The seven trans-membrane spanning G protein couple receptors(GPCRs) constitute the largest family of FDA approved drug targets to treat numerous human diseases, including metabolic associated disorders. The Melanocortin Receptor Accessory Protein 2 (MRAP2), a small single transmembrane protein broadly expressed in multiple tissues has been defined as a vital endocrine pivot of five melanocortin receptors(MC1R-MC5R) and several other GPCRs in the regulation of central neuronal appetite and peripheral energy homeostasis. However, MRAP2 null mouse model exhibited late onset obesity syndrome without alteration on the eating behavior, a huge phenotypic departure from MC4R KO animals. In this study, we identified GLP1R and MCHR1, the two energy regulators as novel GPCR targets and characterized the specific regions of MRAP2 protein that required for the pharmacological modulation of the intracellular cAMP cascades. The simultaneous inhibitory effect of MRAP2 on the anorectic GLP1R and orectic MCHR1 signaling further elucidated the complex endocrine network of GPCR signaling which may explain the composite metabolic phenotypes of MRAP2 deficiency.