Importantly, this acetylcholine-mediated CHRNA2 signaling showed physiological significance to combat obesity and related metabolic dysfunction by demonstrating profound fat accumulation and impaired whole-body glucose metabolism after chronic calorie overload in the absence of Chrna2. The discovery of ChAMs that secrete acetylcholine via β2-AR signaling and induce beige thermogenesis provides novel evidence of the neuro-immune-beige fat axis and may offer a new approach to counteract obesity and metabolic disorders. This evidence concerns the gene ADRB2 and obesity due to melanocortin 4 receptor deficiency.