{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T20:46:29Z","timestamp":1793825189588,"version":"4.6.1"},"reference-count":37,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002711","name":"Ahi Evran University Scientific Researches Coordination Unit","doi-asserted-by":"publisher","award":["TIP.A3.24.010"],"award-info":[{"award-number":["TIP.A3.24.010"]}],"id":[{"id":"10.13039\/501100002711","id-type":"DOI","asserted-by":"publisher"}]},{"award":["TIP.A3.24.010"],"award-info":[{"award-number":["TIP.A3.24.010"]}],"id":[{"id":"https:\/\/ror.org\/05rrfpt58","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Hypothyroidism is associated with metabolic, neurobehavioral, and reproductive alterations that may involve neuroendocrine regulatory peptides. Spexin, a neuropeptide implicated in energy homeostasis, has recently attracted attention for its possible role in thyroid and reproductive axis regulation. Therefore, this study aimed to investigate the effects of spexin on neurobehavioral responses and the tissue-specific expression of irisin and KISS-1 in the cerebral cortex and testis under hypothyroid conditions. Thirty-two male Wistar albino rats were randomly divided into four groups: Control, Hypothyroid (methimazole, 0.03% in drinking water for 35 days), Hypothyroid + Spexin (methimazole plus spexin, 25 \u00b5g\/kg, intraperitoneally), and Spexin (25 \u00b5g\/kg, intraperitoneally). Behavioral assessments were performed using the Open Field Test and Forced Swim Test. Serum thyroid hormone levels were analyzed, and brain and testis tissues were evaluated immunohistochemically for irisin and KISS-1 expression. Hypothyroid rats showed increased thyroid-stimulating hormone levels, decreased thyroxine concentrations. Spexin administration significantly reduced TSH levels and increased T4 concentrations. Spexin treatment reduced thigmotaxis compared to controls. No significant differences were found among groups in overall locomotor activity, time spent in the central zone, or FST parameters. Immunohistochemical analyses demonstrated reduced irisin and KISS-1 expression in hypothyroid rats, which was restored following spexin treatment. In conclusion, spexin exerted TSH-suppressive and T4-enhancing effects in experimental hypothyroidism. Its effects on irisin and KISS-1 expression suggest potential involvement in neuroendocrine and reproductive axis regulation.<\/jats:p>","DOI":"10.3390\/biology15120932","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:49:42Z","timestamp":1781743782000},"page":"932","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Biochemical, Immunohistochemical and Behavioral Effects of Spexin in a Methimazole-Induced Hypothyroidism Rat Model"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1183-4847","authenticated-orcid":false,"given":"Seda","family":"Ko\u00e7ak","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, K\u0131r\u015fehir Ahi Evran University, K\u0131r\u015fehir 40100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fclhan","family":"\u00dcnl\u00fc","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, K\u0131r\u015fehir Ahi Evran University, K\u0131r\u015fehir 40100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K\u00fcbra Tu\u011f\u00e7e","family":"Kalkan","sequence":"additional","affiliation":[{"name":"Department of Embryology and Histology, Faculty of Medicine, K\u0131r\u015fehir Ahi Evran University, K\u0131r\u015fehir 40100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1862-9515","authenticated-orcid":false,"given":"Ferhat","family":"Pekta\u015f","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, K\u0131r\u015fehir Ahi Evran University, K\u0131r\u015fehir 40100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet","family":"T\u00fcrk","sequence":"additional","affiliation":[{"name":"Department of Embryology and Histology, Faculty of Medicine, Ad\u0131yaman University, K\u0131r\u015fehir 02040, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1530\/EJE-13-0459","article-title":"Changes in the prevalence of hypothyroidism","volume":"169","author":"Vatten","year":"2013","journal-title":"Eur. J. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"bvac172","DOI":"10.1210\/jendso\/bvac172","article-title":"Hypothyroidism prevalence in the United States: A retrospective study combining national health and nutrition examination survey and claims data, 2009\u20132019","volume":"7","author":"Wyne","year":"2023","journal-title":"J. Endocr. Soc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1159\/000499751","article-title":"Prevalence of undiagnosed hypothyroidism in Europe: A systematic review and meta-analysis","volume":"8","author":"Mendes","year":"2019","journal-title":"Eur. Thyroid. J."},{"key":"ref_4","first-page":"182","article-title":"Effect of methimazole-induced hypothyroidism on serum levels of LH and testosterone and weights of testes and thyroid gland in rat","volume":"15","author":"Mohamadizadeh","year":"2011","journal-title":"Physiol. