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This Article Full Text Full Text (PDF) All Versions of this Article: 296/5/R1293    most recent 90948.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sánchez, E. Articles by Cerdá-Reverter, J. M. Search for Related Content PubMed PubMed Citation Articles by Sánchez, E. Articles by Cerdá-Reverter, J. M.

APPETITE, OBESITY, AND DIGESTION

Phosphodiesterase inhibitor-dependent inverse agonism of agouti-related protein on melanocortin 4 receptor in sea bass (Dicentrarchus labrax)

¹Department of Fish Physiology and Biotechnology, Instituto de Acuicultura de Torre de la Sal, Ribera de Cabanes, Castellón, Spain; ²Department of Chemistry, University of California, Santa Cruz, California; and ³Department of Organismal Animal Physiology, Institute for Water and Wetland Research, Radboud University Nijmegen, Nijmegen, The Netherlands

Submitted 21 November 2008 ; accepted in final form 14 February 2009

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor mainly expressed in the central nervous system of vertebrates. Activation of the MC4R leads to a decrease in food intake, whereas inactivating mutations are a genetic cause of obesity. The binding of agouti-related protein (AGRP) reduces not only agonist-stimulated cAMP production (competitive antagonist) but also the basal activity of the receptor, as an inverse agonist. Transgenic zebrafish overexpressing AGRP display increased food intake and linear growth, indicative of a physiological role for the melanocortin system in the control of the energy balance in fish. We report on the cloning, pharmacological characterization, tissue distribution, and detailed brain mapping of a sea bass (Dicentrarchus labrax) MC4R ortholog. Sea bass MC4R is profusely expressed within food intake-controlling pathways of the fish brain. However, the activity of the melanocortin system during progressive fasting does not depend on the hypothalamic/pituitary proopiomelanocortin (POMC) and MC4R expression, which suggests that sea bass MC4R is constitutively activated and regulated by AGRP binding. We demonstrate that AGRP acts as competitive antagonist and reduces MTII-induced cAMP production. AGRP also decreases the basal activity of the receptor as an inverse agonist. This observation suggests that MC4R is constitutively active and supports the evolutionary conservation of the AGRP/MC4R interactions. The inverse agonism, but not the competitive antagonism, depends on the presence of a phosphodiesterase inhibitor (IBMX). This suggests that inverse agonism and competitive antagonism operate through different intracellular signaling pathways, a view that opens up new targets for the treatment of melanocortin-induced metabolic syndrome.

melanocyte-stimulating hormone; proopiomelanocortin; constitutive activity; 3-isobutyl-1-methylxanthine; obesity