Effect of the hypothalamic serotonin on body weight change in the context of brain insulin resistance in Alzheimer’s disease

Ebru Afşar

doi:10.66235/kumj.1853640

Effect of the hypothalamic serotonin on body weight change in the context of brain insulin resistance in Alzheimer’s disease

Abstract

Aims: The present work was designed to evaluate how alterations in serotonin (5-hydroxytryptamine, 5-HT), 5-HT receptor subtype 2B (5-HT2BR), and neuropeptide Y (NPY) are associated with body weight regulation in a rat model of brain insulin resistance (B-IR) that mimics the early pathological features of Alzheimer’s disease (AD).

Methods: B-IR was induced in rats through intracerebroventricular (i.c.v.) administration of amyloid-β₁–₄₂ oligomers at a dose of 2.5 nmol in a total volume of 10 μL. 5-HT concentrations were quantified in brainstem and hypothalamic samples, while hypothalamic levels of 5-HT2BR and NPY were determined using enzyme-linked immunosorbent assay (ELISA) methods. Body weight variation for each animal was defined as the difference between post-experimental and initial measurements. Group comparisons were conducted using the Mann–Whitney U test, and statistical significance was accepted at p < 0.05.

Results: Rats in the B-IR group showed a tendency toward increased 5-HT levels in brainstem tissue compared to the control group (p > 0.05), whereas hypothalamic 5-HT levels were significantly decreased in the B-IR group compared to controls (p < 0.01); body weight was significantly reduced in the B-IR group compared to the control group (p<0.01). In addition, rats in the B-IR group showed a downward trend in hypothalamic 5-HT2BR and NPY levels compared with the control group (p > 0.05 for both).

Conclusion: These findings suggest that decreased hypothalamic 5-HT levels in the B-IR group may be associated with the observed reduction in body weight. Additionally, the downward trends observed in 5-HT2BR and NPY levels may also be related to this change.

Keywords

Ethical Statement

Animal Experiments Ethics Committee of the Akdeniz University Experimental Animals Application and Research Center (approval dated 06.05.2024, decision no. 2024/18).

References

Rice DM, Buchsbaum MS, Starr A, Auslander L, Hagman J, Evans WJ. Abnormal EEG slow activity in left temporal areas in senile dementia of the Alzheimer type. J Gerontol. 1990;45(4):145-151. doi:10.1093/geronj/45.4.m145
Park S, Kim DS, Kang S, Kim HJ. The combination of luteolin and l-theanine improved Alzheimer disease-like symptoms by potentiating hippocampal insulin signaling and decreasing neuroinflammation and norepinephrine degradation in amyloid-beta-infused rats. Nutr Res. 2018;60:116-131. doi:10.1016/j.nutres.2018.09.010
Majlath Z, Toldi J, Vecsei L. The potential role of kynurenines in Alzheimer's disease: pathomechanism and therapeutic possibilities by influencing the glutamate receptors. J Neural Transm (Vienna). 2014;121(8):881-889. doi:10.1007/s00702-013-1135-5
Almaça J, Molina J, Menegaz D, et al. Human beta cells produce and release serotonin to ınhibit glucagon secretion from alpha cells. Cell Rep. 2016;(17)12:3281-3291. doi:10.1016/j.celrep.2016.11.072
Nguyen TKO, Nguyen TTD, Giau VV. Type 3 diabetes and its role implications in Alzheimer's disease. Int J Mol Sci. 2020;21(9):3165. doi:10.3390/ijms21093165
van Sloten TT, Sedaghat S, Carnethon MR, Launer LJ, Stehouwer CDA. Cerebral microvascular complications of type 2 diabetes: stroke, cognitive dysfunction, and depression. Lancet Diabetes Endocrinol. 2020;8(4):325-336. doi:10.1016/S2213-8587(19)30405-X
Talbot K. Brain insulin resistance in Alzheimer's disease and its potential treatment with GLP-1 analogs. Neurodegener Dis Manag. 2014;4(1):31-40. doi:10.2217/nmt.13.73
Nonogaki K. The regulatory role of the central and peripheral serotonin network on feeding signals in metabolic diseases. Int J Mol Sci. 2022;23(3):1600. doi:10.3390/ijms23031600.

