During the obesity process, M1‐polarization is induced to promote pro‐inflammatory changes in adipose tissue, which may lead to systemic insulin resistance.[34] Macrophage M2‐polarization is associated with less inflammation, lower body weight,[35, 36] improved insulin sensitivity and white fat browning.[27, 37] Targeting adipose tissue‐resident macrophages may serve as a potential antiobesity immunotherapy.[38, 39] Our study indicates that CD146 is involved in the pro‐inflammatory polarization of macrophages under high‐fat conditions, which affects overall metabolic health. The gene discussed is MCAM; the disease is obesity due to melanocortin 4 receptor deficiency.