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17","DOI":"10.47489\/p000s341z7371-8mc","article-title":"Histological Study of Commiphora mukul, Withania somnifera and Thyroxine in a Murine Model of Hypothyroidism","volume":"34","author":"Zulfiqar","year":"2020","journal-title":"Proceedings"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1007\/s12035-020-02178-9","article-title":"Hypothyroidism induces interleukin-1-dependent autophagy mechanism as a key mediator of hippocampal neuronal apoptosis and cognitive decline in postnatal rats","volume":"58","author":"Mishra","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e220338","DOI":"10.1530\/JOE-22-0338","article-title":"Hypothyroidism induces motor deficit via altered cerebellar HB-EGF\/EGFR and autophagy","volume":"257","author":"Vishwakarma","year":"2023","journal-title":"J. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Al-Suhaimi, E.A., and Khan, F.A. (2022). The pituitary gland: Functional relationship with the hypothalamus, structure, and physiology. Emerging Concepts in Endocrine Structure and Functions, Springer.","DOI":"10.1007\/978-981-16-9016-7_4"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1002\/jemt.20759","article-title":"Is there a role for thyroid hormone on spermatogenesis?","volume":"72","author":"Wagner","year":"2009","journal-title":"Microsc. Res. Tech."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1677\/JOE-08-0218","article-title":"The role of thyroid hormone in testicular development and function","volume":"199","author":"Wagner","year":"2008","journal-title":"J. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/s41574-020-00438-1","article-title":"Functions of galanin, spexin and kisspeptin in metabolism, mood and behaviour","volume":"17","author":"Mills","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1159\/000493482","article-title":"Decreased spexin levels in patients with type 1 and type 2 diabetes","volume":"27","author":"Karaca","year":"2019","journal-title":"Med. Princ. Pract."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e20241313","DOI":"10.1590\/1806-9282.20241313","article-title":"The relationship between spexin and liver steatosis in polycystic ovary syndrome: A novel analysis using ultrasound-guided attenuation parameter","volume":"71","author":"Kavak","year":"2025","journal-title":"Rev. Assoc. M\u00e9d. Bras."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1093\/biolre\/ioad108","article-title":"Spexin role in human granulosa cells physiology and PCOS: Expression and negative impact on steroidogenesis and proliferation","volume":"109","author":"Kurowska","year":"2023","journal-title":"Biol. Reprod."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Chen, X., Feng, Y., Dai, S., Guo, B., Yan, L., Liu, J., and Zhu, H. (2024). Advances in research on spexin-mediated regulation of reproductive function in vertebrates. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1422711"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.bbrc.2022.08.059","article-title":"Levels of spexin and its receptors GALR2 and GALR3 in the hypothalamus and ovary of letrozole-induced polycystic ovary syndrome in rats","volume":"627","author":"Respekta","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wang, B., Wang, K., Tian, Z., Cui, A., Liu, X., Jin, Z., Liu, X., Jiang, Y., and Xu, Y. (2022). New evidence for SPX2 in regulating the brain-pituitary reproductive axis of half-smooth tongue sole (Cynoglossus semilaevis). Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.984797"},{"key":"ref_18","first-page":"283","article-title":"Changes in irisin release in response to peripheral kisspeptin-10 administration in healthy and obese adult men","volume":"15","author":"Shamas","year":"2019","journal-title":"Acta Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"170976","DOI":"10.1016\/j.peptides.2023.170976","article-title":"Investigation of irisin\u2019s role in pubertal onset physiology in female rats","volume":"163","author":"Kutlu","year":"2023","journal-title":"Peptides"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Xie, Q., Kang, Y., Zhang, C., Xie, Y., Wang, C., Liu, J., Yu, C., Zhao, H., and Huang, D. (2022). The role of kisspeptin in the control of the hypothalamic-pituitary-gonadal axis and reproduction. