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, Ondřej Hodek, Thomas Möritz, Lynn M. Alaeddine, Scott Frendo‐Cumbo, Ingrid Dahlman, Alastair G. Kerr, Salwan Maqdasy, Niklas Mejhert, Mikael Rydén
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. (150 words) • ER stress represses CKB transcription and induces inflammation in adipocytes • IRE1-XBP1s downregulates CKB via epigenetic mechanisms • XBP1s interacts with DNMT3A to induce DNA methylation at the CKB promoter • Restoring CKB expression normalizes ER stress-driven inflammation • In obesity, CKB promoter methylation associates with CKB gene expression and adipose inflammation