In fact, the previous studies showed that the downregulation of NPR-A expression and upregulation of NP degradation systems (i.e., NP clearance receptor [NPR-C] and neprilysin) are observed in obese or diabetic subjects27,41,42, which may result in the blunted impact of NPs on obesity. This evidence concerns the gene NPR1 and obesity due to melanocortin 4 receptor deficiency.