Activator of G-protein Signaling (AGS) 3 plays functional roles in cell division, synaptic plasticity, addictive behavior and neuronal development. As part of a broad effort to define the extent of functional diversity of AGS3-regulated-events in vivo, we generated AGS3 null mice. Surprisingly, AGS3 null adult mice exhibited unexpected alterations in cardiovascular and metabolic functions without any obvious changes in motor skills, basic behavioral traits and brain morphology. AGS3 null mice exhibited a lean phenotype, reduced fat mass and increased nocturnal energy expenditure. AGS3 null mice also exhibited altered blood pressure control mechanisms. These studies expand the functional repertoire for AGS3 and other GPR proteins providing unexpected regulatory mechanisms by which G-protein systems may be targeted to influence obesity and cardiovascular function.