SPP1 and obesity due to melanocortin 4 receptor deficiency: KIAA1199 is known to degrade HA,11 which is a ligand for CD44 that regulates adipocyte cell formation.26 Another plausible mechanism is the observed inhibitory effects of KIAA1199 on osteopontin (OPN) and its interaction with its cognate receptor ITGB1.16 OPN is also known for its effects on extramedullary AD differentiation.27 Interestingly, OPN knockout (OPN−/−) mice have been reported to be protected from obesity, insulin resistance, adipose tissue inflammation, and hepatic steatosis during HFD feeding,27–29 which is similar phenotype to what we observed in KIAA1199 KO mice.