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Molecular Cloning, Pharmacological Characterization, and Brain Mapping of the Melanocortin 4 Receptor in the Goldfish: Involvement in the Control of Food Intake

Department of Biological Sciences (J.M.C.-R., R.E.P.), University of Alberta, Edmonton, Alberta, T6G 2E9 Canada; and Department of Neuroscience (A.R., H.B.S.), Unit of Pharmacology, Uppsala University, SE 751 24 Uppsala, Sweden

Address all correspondence and requests for reprints to: Dr. J. M. Cerdá-Reverter, Department of Fish Reproductive Physiology, Instituto de Acuicultura de Torre de la Sal, 12595 Torre de la Sal, Ribera de Cabanes, Castellón, Spain. E-mail: cerdarev{at}iats.csic.es.

We report cloning, pharmacological characterization, tissue distribution, detailed brain mapping, and role in control of food intake of melanocortin 4 receptor in goldfish (gMC4R). The gMC4R protein has 68% identity with the human ortholog and is conserved in important functional domains. Pharmacological profiling showed similar affinities and potency order to hMC4R for MSH peptides, whereas MTII and HS024 were identified as high-affinity agonist and antagonist analogs, respectively. The gMC4R-mRNA was found in brain and some peripheral tissues including the ovary, gill, and spleen. Detailed MC4R-mRNA mapping showed expression in main neuroendocrine and food intake-controlling areas. High expression levels were found in the telencephalon, preoptic area, ventral thalamus, tuberal hypothalamus, and hypothalamic inferior lobe. By RT-PCR, low levels were also detected in the cerebellum, medulla, and spinal cord. Intracerebroventricular MTII administration inhibited food intake in 24-h fasted animals in a dose-dependent manner, whereas HS024 stimulated food intake in fed animals, suggesting that melanocortins exert a tonic inhibitory effect on food intake, which is mediated through central MC4R signaling. The conserved central expression pattern and physiological role in regulation of food intake for the MC4R suggests that neuronal pathways of the melanocortin system may be important for regulation of energy homeostasis in most vertebrates.

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