Many pathogenic mutations in the ectodomain of LepR have been identified from severe early‐onset obesity patients.[58, 59] Several key mutation sites that could disrupt or attenuate the LepR signaling were also reported by structure analysis.[60] These mutations (Figure 4a) resulted in either loss of leptin binding or LepR desensitization. This evidence concerns the gene LEP and obesity due to melanocortin 4 receptor deficiency.