Renzi Gianluca, Vlassakev Ivan, Hansen Mattias, Higos Romane, Lecoutre Simon, Elmastas Merve, Hodek Ondrej, Moritz Thomas, Alaeddine Lynn M, Frendo-Cumbo Scott, Dahlman Ingrid, Kerr Alastair, Maqdasy Salwan, Mejhert Niklas, Rydén Mikael
Department of Medicine (H7), Karolinska Institutet, ME Endokrinologi, Karolinska University Hospital Huddinge, SE-141 83, Huddinge, Sweden.
Nutrition and Obesities: Systemic Approaches Research Group (Nutri-Omics), Sorbonne Université, INSERM, F-75013 Paris, France.
Mol Metab. 2025 Feb;92:102082. doi: 10.1016/j.molmet.2024.102082. Epub 2024 Dec 13.
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.
在白色脂肪组织中，通过降低肌酸激酶B（CKB）转录而导致的肌酸代谢紊乱会引发与肥胖相关的炎症。然而，调节人类白色脂肪细胞中CKB表达的机制仍不清楚。通过筛选肥胖中受到干扰的条件，我们确定内质网（ER）应激是多种细胞类型中CKB转录的关键抑制因子。通过后续研究，我们发现内质网应激通过IRE1-XBP1s途径，经由甲基转移酶DNMT3A促进CKB启动子甲基化。这种表观遗传变化抑制CKB转录，使代谢转向糖酵解并增加促炎趋化因子CCL2的产生。我们在体内验证了我们的发现，表明肥胖个体白色脂肪细胞中CKB表达与启动子甲基化呈负相关，同时CCL2分泌增加。总体而言，我们的研究揭示了一个调节轴，即内质网应激通过降低CKB丰度，进而改变细胞的生物能量状态，从而在肥胖中引发炎症。
