Adrenomedullin inhibits feeding in the rat by a mechanism involving calcitonin gene-related peptide receptors.
The central effect of adrenomedullin on feeding was investigated in fasted rats. After intracerebroventricular administration, adrenomedullin decreased 2-h food intake in a dose-dependent manner. A dose of 1.7 nmol adrenomedullin decreased 2-h food intake by 57%. Adrenomedullin shares sequence homology with calcitonin gene-related peptide (CGRP), a central anorectic agent, and binding sites for both are present in the hypothalamus. Adrenomedullin competed for [125I]adrenomedullin- and [125I]CGRP-binding sites in hypothalamic membranes. The Kd for the [125I]adrenomedullin-binding site was 0.54 +/- 0.07 nM, with a binding capacity of 214 +/- 27 fmol/mg membrane protein (n = 3). CGRP and the CGRP receptor antagonist CGRP-(8-37) at concentrations up to 1 microM did not compete at these sites. The Kd for the CGRP-binding site was 0.10 +/- 0.02 nM, with a binding capacity of 250 +/- 31 fmol/mg, and the Ki values for adrenomedullin and CGRP-(8-37) were 4.6 +/- 2.1 and 4.0 +/- 1.6 nM, respectively (n = 3). Thus, adrenomedullin showed high affinity binding at both adrenomedullin- and CGRP-binding sites. To establish whether adrenomedullin reduces feeding via CGRP receptors, we coadministered adrenomedullin (1.7 nmol) and CGRP-(8-37) (30 nmol). The reduction in 2-h food intake induced by adrenomedullin was 50% inhibited by CGRP-(8-37). These results show that adrenomedullin decreases food intake in the rat, and this effect is mediated at least in part via CGRP receptors.
Taylor
G M
GM
Division of Endocrinology and Metabolic Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
Meeran
K
K
O'Shea
D
D
Smith
D M
DM
Ghatei
M A
MA
Bloom
S R
SR
D053607:Adrenomedullin; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001667:Binding, Competitive; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000502:physiology*
D000959:Antihypertensive Agents; D010446:Peptide Fragments; D010455:Peptides; D018015:Receptors, Calcitonin Gene-Related Peptide; C058636:calcitonin gene-related peptide (8-37); D053607:Adrenomedullin; D015740:Calcitonin Gene-Related Peptide