beta-MSH: a functional ligand that regulated energy homeostasis via hypothalamic MC4-R. beta-MSH is also capable of activating MC4-R and inhibiting feeding. beta-MSH acts as an endogenous MC4-R agonist and that this melanocortin peptide plays a role in the regulation of feeding and energy balance. Food-restriction significantly increased beta-MSH levels in the VMH, DMH and ARC above freely-fed controls, whilst alpha-MSH concentrations were unchanged. beta-MSH has higher affinity at MC4-R than alpha-MSH;beta-MSH activates GPCR in these sites, which are rich in MC4-R; beta-MSH is present in hypothalamic nuclei that regulate feeding and its concentrations alter with nutritional state. beta-MSH rather than alpha-MSH is the key ligand at the MC4-R populations that regulate feeding, and that inhibition of tonic release of beta-MSH is one mechanism contributing to hunger in under-feeding.