Abstract
High-fat diet (HFD) induces low-grade chronic inflammation, contributing to obesity and insulin resistance. However, the precise mechanisms triggering obesity-associated metabolic inflammation remain elusive. In this study, we identified epigenetic factor Brd4 as a key player in this process by regulating the expression of Ccr2/Ccr5 in colonic macrophage. Upon 4-week HFD, myeloid-lineage-specific Brd4 deletion (Brd4-CKO) mice showed reduced colonic inflammation and macrophage infiltration with decreased expression of Ccr2 and Ccr5. Mechanistically, Brd4 was recruited by NF-κB to the enhancer regions of Ccr2 and Ccr5, promoting enhancer RNA expression, which facilitated Ccr2/Ccr5 expression and macrophage migration. Furthermore, decreased infiltration of Ccr2/Ccr5-positive colonic macrophages in Brd4-CKO mice altered gut microbiota composition and reduced intestinal permeability, thereby lowering metabolic endotoxemia. Finally, Brd4-CKO mice subjected to a 4-week LPS infusion exhibited restored susceptibility to HFD-induced obesity and insulin resistance. This study identifies Brd4 as a critical initiator of colonic macrophage-mediated inflammation and metabolic endotoxemia upon HFD, suggesting Brd4 as a potential target for mitigating HFD-induced inflammation, obesity, and its metabolic complications.