed  Google Scholar 

  9. C. Meng, Nitric oxide (NO) levels in patients with polycystic ovary syndrome (PCOS): a meta-analysis. J. Int. Med. Res. 47(9), 4083–94. (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. W.M. Wolf, R.A. Wattick, O.N. Kinkade, M.D. Olfert, Geographical prevalence of polycystic ovary syndrome as determined by region and race/ethnicity. Int. J. Environ. Res. public health 15(11), 2589 (2018)

    Article  PubMed Central  Google Scholar 

  11. S. Li, D. Zhu, H. Duan, Q. Tan, Genetic investigation into ethnic disparity in polycystic ovarian syndrome. Gynecol. Endocrinol. 29(10), 878–882 (2013)

    Article  PubMed  Google Scholar 

  12. S. Brakta, D. Lizneva, K. Mykhalchenko, A. Imam, W. Walker, M.P. Diamond, R. Azziz, Perspectives on polycystic ovary syndrome: is polycystic ovary syndrome research underfunded? J. Clin. Endocrinol. Metab. 102(12), 4421–4427 (2017)

    Article  PubMed  Google Scholar 

  13. E. Kandaraki, A. Chatzigeorgiou, C. Piperi, E. Palioura, S. Palimeri, P. Korkolopoulou, M. Koutsilieris, A.G. Papavassiliou, Reduced ovarian glyoxalase-I activity by dietary glycotoxins and androgen excess: a causative link to polycystic ovarian syndrome. Mol. Med. 18(8), 1183–1189 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. P. Moghetti, Insulin resistance and polycystic ovary syndrome. Curr. Pharm. Des. 22(36), 5526–5534 (2016). https://doi.org/10.2174/1381612822666160720155855

    Article  CAS  PubMed  Google Scholar 

  15. E. Diamanti-Kandarakis, A.G. Papavassiliou, Outstanding questions. Trends Mol. Med. 7(12), 324–32. (2006)

    Article  Google Scholar 

  16. F.K.H. Shirazi, Z. Khodamoradi, M. Jeddi, Insulin resistance and high molecular weight adiponectin in obese and non-obese patients with Polycystic Ovarian Syndrome (PCOS).BMC Endocr. Disord. 21, 45 (2021). :https://doi.org/10.1186/s12902-021-00710-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. L. Ibanez, E. Oberfield Sh, S.F. Witchel, R.J. Auchus, R.J. Chang, E. Codner et al. An international consortium apdate: pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Horm. Res. Paediatr. 8896, 371–395 (2017).

    Article  Google Scholar 

  18. N.E. Baskind, A.H. Balen, Hypothalamic–pituitary, ovarian and adrenal contributions to polycystic ovary syndrome. Best. Pract. Res. Clin. Obstet. Gynaecol. 37, 80–97 (2016)

    Article  PubMed  Google Scholar 

  19. N.M. Orsi, N.E. Baskind, M. Cummings, Anatomy, development, histology, and normal function of the ovary. in Pathology of the Ovary, Fallopian Tube and Peritoneum, (Springer, London, 2014) pp. 1–32.

  20. A.M. Moore, R.E. Campbell, The neuroendocrine genesis of polycystic ovary syndrome: a role for arcuate nucleus GABA neurons. J. Steroid Biochem. Mol. Biol. 160, 106–117 (2016)

    Article  CAS  PubMed  Google Scholar 

  21. J.E. Hall, A.E. Taylor, F.J. Hayes, W.F. Crowley, Insights into hypothalamic-pituitary dysfunction in polycystic ovary syndrome. J. Endocrinol. Investig. 21(9), 602–611 (1998).

    Article  CAS  Google Scholar 

  22. D. Barlampa, M.S. Bompoula, A. Bargiota, S. Kalantaridou, G. Mastorakos, G. Valsamakis, Hypothalamic inflammation as a potential pathophysiologic basis for the heterogeneity of clinical, hormonal, and metabolic presentation in PCOS. Nutrients 13(2), 520 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. K.S. Olaniyi, A.A. Oniyide, O.A. Adeyanju, L.S. Ojulari, A.O. Omoaghe, O.E. Olaiya, Low dose spironolactone-mediated androgen-adiponectin modulation alleviates endocrine-metabolic disturbances in letrozole-induced PCOS. Toxicol. Appl. Pharmacol. 411, 115381 (2021a)

    Article  CAS  PubMed  Google Scholar 

  24. A.P. Delitala, G. Capobianco, G. Delitala, P.L. Cherchi, S. Dessole, Polycystic ovary syndrome, adipose tissue and metabolic syndrome. Arch. Gynecol. Obstet. 296(3), 405–419 (2017)

