To this end, we performed whole‐exome sequencing (WES) in a large sample‐size cohort of young, severely obese subjects and lean controls[16, 18] targeting WNT‐related genes and identified a gain‐of‐function mutation (p.R219W) in the human RSPO1 gene that specifically disrupts its electrostatic interaction with the ECM and leads to increased RSPO1 release to the extracellular space, amplifying WNT signaling of the targeted preadipocytes and inhibiting the thermogenic capacity of beige adipocytes, and consequently contributes to diet‐induced obesity. This evidence concerns the gene RSPO1 and obesity due to melanocortin 4 receptor deficiency.