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 [I-125]adrenomedullin- and [(125)]CGRP-binding sites in hypothalamic membranes. The K-d for the [I-125]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 mu M did not compete at these sites. The K-d for the CGRP-binding site was 0.10 +/- 0.02 nM, with a binding capacity of 259 +/- 31 fmol/mg, and the K-i 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.