title: Aminoprocalcitonin-mediated suppression of feeding involves the hypothalamic melanocortin system.
abstract: Aminoprocalcitonin (N-PCT), a neuroendocrine peptide encoded by the calcitonin-I (CALC-I) gene, suppresses food intake when administered centrally in rats. However, the neural pathways underlying this effect remain unclear. N-PCT and calcitonin receptors (CT-R) have been identified in hypothalamic regions involved in energy homeostasis, including the arcuate nucleus (ARC). Here, we hypothesized an involvement of the hypothalamic ARC in mediating the anorexic effects of central N-PCT based on its content of peptidergic neurons involved in feeding and its expression of N-PCT and CT-R. Fasting strongly reduced expression of the N-PCT precursor gene CALC-I in the ARC, and central immunoneutralization of endogenous N-PCT increased food intake. Intracerebroventricular administration of N-PCT reduced food intake in fed and fasted rats, and its effect was attenuated by a neutralizing anti-N-PCT antibody. Immunohistochemistry for N-PCT showed that it is expressed in astrocytes and neurons in the ARC and is colocalized with anorexigenic proopiomelanocortin (POMC) neurons. Fasting reduced coexpression of N-PCT and POMC, and N-PCT administration activated hypothalamic neurons, including rostral POMC neurons. We also found that N-PCT stimulates POMC mRNA expression in fed and fasted rats, whereas it reduced the expression of orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP) only in fasted rats in which those mRNAs are normally elevated. Finally, we showed that the melanocortin-3/4 receptor antagonist SHU 9119 attenuates the intake-suppressive effect of N-PCT. These data demonstrate that hypothalamic N-PCT is involved in control of energy balance and that its anorexigenic effects are mediated through the melanocortin system.
authors.affiliation: Unidad de Farmacología Experimental y Clínica, Hospital Universitario de Valme, Seville, Spain; and.
authors.forename: Eva
authors.initials: E
authors.lastname: Tavares
authors.forename: Rosario
authors.initials: R
authors.lastname: Maldonado
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Miñano
mesh_terms: D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000855:Anorexia / Q000378:metabolism / Q000503:physiopathology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001111:Arcuate Nucleus of Hypothalamus / Q000502:physiology*; D002116:Calcitonin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide; D004435:Eating / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D005247:Feeding Behavior / Q000502:physiology*; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044101:Receptors, Melanocortin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C515197:AGRP protein, rat; D054369:Agouti-Related Protein; D057134:Antibodies, Neutralizing; C000606591:Calca protein, rat; D009478:Neuropeptide Y; D011498:Protein Precursors; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D044101:Receptors, Melanocortin; C514973:melanocortin 3 receptor, rat; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide
keywords: aminoprocalcitonin; arcuate nucleus; food intake; melanocortin system; neuropeptide Y; proopiomelanocortin