ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1633326
This article is part of the Research TopicAdvances in Novel Pharmacotherapeutics and Drug Discovery: Computational, Experimental, Translational, and Clinical Models, Volume IIView all articles
MT2 Receptor Mediates Melatonin-Induced Thermogenic Program in Human Myoblasts: Insights for Circadian Syndrome and Diabesity Treatment
Provisionally accepted
- 1University of Granada, Granada, Spain
- 2Instituto de Investigacion Biosanitaria de Granada, Granada, Spain
- 3Centro Pfizer - Universidad de Granada - Junta de Andalucia de Genomica e Investigacion Oncologica, Granada, Spain
- 4Universidad de Cordoba, Crdoba, Spain
- 5Sohag University Faculty of Veterinary Medicine, Sohag, Egypt
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Background: Melatonin is crucial for regulating circadian rhythms. Previous studies have demonstrated its ability to improve metabolic disorders, including obesity and associated diabetes (diabesity), in addition to its antioxidant, anti-inflammatory and anti-apoptotic properties. Recently, melatonin was shown to reduce obesity by increasing skeletal muscle (SKM) energy expenditure through non-shivering thermogenesis (NST). Small interfering RNAs (siRNAs) are powerful tools for inhibiting gene expression, enabling the analysis of gene functions and roles in molecular pathway activation. This study aimed to identify the receptor mediating melatonin's pharmacological actions in SKM NST.Methods: Bioinformatics and protein-protein interaction (PPI) analyses were conducted. To examine the role of the melatonin receptor 2 (MT2) encoded by MTNR1B, we cultured human primary myoblasts and then silenced MTNR1B using siRNA transfection for 72 hours, followed by 1 mM melatonin treatment for 24 hours. Gene and protein expression were analyzed using semi-quantitative reverse transcriptase PCR and Western blotting respectively.Results: PPI analysis revealed MTNR1B's strong association with diabetes, obesity, cancer, and circadian rhythm disorders, collectively known as circadian syndrome, and MTNR1B's close interaction with thermogenic genes (UCP1, PPARG, and PPARGC1A). Silencing MTNR1B reduced the gene expression and inhibited the melatonin-induced upregulation of MT2 and NST-related proteins. Melatonin increased SERCA1/2, SLN, and Ca²⁺-dependent thermogenic pathway activation; however, these effects were abolished following MTNR1B knockdown.Our findings confirm that MT2 plays a key role in melatonin-driven SERCA-SLN uncoupling and the activation of the thermogenic program in SKM via the CaMKII/AMPK/PGC1α pathway upregulation. This study provides new insights into the molecular mechanisms underlying melatonin's effects on thermogenesis and suggests potential melatonin-based therapeutic strategies against diabesity.
Keywords: human primary myoblast, Melatonin, MT2, skeletal muscle, non-shivering thermogenesis, Diabesity, circadian syndrome
Received: 22 May 2025; Accepted: 16 Jun 2025.
Copyright: © 2025 SALAGRE, Sanjuán-Hidalgo, Elmahallawy, Medina and Agil. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ahmad Agil, University of Granada, Granada, Spain
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