Wang Y, Qi F, Li M, Dong L, Cai P. Traditional Chinese medicine modulates hypothalamic neuropeptides for appetite regulation: A comprehensive review. Biosci Trends. 2025;4:19(3):281-295. doi:10.5582/bst.2025.01087.
Wang Q, Zhou Y, Huang J, Huang N. Structure, function, and pharmaceutical ligands of 5-hydroxytryptamine 2B receptor. Pharmaceuticals (Basel). 2021;14(2):76. doi:10.3390/ph14020076.
Tian J, Stucky CS, Wang T, Muma NA, Johnson M, Du H. Mitochondrial dysfunction Links to impaired hippocampal serotonin release in a mouse model of Alzheimer's disease. J Alzheimers Dis. 2023;93(2):605-619. doi:10.3233/JAD-230072
Bassendine MF, Taylor-Robinson SD, Fertleman M, Khan M, Neely D. Is Alzheimer's disease a liver disease of the brain? J Alzheimers Dis. 2020;75(1): 1-14. doi:10.3233/JAD-190848.
Acun, AD, Kantar D, Er H, Erkan O, Derin N, Yargıcoglu P. Investigation of cyclo-Z therapeutic effect on insulin pathway in Alzheimer's rat model: Biochemical and electrophysiological parameters. Mol Neurobiol. 2023;60(7):4030–4048. doi:10.1007/s12035-023-03334-7
Paxinos G, Watson CR, Emson PC. AChE-stained horizontal sections of the rat brain in stereotaxic coordinates. J Neurosci Methods. 1980;3(2):129-49. doi:10.1016/0165-0270(80)90021-7
Afşar E, Doğan K, Arslan E, et al. Does Zn-mediated regulation of the Kynurenine pathway provide the link between periodontal disease and diabetes? Biol Trace Elem Res. 2026;204(1):1-12. doi:10.1007/s12011-025-04776-x.
Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;(72):248-254. doi:10.1016/0003-2697(76)90527-3
Afşar E, Doğan K, Kantar D, Kuzzu AD. Arı Ekmeğinin Alzheimer sıçan modelinde karaciğer 5ht2b aracılı glukoz düzenlemesi üzerine etkisi. Kocatepe Med J. 2024;25(4):466-475. doi:10.18229/kocatepetip.1433727
Kshirsagar V, Thingore C, Juvekar A. Insulin resistance: a connecting link between Alzheimer's disease and metabolic disorder. Metab Brain Dis. 2021;36(1):67-83. doi:10.1007/s11011-020-00622-2.
Aydemir HA, Bayraktar M. Screening patients with metabolic syndrome for risk of obstructive sleep apnea: the syndrome Z. Kastamonu Med J. 2025;5(3):145-149. doi:10.51271/KMJ-0200
Olgun E, Topçu E, Çetin Ş. Relationship of atherogenic index of plasma with exercise, obesity and biochemical parameters. Kastamonu Med J. 2024;4(2):33-38. doi:10.51271/KMJ-0139
Himmerich H, Treasure J. Psychopharmacological advances in eating disorders. Expert Rev Clin Pharmacol. 2018;11(1):95-108. doi:10.1080/17512433.2018.1383895
Brüge A, Ponimaskin E, Labus J. Targeting the serotonergic system in the treatment of neurodegenerative diseases-emerging therapies and unmet challenges. Pharmacol Rev. 2025;77(5):100071. doi:10.1016/j.pharmr.2025.100071.
Chen M, Wang C, Lin Y, et al. Dorsal raphe nucleus-hippocampus serotonergic circuit underlies the depressive and cognitive impairments in 5×FAD male mice. Transl Neurodegener. 2024;13(1):34. doi:10.1186/s40035-024-00425-w.
Rao JS, Tangarife MA, Rodríguez-Soacha DA, et al. Dysregulated Neurotransmitters and CB1 Receptor Dysfunction and Their Roles in Agitation Associated with Alzheimer’s Disease. J. Dement. Alzheimer's Dis. 2025; 2(2):15. doi:10.3390/jdad2020015
He Y, Cai X, Liu H, et al. 5-HT recruits distinct neurocircuits to inhibit hunger-driven and non-hunger-driven feeding. Mol Psychiatry. 2021;26(12):7211-7224. doi:10.1038/s41380-021-01220-z.
Heisler LK, Cowley MA, Tecott L H, et al. Activation of central melanocortin pathways by fenfluramine. Science. 2002;297(5581):609-611. doi:10.1126/science.1072327.
Oury F, Karsenty G. Towards a serotonin-dependent leptin roadmap in the brain. Trends Endocrinol Metab.2011;22(9):382-387. doi:10.1016/j.tem.2011.04.006
Sugimoto Y, Inoue K, Yamada J. The tricyclic antidepressant clomipramine increases plasma glucose levels of mice. J Pharmacol Sci. 2003;93(1):74-9. doi:10.1254/jphs.93.74.
Baldini G, Phelan KD. The melanocortin pathway and control of appetite-progress and therapeutic implications. J Endocrinol. 2019;1:241(1):R1-R33. doi:10.1530/JOE-18-0596.
Jin HK, Bae JS, Furuya S, Carter JE. Amyloid beta-derived neuroplasticity in bone marrow-derived mesenchymal stem cells is mediated by NPY and 5-HT2B receptors via ERK1/2 signalling pathways. Cell Prolif. 2009;42(5):571-86. doi:10.1111/j.1365-2184.2009.00625.x.

