Introduction

The initial report that melanocortin peptides potently inhibit food intake after central administration was published in 1986 (Poggioli et al., 1986). Because the melanocortin receptors had not yet been cloned or shown to be expressed in the brain, there was no physiological context to fully appreciate the significance of these data. In the two decades since that first publication, a remarkable web of experimental findings has firmly established the melanocortin system as a critical component in the brain's control of energy homeostasis. A key breakthrough was the cloning and characterization of the agouti gene from the “obese yellow” mouse (Lu et al., 1994). This spontaneous mutant strain expresses a dominant agouti AY allele and has an obesity phenotype in addition to a yellow coat color. The demonstration that agouti is an antagonist of melanocortin receptors (MCR), together with the findings of ectopic brain expression of the peptide and expression of MC3R and MC4R in the brain was the genesis of the “agouti-melanocortin” hypothesis for the mechanism of obesity in AY mice. Critical elements of this hypothesis were substantiated in 1997 by a trilogy of publications. First, targeted inactivation of the gene encoding the brain-specific MC4R caused an obesity phenotype similar to that of AY mice (Huszar et al., 1997). Second, novel agonists and antagonists of the MC3/4R inhibited or stimulated feeding, respectively, when injected into the 3rd ventricle in rodents (Fan et al., 1997).