Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation

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

doi:10.1016/j.molmet.2024.102082

Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation

Mol Metab. 2024 Dec 13:92:102082. doi: 10.1016/j.molmet.2024.102082. Online ahead of print.

Authors

Affiliations

¹ Department of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, Sweden.
² Nutrition and Obesities: Systemic Approaches Research Group (Nutri-Omics), Sorbonne Université, INSERM, F-75013 Paris, France.
³ Swedish Metabolomics Center, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden.
⁴ Swedish 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, Denmark.
⁵ Department of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden.
⁶ Department of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, Sweden; Steno Diabetes Center, Copenhagen, Herlev, Denmark. Electronic address: [email protected].
⁷ Department of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, Sweden; Steno Diabetes Center, Copenhagen, Herlev, Denmark. Electronic address: [email protected].

PMID: 39675471
DOI: 10.1016/j.molmet.2024.102082

Abstract

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.

Keywords: Chromatin remodeling; Creatine pathway; Glycolysis; Immunometabolism; Tunicamycin.