Genetic loss of HIF2α in mice reversed UMP‐mediated Acer2 activation and obesity alleviation, and we conclude from our findings that a HIF2α‐ACER2‐ceramide axis underlies the mechanism through which UMP supplementation can alleviate obesity features and restore metabolic traits. This evidence concerns the gene ACER2 and obesity due to melanocortin 4 receptor deficiency.