Nesfatin-1 and Ghrelin/GOAT as Potential Biomarkers in Adolescent Headache with Temporomandibular Disorders: A Cross-Sectional Study

Anna Sojka; Barbara Dorocka-Bobkowska; Yasmin  Bartosik; Ozgun Yetkin; Barbara Steinborn; Marcin Żarowski

doi:10.20883/medical.e1418

Authors

Anna Sojka Chair and Clinic of Prosthodontics and Gerodontology, Poznan University of Medical Sciences, Poznań, Poland https://orcid.org/0000-0002-0193-0491
Barbara Dorocka-Bobkowska Chair and Clinic of Prosthodontics and Gerodontology, Poznan University of Medical Sciences, Poznań, Poland https://orcid.org/0000-0003-3659-7761
Yasmin Bartosik Chair and Clinic of Prosthodontics and Gerodontology, Poznan University of Medical Sciences, Poznań, Poland https://orcid.org/0009-0007-8932-1810
Ozgun Yetkin Department of Developmental Neurology, Poznan University of Medical Sciences, Poznań, Poland; Doctoral School, Poznan University of Medical Sciences, Poznań, Poland https://orcid.org/0000-0003-4110-8002
Barbara Steinborn Poznan University of Medical Sciences Department of Developmental Neurology, Poznań, Poland https://orcid.org/0000-0002-9839-8162
Marcin Żarowski Poznan University of Medical Sciences Department of Developmental Neurology, Poznań, Poland https://orcid.org/0000-0002-9800-9446

DOI:

https://doi.org/10.20883/medical.e1418

Keywords:

nesfatin-1, ghrelin/GOAT, headache, temporomandibular disorders, adolescent

Abstract

Introduction. Nesfatin-1 and Ghrelin O-acetyltransferase (GOAT) are peptide hormones involved in stress response and pain modulation beyond their metabolic functions. This study investigated whether these biomarkers differ between adolescents with headaches and healthy controls and examined their relationship with temporomandibular disorders (TMD).

Material and methods. This cross-sectional study measured Nesfatin-1 and Ghrelin/GOAT levels in the serum and saliva of 44 adolescents with headaches (aged 10-17 years, diagnosed per ICHD-3 beta criteria) and 20 age-matched healthy controls. TMD was assessed using the Diagnostic Criteria for TMD (DC/TMD). Statistical comparisons were performed using non-parametric tests, with significance set at p < 0.05.

Results. Nesfatin-1 was elevated in all headache patients compared to controls in both blood (patient median range: 39.5-45.0 ng/mL vs. control median range: 8.1-9.0 ng/mL, p<0.001) and saliva (patient median range: 6.6-8.2 ng/mL vs. control median range: 1.8-2.3 ng/mL, p<0.001) regardless of headache type (migraine vs. tension-type) or TMD status. Ghrelin/GOAT showed opposite patterns in blood versus saliva: serum levels were higher in patients (median range: 5.9-6.6 ng/mL vs. 1.4 ng/mL in controls, p<0.001), while salivary levels were lower (median range: 0.2 ng/mL vs. 1.4 ng/mL in controls, p<0.001). Gender differences emerged in clinical manifestations: females had more muscle pain (74% vs 38%, p = 0.016), while males reported more psychological distress (90% vs 48%, p = 0.003).

Conclusions. This study reveals altered Nesfatin-1 and Ghrelin/GOAT levels in adolescents with headaches, independent of headache type or TMD status. These findings suggest potential utility as pain-related biomarkers, though validation studies with larger sample sizes and receiver operating characteristic analyses are needed before clinical implementation. Gender specific clinical patterns underscore the importance of sex-stratified approaches in adolescent pain management.

Downloads

Download data is not yet available.

References

Dao JM, Qubty W. Headache Diagnosis in Children and Adolescents. Curr Pain Headache Rep. 2018;22(3):17. https://doi.org/10.1007/s11916-018-0675-7.

Wöber-Bingöl C. Epidemiology of migraine and headache in children and adolescents. Curr Pain Headache Rep. 2013;17(6):341. https://doi.org/10.1007/s11916-013-0341-z.

