beta-MSH: a functional ligand that regulated energy homeostasis via hypothalamic MC4-R?
alpha-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, beta-MSH is also capable of activating MC4-R and inhibiting feeding. Here, we investigated the possibility that 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. We found that beta-MSH had significantly higher affinities than alpha-MSH at both human MC4-R transfected into CHO cells (K(i): beta-MSH, 11.4+/-0.4 nmol/l versus alpha-MSH, 324+/-16 nmol/l, P<0.001) and MC4-R in rat hypothalamic homogenates (K(i): beta-MSH, 5.0+/-0.4 nmol/l versus alpha-MSH, 22.5+/-2.3 nmol/l, P<0.001). Incubation of brain slices with 5 microM beta-MSH significantly increased [35S]GTPgammaS 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 beta-MSH immunoreactive fibres and also the distribution of MC4-R binding sites which we and others previously reported. Food-restriction significantly increased beta-MSH levels in the VMH, DMH and ARC (all P<0.05) above freely-fed controls, whilst alpha-MSH concentrations were unchanged. We propose that increased beta-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). beta-MSH has higher affinity at MC4-R than alpha-MSH; (2). beta-MSH activates GPCR in these sites, which are rich in MC4-R; and (3). beta-MSH is present in hypothalamic nuclei that regulate feeding and its concentrations alter with nutritional state. We suggest that 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.
Department of Medicine, University of Liverpool, Daulby Street, L69 3GA Liverpool, UK. harrold@liverpool.ac.uk
Joanne A
JA
Harrold
Peter S
PS
Widdowson
Gareth
G
Williams
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004734:Energy Metabolism; D005508:Food Deprivation; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D008024:Ligands; D008297:Male; D009765:Obesity / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D019824:beta-MSH / Q000378:metabolism*
D007328:Insulin; D008024:Ligands; D044105:Receptor, Melanocortin, Type 4; D019824:beta-MSH; D016244:Guanosine 5'-O-(3-Thiotriphosphate)