In an effort to explore the potential role of Brd4 in ATMs and in the development of obesity and insulin resistance, we found that mice with deficiency of Brd4 in myeloid lineage-specific cells were protected from high-fat diet–induced (HFD-induced) obesity, inflammation, and insulin resistance with increased energy expenditure and enhanced lipolysis in adipose tissue. Here, BRD4 is linked to obesity due to melanocortin 4 receptor deficiency.