Inactivation of the CD146 gene or antibody targeting of CD146 releases the Gp130 protein from its association with CD146, steering ATMs toward anti‐inflammatory polarization, thus attenuating obesity‐associated adipose tissue inflammation and metabolic abnormalities, which is similar to the effect of IL‐6 on macrophage polarization. Here, MCAM is linked to obesity due to melanocortin 4 receptor deficiency.