Fig. 6: Schematic model of Brd4 regulation in metabolic endotoxemia-induced inflammation, obesity, and insulin resistance via promoting colonic macrophage infiltration.

During the early stage of HFD, Brd4 activates the expression of enhancer RNA of Ccr2 and Ccr5, which facilitates mRNA synthesis of Ccr2 and Ccr5, and then promotes the infiltration of macrophages into the colon and induces colonic inflammation. The presence of colonic macrophages affects gut microbiota composition and enhances intestinal permeability, leading to increased LPS levels in the circulation and metabolic tissue such as adipose tissue. Ultimately, these processes contribute to the development of meta-inflammation, obesity, and insulin resistance.