Abu-Arafeh I, Razak S, Sivaraman B, Graham C. Prevalence of headache and migraine in children and adolescents: a systematic review of population-based studies. Dev Med Child Neurol. 2010;52(12):1088-97. https://doi.org/10.1111/j.1469-8749.2010.03793.x.

Hershey AD, Powers SW, Vockell AL, LeCates SL, Segers A, Kabbouche MA. Development of a patient-based grading scale for PedMIDAS. Cephalalgia. 2004;24(10):844-9. https://doi.org/10.1111/j.1468-2982.2004.00757.x.

Hershey AD. Current approaches to the diagnosis and management of paediatric migraine. Lancet Neurol. 2010;9(2):190-204. https://doi.org/10.1016/s1474-4422(09)70303-5.

Gauer RL, Semidey MJ. Diagnosis and treatment of temporomandibular disorders. Am Fam Physician. 2015;91(6):378-86. PMID: 25822556.

Wieckiewicz M, Grychowska N, Nahajowski M, Hnitecka S, Kempiak K, Charemska K, et al. Prevalence and Overlaps of Headaches and Pain-Related Temporomandibular Disorders Among the Polish Urban Population. Journal of Oral & Facial Pain and Headache. 2020;34(1):31-9. https://doi.org/10.11607/ofph.2386.

Błaszczyk B, Waliszewska-Prosół M, Smardz J, Więckiewicz M, Wojakowska A, Martynowicz H. Exploring the associations of sleep bruxism and obstructive sleep apnea with migraine among patients with temporomandibular disorder: A polysomnographic study. Headache: The Journal of Head and Face Pain. 2025;65(2):242-57. https://doi.org/10.1111/head.14892.

The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9):629-808. https://doi.org/10.1177/0333102413485658.

van Dongen RM, Zielman R, Noga M, Dekkers OM, Hankemeier T, van den Maagdenberg AM, et al. Migraine biomarkers in cerebrospinal fluid: A systematic review and meta-analysis. Cephalalgia. 2017;37(1):49-63. https://doi.org/10.1177/0333102415625614.

Loder E, Rizzoli P. Biomarkers in migraine: their promise, problems, and practical applications. Headache. 2006;46(7):1046-58. https://doi.org/10.1111/j.1526-4610.2006.00498.x.

Oh IS, Shimizu H, Satoh T, Okada S, Adachi S, Inoue K, et al. Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature. 2006;443(7112):709-12. https://doi.org/10.1038/nature05162.

Aydin S, Dag E, Ozkan Y, Erman F, Dagli AF, Kilic N, et al. Nesfatin-1 and ghrelin levels in serum and saliva of epileptic patients: hormonal changes can have a major effect on seizure disorders. Mol Cell Biochem. 2009;328(1-2):49-56. https://doi.org/10.1007/s11010-009-0073-x.

Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656-60. https://doi.org/10.1038/45230.

Kojima M, Hamamoto A, Sato T. Ghrelin O -acyltransferase (GOAT), a specific enzyme that modifies ghrelin with a medium-chain fatty acid. The Journal of Biochemistry. 2016;160(4):189-94. https://doi.org/10.1093/jb/mvw046.

Ozmen S, Şeker A, Demirci E. Ghrelin and leptin levels in children with anxiety disorders. J Pediatr Endocrinol Metab. 2019;32(10):1043-7. https://doi.org/10.1515/jpem-2019-0229.

Minervini G, Franco R, Marrapodi MM, Fiorillo L, Cervino G, Cicciù M. Prevalence of temporomandibular disorders in children and adolescents evaluated with Diagnostic Criteria for Temporomandibular Disorders: A systematic review with meta-analysis. J Oral Rehabil. 2023;50(6):522-30. https://doi.org/10.1111/joor.13446.

Nilsson IM, Drangsholt M, List T. Impact of temporomandibular disorder pain in adolescents: differences by age and gender. J Orofac Pain. 2009;23(2):115-22. PMID: 19492536.

World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Jama. 2013;310(20):2191-4. https://doi.org/10.1001/jama.2013.281053.

