Similarly, conditioned media collected from p.R219W/Q mutant‐transfected cells also increased TOP‐Flash reporter transcriptional activity, while this effect was abolished upon treatment with anti‐RSPO1 neutralizing antibody (Figure 5H).[30] Taken together, these results suggest that p.R219W/Q mutations identified in human obesity disrupt their affinity to HSPG and thus increase RSPO1 protein release from ECM to extracellular space, consequently over‐activating Wnt/β‐catenin signaling. This evidence concerns the gene RSPO1 and obesity disorder.