Details

Primary Language

English

Subjects

Clinical Chemistry

Journal Section

Research Article

Authors

Ebru Afşar ^*
0000-0002-7817-855X
Türkiye

Publication Date

June 16, 2026

Submission Date

January 1, 2026

Acceptance Date

April 20, 2026

Published in Issue

Year 2026 Volume: 6 Number: 2

DOI

https://doi.org/10.66235/kumj.1853640

IZ

https://izlik.org/JA28NZ59NM

Cite

RIS / Bibtex

APA

Afşar, E. (2026). Effect of the hypothalamic serotonin on body weight change in the context of brain insulin resistance in Alzheimer’s disease. Kastamonu Medical Journal, 6(2), 120-126. https://doi.org/10.66235/kumj.1853640

AMA

1.Afşar E. Effect of the hypothalamic serotonin on body weight change in the context of brain insulin resistance in Alzheimer’s disease. Kastamonu Medical Journal. 2026;6(2):120-126. doi:10.66235/kumj.1853640

Chicago

Afşar, Ebru. 2026. “Effect of the Hypothalamic Serotonin on Body Weight Change in the Context of Brain Insulin Resistance in Alzheimer’s Disease”. Kastamonu Medical Journal 6 (2): 120-26. https://doi.org/10.66235/kumj.1853640.

EndNote

Afşar E (June 1, 2026) Effect of the hypothalamic serotonin on body weight change in the context of brain insulin resistance in Alzheimer’s disease. Kastamonu Medical Journal 6 2 120–126.

IEEE

[1]E. Afşar, “Effect of the hypothalamic serotonin on body weight change in the context of brain insulin resistance in Alzheimer’s disease”, Kastamonu Medical Journal, vol. 6, no. 2, pp. 120–126, June 2026, doi: 10.66235/kumj.1853640.

ISNAD

Afşar, Ebru. “Effect of the Hypothalamic Serotonin on Body Weight Change in the Context of Brain Insulin Resistance in Alzheimer’s Disease”. Kastamonu Medical Journal 6/2 (June 1, 2026): 120-126. https://doi.org/10.66235/kumj.1853640.

JAMA

1.Afşar E. Effect of the hypothalamic serotonin on body weight change in the context of brain insulin resistance in Alzheimer’s disease. Kastamonu Medical Journal. 2026;6:120–126.

MLA

Afşar, Ebru. “Effect of the Hypothalamic Serotonin on Body Weight Change in the Context of Brain Insulin Resistance in Alzheimer’s Disease”. Kastamonu Medical Journal, vol. 6, no. 2, June 2026, pp. 120-6, doi:10.66235/kumj.1853640.

Vancouver

1.Ebru Afşar. Effect of the hypothalamic serotonin on body weight change in the context of brain insulin resistance in Alzheimer’s disease. Kastamonu Medical Journal. 2026 Jun. 1;6(2):120-6. doi:10.66235/kumj.1853640