Gutierrez-Castro K, Kornhauser-Araujo C, Gomez A, Luevano-Contreras C, Fafutis-Morris M, Gugliucci A, et al. Serum nesfatin-1 levels are higher in obese vs lean adolescents and associate with cardiometabolic dyslipidemia. Journal of Clinical and Molecular Medicine. 2020;4. https://doi.org/10.15761/JCMM.1000140.

Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, et al. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab. 2002;87(1):240-4. https://doi.org/10.1210/jcem.87.1.8129.

Schiffman E, Ohrbach R, Truelove E, Look J, Anderson G, Goulet JP, et al. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research Applications: recommendations of the International RDC/TMD Consortium Network* and Orofacial Pain Special Interest Group†. J Oral Facial Pain Headache. 2014;28(1):6-27. https://doi.org/10.11607/jop.1151.

Ohrbach R, Knibbe W. Diagnostic criteria for temporomandibular disorders (DC/TMD) scoring manual for self-report instruments. NY, US and ACTA, Amsterdam, The Netherlands: University at Buffalo. 2018. Corpus ID: 45047162.

Zawawi KH, Al-Badawi EA, Lobo SL, Melis M, Mehta NR. An index for the measurement of normal maximum mouth opening. Journal (Canadian Dental Association). 2003;69(11):737-41.PMID: 14653940.

Hofmann T, Ahnis A, Elbelt U, Rose M, Klapp BF, Stengel A. NUCB2/nesfatin-1 Is Associated with Elevated Levels of Anxiety in Anorexia Nervosa. PLoS One. 2015;10(7):e0132058. https://doi.org/10.1371/journal.pone.0132058.

Xiao MM, Li JB, Jiang LL, Shao H, Wang BL. Plasma nesfatin-1 level is associated with severity of depression in Chinese depressive patients. BMC Psychiatry. 2018;18(1):88. https://doi.org/10.1186/s12888-018-1672-4.

Christensen CE, Ashina M, Amin FM. Calcitonin Gene-Related Peptide (CGRP) and Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Migraine Pathogenesis. Pharmaceuticals. 2022;15(10):1189. https://doi.org/10.3390/ph15101189

Pallegama RW, Ranasinghe AW, Weerasinghe VS, Sitheeque MA. Anxiety and personality traits in patients with muscle related temporomandibular disorders. J Oral Rehabil. 2005;32(10):701-7. https://doi.org/10.1111/j.1365-2842.2005.01503.x.

AKHTER R, MORITA M, ESAKI M, NAKAMURA K, KANEHIRA T. Development of temporomandibular disorder symptoms: a 3-year cohort study of university students. Journal of Oral Rehabilitation. 2011;38(6):395-403. https://doi.org/10.1111/j.1365-2842.2010.02195.x.

Nilsson IM, List T, Drangsholt M. Headache and co-morbid pains associated with TMD pain in adolescents. J Dent Res. 2013;92(9):802-7. https://doi.org/10.1177/0022034513496255.

Orzeszek S, Martynowicz H, Smardz J, Wojakowska A, Bombała W, Mazur G, et al. Assessment of sleep quality in patients with orofacial pain and headache complaints: A polysomnographic study. Dent Med Probl. 2024;61(4):549-62. https://doi.org/10.17219/dmp/177008.

Liljeström M-R, Le Bell Y, Anttila P, Aromaa M, Jämsä T, Metsähonkala L, et al. Headache Children with Temporomandibular Disorders have Several Types of Pain and other Symptoms. Cephalalgia. 2005;25(11):1054-60. https://doi.org/10.1111/j.1468-2982.2005.00957.x.

Machado E, Dal-Fabbro C, Cunali PA, Kaizer OB. Prevalence of sleep bruxism in children: a systematic review. Dental Press J Orthod. 2014;19(6):54-61. https://doi.org/10.1590/2176-9451.19.6.054-061.oar.

Manfredini D, Restrepo C, Diaz-Serrano K, Winocur E, Lobbezoo F. Prevalence of sleep bruxism in children: a systematic review of the literature. J Oral Rehabil. 2013;40(8):631-42. https://doi.org/10.1111/joor.12069.