Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation
In white adipose tissue, disturbed creatine metabolism through reduced creatine kinase B (CKB) transcription contributes to obesity-related inflammation. However, the mechanisms regulating CKB expression in human white adipocytes remain unclear. By screening conditions perturbed in obesity, we ident...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877824002138 |
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| author | Gianluca Renzi Ivan Vlassakev Mattias Hansen Romane Higos Simon Lecoutre Merve Elmastas Ondrej Hodek Thomas Moritz Lynn M. Alaeddine Scott Frendo–Cumbo Ingrid Dahlman Alastair Kerr Salwan Maqdasy Niklas Mejhert Mikael Rydén |
| author_facet | Gianluca Renzi Ivan Vlassakev Mattias Hansen Romane Higos Simon Lecoutre Merve Elmastas Ondrej Hodek Thomas Moritz Lynn M. Alaeddine Scott Frendo–Cumbo Ingrid Dahlman Alastair Kerr Salwan Maqdasy Niklas Mejhert Mikael Rydén |
| author_sort | Gianluca Renzi |
| collection | DOAJ |
| description | In white adipose tissue, disturbed creatine metabolism through reduced creatine kinase B (CKB) transcription contributes to obesity-related inflammation. However, the mechanisms regulating CKB expression in human white adipocytes remain unclear. By screening conditions perturbed in obesity, we identified endoplasmic reticulum (ER) stress as a key suppressor of CKB transcription across multiple cell types. Through follow-up studies, we found that ER stress through the IRE1–XBP1s pathway, promotes CKB promoter methylation via the methyltransferase DNMT3A. This epigenetic change represses CKB transcription, shifting metabolism towards glycolysis and increasing the production of the pro-inflammatory chemokine CCL2. We validated our findings in vivo, demonstrating that individuals living with obesity show an inverse relationship between CKB expression and promoter methylation in white adipocytes, along with elevated CCL2 secretion. Overall, our study uncovers a regulatory axis where ER stress drives inflammation in obesity by reducing CKB abundance, and consequently altering the bioenergetic state of the cell. |
| format | Article |
| id | doaj-art-12f6cd5498624bfdb7d118a2d80103ec |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-12f6cd5498624bfdb7d118a2d80103ec2025-02-01T04:11:56ZengElsevierMolecular Metabolism2212-87782025-02-0192102082Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammationGianluca Renzi0Ivan Vlassakev1Mattias Hansen2Romane Higos3Simon Lecoutre4Merve Elmastas5Ondrej Hodek6Thomas Moritz7Lynn M. Alaeddine8Scott Frendo–Cumbo9Ingrid Dahlman10Alastair Kerr11Salwan Maqdasy12Niklas Mejhert13Mikael Rydén14Department of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, SwedenDepartment of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, SwedenDepartment of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, SwedenDepartment of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, SwedenNutrition and Obesities: Systemic Approaches Research Group (Nutri-Omics), Sorbonne Université, INSERM, F-75013 Paris, FranceDepartment of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, SwedenSwedish Metabolomics Center, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, SwedenSwedish Metabolomics Center, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkDepartment of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, SwedenDepartment of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, SwedenDepartment of Clinical Science and Education, Karolinska Institutet, Stockholm, SwedenDepartment of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, SwedenDepartment of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, SwedenDepartment of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, Sweden; Steno Diabetes Center, Copenhagen, Herlev, Denmark; Corresponding author. Department of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, Sweden.Department of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, Sweden; Steno Diabetes Center, Copenhagen, Herlev, Denmark; Corresponding author. Department of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, Sweden.In white adipose tissue, disturbed creatine metabolism through reduced creatine kinase B (CKB) transcription contributes to obesity-related inflammation. However, the mechanisms regulating CKB expression in human white adipocytes remain unclear. By screening conditions perturbed in obesity, we identified endoplasmic reticulum (ER) stress as a key suppressor of CKB transcription across multiple cell types. Through follow-up studies, we found that ER stress through the IRE1–XBP1s pathway, promotes CKB promoter methylation via the methyltransferase DNMT3A. This epigenetic change represses CKB transcription, shifting metabolism towards glycolysis and increasing the production of the pro-inflammatory chemokine CCL2. We validated our findings in vivo, demonstrating that individuals living with obesity show an inverse relationship between CKB expression and promoter methylation in white adipocytes, along with elevated CCL2 secretion. Overall, our study uncovers a regulatory axis where ER stress drives inflammation in obesity by reducing CKB abundance, and consequently altering the bioenergetic state of the cell.http://www.sciencedirect.com/science/article/pii/S2212877824002138Creatine pathwayGlycolysisImmunometabolismTunicamycinChromatin remodeling |
| spellingShingle | Gianluca Renzi Ivan Vlassakev Mattias Hansen Romane Higos Simon Lecoutre Merve Elmastas Ondrej Hodek Thomas Moritz Lynn M. Alaeddine Scott Frendo–Cumbo Ingrid Dahlman Alastair Kerr Salwan Maqdasy Niklas Mejhert Mikael Rydén Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation Molecular Metabolism Creatine pathway Glycolysis Immunometabolism Tunicamycin Chromatin remodeling |
| title | Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation |
| title_full | Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation |
| title_fullStr | Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation |
| title_full_unstemmed | Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation |
| title_short | Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation |
| title_sort | epigenetic suppression of creatine kinase b in adipocytes links endoplasmic reticulum stress to obesity associated inflammation |
| topic | Creatine pathway Glycolysis Immunometabolism Tunicamycin Chromatin remodeling |
| url | http://www.sciencedirect.com/science/article/pii/S2212877824002138 |
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