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.925206"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1007\/s12272-010-0317-z","article-title":"The beneficial effects of olibanum on memory deficit induced by hypothyroidism in adult rats tested in Morris water maze","volume":"33","author":"Hosseini","year":"2010","journal-title":"Arch. Pharmacal Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1002\/oby.20725","article-title":"Spexin is a novel human peptide that reduces adipocyte uptake of long chain fatty acids and causes weight loss in rodents with diet-induced obesity","volume":"22","author":"Walewski","year":"2014","journal-title":"Obesity"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Perumal Kannabiran, B., Palaniappan, N.A., Manoharan, T., Paramasivam, P.K., Saini, J.K., Ansari, M.S., Jayabal, L., Aggarwal, A.N., Garg, R., and Subramanyam, B. (2024). Safety and efficacy of 25 mg\/kg and 35 mg\/kg vs 10 mg\/kg rifampicin in pulmonary TB: A phase IIb randomized controlled trial. Open Forum Infectious Diseases, Oxford University Press.","DOI":"10.1093\/ofid\/ofae034"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kraeuter, A.-K., Guest, P.C., and Sarnyai, Z. (2018). The open field test for measuring locomotor activity and anxiety-like behavior. Pre-Clinical Models: Techniques and Protocols, Springer.","DOI":"10.1007\/978-1-4939-8994-2_9"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"106917","DOI":"10.1016\/j.phrs.2023.106917","article-title":"A systematic mapping review of the evolution of the rat Forced Swim Test: Protocols and outcome parameters","volume":"196","author":"Brandwein","year":"2023","journal-title":"Pharmacol. Res."},{"key":"ref_26","first-page":"1","article-title":"Effect of Cortexin administration on Kisspeptin and Spexin expression after testicular torsion","volume":"35","author":"Turk","year":"2025","journal-title":"Rev. Cient. Fac. Vet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"114401","DOI":"10.1016\/j.physbeh.2023.114401","article-title":"Spexin may induce mitochondrial biogenesis in white and brown adipocytes via the hypothalamus-pituitary-thyroid (HPT) axis","volume":"273","author":"Yilmaz","year":"2024","journal-title":"Physiol. Behav."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E313","DOI":"10.1152\/ajpendo.00213.2024","article-title":"Exercise training and Spexin ameliorate thyroid changes in obese type 2 diabetic rats: The possible interlaying mechanisms","volume":"327","author":"Rizk","year":"2024","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.theriogenology.2020.08.031","article-title":"No evidence that Spexin impacts LH release and seasonal breeding in the ewe","volume":"158","author":"Lomet","year":"2020","journal-title":"Theriogenology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1007\/s12011-022-03204-8","article-title":"The effect of Irisin on thyroid hormone levels in chronic paroxetine-treated rats","volume":"201","author":"Ercan","year":"2023","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"119929","DOI":"10.1016\/j.cca.2024.119929","article-title":"Irisin in thyroid diseases","volume":"564","author":"Chen","year":"2025","journal-title":"Clin. Chim. Acta"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Yun, S., Reyes-Alcaraz, A., Lee, Y.-N., Yong, H.J., Choi, J., Ham, B.-J., Sohn, J.-W., Kim, D.-H., Son, G.H., and Kim, H. (2019). Spexin-based galanin receptor type 2 agonist for comorbid mood disorders and abnormal body weight. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00391"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.physbeh.2013.10.036","article-title":"Diphenyl diselenide supplemented diet reduces depressive-like behavior in hypothyroid female rats","volume":"124","author":"Dias","year":"2014","journal-title":"Physiol. Behav."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.ejphar.2018.01.017","article-title":"Chrysin reverses the depressive-like behavior induced by hypothyroidism in female mice by regulating hippocampal serotonin and dopamine","volume":"822","author":"Bortolotto","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"439","DOI":"10.4274\/jcrpe.3498","article-title":"The effect of congenital and postnatal hypothyroidism on depression-like behaviors in juvenile rats","volume":"8","author":"Aksu","year":"2016","journal-title":"J. Clin. Res. Pediatr. Endocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.bbr.2006.10.030","article-title":"Behavioral inhibition and impaired spatial learning and memory in hypothyroid mice lacking thyroid hormone receptor \u03b1","volume":"177","author":"Wilcoxon","year":"2007","journal-title":"Behav. Brain Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"112084","DOI":"10.1016\/j.bbr.2019.112084","article-title":"Effects of exercise training on anxiety in diabetic rats","volume":"376","author":"Caliskan","year":"2019","journal-title":"Behav. Brain Res."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/12\/932\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T01:25:17Z","timestamp":1781745917000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/12\/932"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,15]]},"references-count":37,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["biology15120932"],"URL":"https:\/\/doi.org\/10.3390\/biology15120932","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,15]]}}}