β-MSH: a functional ligand that regulated energy homeostasis via hypothalamic MC4-R?

Abstract

α-Melanocyte stimulating hormone (MSH) has generally been assumed to be the endogenous ligand acting at the melanocortin-4 receptor (MC4-R), activation of which in the hypothalamus leads to reduced feeding. However, β-MSH is also capable of activating MC4-R and inhibiting feeding. Here, we investigated the possibility that β-MSH acts as an endogenous MC4-R agonist and that this melanocortin peptide plays a role in the regulation of feeding and energy balance. We found that β-MSH had significantly higher affinities than α-MSH at both human MC4-R transfected into CHO cells ( K i: β-MSH, 11.4±0.4 nmol/l versus α-MSH, 324±16 nmol/l, P<0.001) and MC4-R in rat hypothalamic homogenates ( K i: β-MSH, 5.0±0.4 nmol/l versus α-MSH, 22.5±2.3 nmol/l, P<0.001). Incubation of brain slices with 5 μM β-MSH significantly increased [ 35 S ]GTPγS binding by 140–160% ( P<0.001), indicating activation of G-protein-coupled receptors (GPCRs), in the hypothalamic ventromedial (VMH), dorsomedial (DMH), arcuate (ARC) and paraventricular (PVN) nuclei. These sites match the distribution of β-MSH immunoreactive fibres and also the distribution of MC4-R binding sites which we and others previously reported. Food-restriction significantly increased β-MSH levels in the VMH, DMH and ARC (all P<0.05) above freely-fed controls, whilst α-MSH concentrations were unchanged. We propose that increased β-MSH concentrations reflect blockade of the peptide’s release in these sites, consistent with the increased hunger and the known up-regulation of MC4-R in the same nuclei. Thus, we conclude that (1) β-MSH has higher affinity at MC4-R than α-MSH; (2) β-MSH activates GPCR in these sites, which are rich in MC4-R; and (3) β-MSH is present in hypothalamic nuclei that regulate feeding and its concentrations alter with nutritional state. We suggest that β-MSH rather than α-MSH is the key ligand at the MC4-R populations that regulate feeding, and that inhibition of tonic release of β-MSH is one mechanism contributing to hunger in under-feeding.