Jamaluddin et al. investigated how the MRAP2 accessory protein enhances signaling by three appetite-regulating GPCRs. MRAP2 disrupts GPCR oligomerization to form interactions, and its cytoplasmic region is essential for signaling. MRAP2 variants modulate receptor constitutive activity, enhance internalization, and reduce signaling, contributing to weight gain and hyperglycemia observed in humans.