    Article  CAS  PubMed  Google Scholar 

  25. P.M. Spritzer, S.B. Lecke, F. Satler, D.M. Morsch, Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome. Reproduction 149(5), R219–R227 (2015)

    Article  CAS  PubMed  Google Scholar 

  26. R. Pasquali, Lifestyle Interventions and Natural and Assisted Reproduction in Patients with PCOS. InInfertility in Women with Polycystic Ovary Syndrome 2018 (pp. 169–180). Springer, Cham

  27. B. Zeng, Z. Lai, L. Sun, Z. Zhang, J. Yang, Z. Li, J. Lin, Z. Zhang, Structural and functional profiles of the gut microbial community in polycystic ovary syndrome with insulin resistance (IR-PCOS): a pilot study. Res. Microbiol. 170(1), 43–52 (2019)

    Article  CAS  PubMed  Google Scholar 

  28. L.G. Silveira, C. Tusset, A.C. Latronico, Impact of mutations in kisspeptin and neurokinin B signaling pathways on human reproduction. Brain Res. 1364, 72–80 (2010)

    Article  CAS  PubMed  Google Scholar 

  29. B.S. Araújo, M.C. Baracat, R. dos Santos Simões, C. de Oliveira Nuñes, G.A. Maciel, R.A. Lobo, J.M. Soares-Jr, E.C. Baracat, Kisspeptin Influence on Polycystic Ovary Syndrome—A Mini Review. Reprod. Sci. 27(2), 455–460 (2020)

    Article  PubMed  Google Scholar 

  30. R.E. Brown, D.A. Wilkinson, S.A. Imran, A. Caraty, M. Wilkinson, Hypothalamic kiss1 mRNA and kisspeptin immunoreactivity are reduced in a rat model of polycystic ovary syndrome (PCOS). Brain Res. 1467, 1–9 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. S. Osuka, A. Iwase, T. Nakahara, M. Kondo, A. Saito, T. Nakamura, S. Takikawa, M. Goto, T. Kotani, F. Kikkawa, Kisspeptin in the hypothalamus of 2 rat models of polycystic ovary syndrome. Endocrinology 158(2), 367–377 (2017).

    CAS  PubMed  Google Scholar 

  32. J.C. Venancio, L.O. Margatho, R. Rorato, R.R. Rosales, L.K. Debarba, R. Coletti, J. Antunes-Rodrigues, C.F. Elias, L.L. Elias, Short-term high-fat diet increases leptin activation of CART neurons and advances puberty in female mice. Endocrinology 158(11), 3929–3942 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. C.Y. Lee, S. Li, X.F. Li, D.A. Stalker, C. Cooke, B. Shao, H. Kelestimur, B.A. Henry, G. Conductier, K.T. O’Byrne, I.J. Clarke, Lipopolysaccharide reduces gonadotrophin-releasing hormone (GnRH) gene expression: Role of RFamide-related peptide-3 and kisspeptin. Reprod., Fertil. Dev. 31(6), 1134–1143 (2019)

    Article  CAS  Google Scholar 

  34. M.A. González Hernández, E.E. Canfora, J.W. Jocken, E.E. Blaak, The short-chain fatty acid acetate in body weight control and insulin sensitivity. Nutrients 11(8), 1943 (2019)

    Article  PubMed Central  Google Scholar 

  35. K.S. Olaniyi, O.A. Amusa, Sodium acetate-mediated inhibition of histone deacetylase alleviates hepatic lipid dysregulation and its accompanied injury in streptozotocin-nicotinamide-induced diabetic rats. Biomedicine Pharmacother. 128, 110226 (2020)

    Article  CAS  Google Scholar 

  36. V. Karoor, D. Strassheim, T. Sullivan, A. Verin, N.S. Umapathy, E.C. Dempsey, D.N. Frank, K.R. Stenmark, E. Gerasimovskaya, The short-chain fatty acid butyrate attenuates pulmonary vascular remodeling and inflammation in hypoxia-induced pulmonary hypertension. Int. J. Mol. Sci. 22(18), 9916 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. O.A. Adeyanju, T.O. Falodun, O.S. Michael, O.A. Soetan, A.L. Oyewole, R.D. Agbana, Spironolactone reversed hepato-ovarian triglyceride accumulation caused by letrozole-induced polycystic ovarian syndrome: tissue uric acid—a familiar foe. Naunyn-Schmiedeberg’s Arch. Pharmacol. 393(6), 1055–1066 (2020).

