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The endogenous melanocortin system is physiologically regulated not only by MSH peptide agonists but also by endogenous antagonists agouti (a selective MC1R and MC4R antagonist) and agouti-related peptide (AgRP), which is an inverse agonist at MC3R and MC4R expressed in the arcuate nucleus and is the primary endogenous inhibitory regulator of the melanocortin pathway in energy balance