Here, the authors screen all Wnt‐related paracrine factors in 1994 obese cases and 2161 controls using whole‐exome sequencing (WES) and identify that 12 obese patients harbor the same mutations in RSPO1 (p.R219W/Q) predisposing to human obesity. This evidence concerns the gene RSPO1 and obesity due to melanocortin 4 receptor deficiency.