    Article  CAS  Google Scholar 

  38. H. Kafali, M. Iriadam, I. Ozardali, N. Demir, Letrozole-induced polycystic ovaries in the rat: a new model for cystic ovarian disease. Arch. Med. Res. 35, 103–108 (2004)

    Article  CAS  PubMed  Google Scholar 

  39. K.S. Olaniyi, M.N. Owolabi, C.L. Atuma, T.B. Agunbiade, B.Y. Alabi, Acetate rescues defective brain-adipose metabolic network in obese Wistar rats by modulation of peroxisome proliferator-activated receptor-γ. Sci. Rep. 11(1), 1–5 (2021b)

    Article  Google Scholar 

  40. A.W. Hsing, Y.T. Gao, S. Chua Jr, J. Deng, F.Z. Stanczyk, Insulin resistance and prostate cancer risk. J. Natl Cancer Inst. 95(1), 67–71 (2003)

    Article  CAS  PubMed  Google Scholar 

  41. K.S. Olaniyi, L.A. Olatunji, Inhibition of pyruvate dehydrogenase kinase-4 by l-glutamine protects pregnant rats against fructose-induced obesity and hepatic lipid accumulation. Biomed. Pharmacother. 110, 59–67 (2019)

    Article  CAS  PubMed  Google Scholar 

  42. S. Malamed, J.A. Gibney, S.R. Ojeda, Ovarian innervation develops before initiation of folliculogenesis in the rat. Cell Tissue Res. 270(1), 87–93 (1992)

    Article  CAS  PubMed  Google Scholar 

  43. K.S. Olaniyi, O.A. Amusa, I.O. Ajadi, B.Y. Alabi, T.B. Agunbiade, M.B. Ajadi, Repression of HDAC5 by acetate restores hypothalamic-pituitary-ovarian function in type 2 diabetes mellitus. Reprod. Toxicol. 106, 69–81 (2021)

    Article  CAS  PubMed  Google Scholar 

  44. K.A. Posey, D.J. Clegg, R.L. Printz, J. Byun, G.J. Morton, A. Vivekanandan-Giri, S. Pennathur, D.G. Baskin, J.W. Heinecke, S.C. Woods, M.W. Schwartz, Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am. J. Physiol.-Endocrinol. Metab. 296(5), E1003–E1012 (2009)

    Article  CAS  PubMed  Google Scholar 

  45. I. Kojta, M. Chacińska, A.Błachnio-Zabielska,, Obesity, bioactive lipids, and adipose tissue inflammation in insulin resistance. Nutrients 12(5), 1305 (2020). https://doi.org/10.3390/nu12051305

    Article  CAS  PubMed Central  Google Scholar 

  46. K.S. Olaniyi, L.A. Olatunji, L-glutamine ameliorates adipose-hepatic dysmetabolism in OC-treated female rats. J. Endocrinol. 246(1), 1–12 (2020). https://doi.org/10.1530/JOE-19-0582

    Article  CAS  PubMed  Google Scholar 

  47. S. Cinti, Adipose organ development and remodeling. Compr. Physiol. 8(4), 1357–1431 (2018). https://doi.org/10.1002/cphy.c170042

    Article  PubMed  Google Scholar 

  48. K. Sun, C.M. Kusminski, P.E. Scherer, Adipose tissue remodeling and obesity. J. Clin. Investig. 121(6), 2094–2101 (2011). https://doi.org/10.1172/JCI45887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. A.T. Vieira, I. Galvão, L.M. Macia, E.M. Sernaglia, M.A. Vinolo, C.C. Garcia, L.P. Tavares, F.A. Amaral, L.P. Sousa, F.S. Martins, C.R. Mackay, Dietary fiber and the short‐chain fatty acid acetate promote resolution of neutrophilic inflammation in a model of gout in mice. J. Leukoc. Biol. 101(1), 275–84. (2017)

    Article  CAS  PubMed  Google Scholar 

  50. M.A. Vinolo, H.G. Rodrigues, R.T. Nachbar, R. Curi, Regulation of inflammation by short chain fatty acids. Nutrients 3(10), 858–876 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Cardio/Repro-metabolic and Microbiome Research Unit, Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, 360101, Nigeria

    Kehinde S. Olaniyi, Stephanie E. Areloegbe & Mosunmola B. Oyeleke

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Contributions

Conceptualization and design of this research were attributed to K.S.O. The experiment, analysis and interpretation of data were performed by K.S.O. and S.E.A., and K.S.O. and M.B.O. contributed reagents to the study. K.S.O. and S.E.A. drafted the manuscript. K.S.O., S.E.A., and M.B.O. read, revised and approved the final manuscript.

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Correspondence to Kehinde S. Olaniyi.

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Olaniyi, K.S., Areloegbe, S.E. & Oyeleke, M.B. Acetate restores hypothalamic-adipose kisspeptin status in a rat model of PCOS by suppression of NLRP3 immunoreactivity. Endocrine 78, 628–640 (2022). https://doi.org/10.1007/s12020-022-03191-9

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