Effects of melanocortin receptor ligands on thyrotropin-releasing hormone release: evidence for the differential roles of melanocortin 3 and 4 receptors.
The hypothalamic melanocortin system is important in the central regulation of food intake and body weight. We have previously demonstrated that intracerebroventricular administration of alpha-melanocyte stimulating hormone (alpha-MSH), a nonselective MC3 and MC4 receptor agonist, stimulated plasma thyroid-stimulating hormone, and agouti-related protein (AgRP), an MC3 and MC4 receptor antagonist, suppressed it. In this study, we investigated the effects of MC3 and MC4 receptor (MC3-R and MC4-R) selective agonists and antagonists on the release of thyrotropin-releasing hormone (TRH) from hypothalamic explants in vitro. alpha-MSH stimulated TRH release from the rat hypothalamic explants (alpha-MSH 100 nm 230 +/- 22.9% basal, P < 0.005). In contrast, gamma 2-MSH, a selective MC3-R agonist, suppressed TRH release (gamma 2-MSH 10 microns 76.2 +/- 7.4% basal, P < 0.05). AgRP (83-132), a nonselective MC3/4-R antagonist, induced no change in TRH release whilst JKC-363 (cyclic [Mpr11, D-Nal14, Cys18, Asp22-NH2]-beta-MSH 11-22), a selective MC4-R antagonist, suppressed it (JKC-363 10 nm 57.2 +/- 11.5% basal, P < 0.05). Both AgRP (83-132) and JKC-363 blocked alpha-MSH stimulated TRH release but only AgRP (83-132) blocked the inhibitory effect of gamma 2-MSH on TRH release. These data suggest differential roles for the MC3 and MC4 receptors in TRH release; MC3-R agonism inhibiting and MC4-R agonism stimulating TRH release.
Kim
M S
MS
Endocrine Unit, Department of Metabolic Medicine, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK.
Small
C J
CJ
Russell
S H
SH
Morgan
D G A
DG
Abbott
C R
CR
alAhmed
S H
SH
Hay
D L
DL
Ghatei
M A
MA
Smith
D M
DM
Bloom
S R
SR
D054369:Agouti-Related Protein; D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D002460:Cell Line; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D007457:Iodine Radioisotopes; D007668:Kidney / Q000166:cytology; D008024:Ligands; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000378:metabolism*; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism*; D000521:alpha-MSH / Q000378:metabolism / Q000494:pharmacology; D019825:gamma-MSH / Q000378:metabolism / Q000494:pharmacology
D054369:Agouti-Related Protein; D007457:Iodine Radioisotopes; D008024:Ligands; D010446:Peptide Fragments; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; C430443:agouti-related protein (86-132), human; D019825:gamma-MSH; D000521:alpha-MSH; D013973:Thyrotropin-Releasing Hormone