We previously reported the genetic mutations and biological roles of Wnt/β‐catenin signaling molecules in the development of obesity.[16, 28, 33] In this study, using systematic genetic screening of all known WNT genes as well as their paracrine activators and inhibitors, we reveal that a gain‐of‐function mutation in RSPO1 (p.R219W), which is enriched in young, severely obese subjects, inhibits the thermogenic capacities and mitochondrial respiration of brown/beige fat, reduces whole‐body energy expenditure, and results in adiposity in the homologous mutation knock‐in mouse model. Here, RSPO1 is linked to obesity disorder.