Effects of celastrol on the heart and liver galaninergic system expression in a mouse model of Western-type diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitis
BackgroundThe complexity of the galaninergic system is still not fully understood, especially under specific pre-existing comorbidities related to metabolic dysfunction. A plant-derived triterpenoid celastrol was demonstrated to exert a complex effect on the galaninergic system and to have hepatopro...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1476994/full |
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| author | Nikolina Canová Jana Šípková Mahak Arora Zuzana Pavlíková Zuzana Pavlíková Tomáš Kučera Ondřej Šeda Tijana Šopin Tomáš Vacík Ondřej Slanař |
| author_facet | Nikolina Canová Jana Šípková Mahak Arora Zuzana Pavlíková Zuzana Pavlíková Tomáš Kučera Ondřej Šeda Tijana Šopin Tomáš Vacík Ondřej Slanař |
| author_sort | Nikolina Canová |
| collection | DOAJ |
| description | BackgroundThe complexity of the galaninergic system is still not fully understood, especially under specific pre-existing comorbidities related to metabolic dysfunction. A plant-derived triterpenoid celastrol was demonstrated to exert a complex effect on the galaninergic system and to have hepatoprotective and anti-obesity properties. However, the exact molecular mechanisms responsible for these effects remain unclear. Specifically, there are no data on the impact of celastrol on the heart and liver galaninergic system. Therefore, this study aimed to investigate the effects of celastrol on the galaninergic system expression in the heart and liver of mice suffering from diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH).MethodsThe male mice C57BL/6J were fed a Western-type high-fat diet for 16 and 20 weeks to induce obesity and MASLD/MASH. Celastrol was administered along with a specific diet for the last 4 weeks to evaluate its impact on the progression of these conditions. Moreover, the inhibitor of sterol regulatory element-binding protein 1/2 (SREBP1/2), fatostatin, was also tested to compare its influence on the galaninergic system with celastrol.ResultsThe study demonstrates that celastrol treatment was safe and led to a reduction in food and energy intake, body fat and liver weights, and MASLD-to-MASH progression and improved glucose tolerance, serum biochemistry markers, and hepatic lipid peroxidation in mice. Quantitative gene expression originally showed significant regulation of galanin and all three of its receptors (GalR1/2/3) in the heart ventricles and only GalR2 in the liver of obese mice. Celastrol influenced the gene expression of galanin receptors: it downregulated Galr1 in the heart and upregulated Galr2 in the liver and Galr3 in the heart ventricles, potentially affecting energy metabolism, oxidative stress, and inflammation. Fatostatin suppressed gene expression of all the detected members of the galaninergic system in the heart ventricles, depicting the role of SREBP in this process.ConclusionThese findings suggest that celastrol may beneficially modulate the galaninergic system under obesity and MASLD-to-MASH progression, indicating its potential as a therapeutic agent for disorders associated with metabolic dysfunction. |
| format | Article |
| id | doaj-art-b4a1f87313414e519d5193c93b5f6470 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| spelling | doaj-art-b4a1f87313414e519d5193c93b5f64702025-02-04T05:28:07ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-02-011610.3389/fphar.2025.14769941476994Effects of celastrol on the heart and liver galaninergic system expression in a mouse model of Western-type diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitisNikolina Canová0Jana Šípková1Mahak Arora2Zuzana Pavlíková3Zuzana Pavlíková4Tomáš Kučera5Ondřej Šeda6Tijana Šopin7Tomáš Vacík8Ondřej Slanař9Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, CzechiaInstitute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, CzechiaInstitute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, CzechiaInstitute of Histology and Embryology, First Faculty of Medicine, Charles University, Prague, CzechiaDepartment of Anthropology and Human Genetics, Faculty of Science, Charles University, Prague, CzechiaInstitute of Histology and Embryology, First Faculty of Medicine, Charles University, Prague, CzechiaInstitute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital, Prague, CzechiaInstitute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital, Prague, CzechiaInstitute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital, Prague, CzechiaInstitute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, CzechiaBackgroundThe complexity of the galaninergic system is still not fully understood, especially under specific pre-existing comorbidities related to metabolic dysfunction. A plant-derived triterpenoid celastrol was demonstrated to exert a complex effect on the galaninergic system and to have hepatoprotective and anti-obesity properties. However, the exact molecular mechanisms responsible for these effects remain unclear. Specifically, there are no data on the impact of celastrol on the heart and liver galaninergic system. Therefore, this study aimed to investigate the effects of celastrol on the galaninergic system expression in the heart and liver of mice suffering from diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH).MethodsThe male mice C57BL/6J were fed a Western-type high-fat diet for 16 and 20 weeks to induce obesity and MASLD/MASH. Celastrol was administered along with a specific diet for the last 4 weeks to evaluate its impact on the progression of these conditions. Moreover, the inhibitor of sterol regulatory element-binding protein 1/2 (SREBP1/2), fatostatin, was also tested to compare its influence on the galaninergic system with celastrol.ResultsThe study demonstrates that celastrol treatment was safe and led to a reduction in food and energy intake, body fat and liver weights, and MASLD-to-MASH progression and improved glucose tolerance, serum biochemistry markers, and hepatic lipid peroxidation in mice. Quantitative gene expression originally showed significant regulation of galanin and all three of its receptors (GalR1/2/3) in the heart ventricles and only GalR2 in the liver of obese mice. Celastrol influenced the gene expression of galanin receptors: it downregulated Galr1 in the heart and upregulated Galr2 in the liver and Galr3 in the heart ventricles, potentially affecting energy metabolism, oxidative stress, and inflammation. Fatostatin suppressed gene expression of all the detected members of the galaninergic system in the heart ventricles, depicting the role of SREBP in this process.ConclusionThese findings suggest that celastrol may beneficially modulate the galaninergic system under obesity and MASLD-to-MASH progression, indicating its potential as a therapeutic agent for disorders associated with metabolic dysfunction.https://www.frontiersin.org/articles/10.3389/fphar.2025.1476994/fullcelastrolfatostatingalanin receptorheartobesityMASLD |
| spellingShingle | Nikolina Canová Jana Šípková Mahak Arora Zuzana Pavlíková Zuzana Pavlíková Tomáš Kučera Ondřej Šeda Tijana Šopin Tomáš Vacík Ondřej Slanař Effects of celastrol on the heart and liver galaninergic system expression in a mouse model of Western-type diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitis Frontiers in Pharmacology celastrol fatostatin galanin receptor heart obesity MASLD |
| title | Effects of celastrol on the heart and liver galaninergic system expression in a mouse model of Western-type diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitis |
| title_full | Effects of celastrol on the heart and liver galaninergic system expression in a mouse model of Western-type diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitis |
| title_fullStr | Effects of celastrol on the heart and liver galaninergic system expression in a mouse model of Western-type diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitis |
| title_full_unstemmed | Effects of celastrol on the heart and liver galaninergic system expression in a mouse model of Western-type diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitis |
| title_short | Effects of celastrol on the heart and liver galaninergic system expression in a mouse model of Western-type diet-induced obesity and metabolic dysfunction-associated steatotic liver disease and steatohepatitis |
| title_sort | effects of celastrol on the heart and liver galaninergic system expression in a mouse model of western type diet induced obesity and metabolic dysfunction associated steatotic liver disease and steatohepatitis |
| topic | celastrol fatostatin galanin receptor heart obesity MASLD |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1476994/full |
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