RESUMEN
NOR1, Nur77 and Nurr1 are orphan nuclear receptors and members of the NR4A subfamily. Here, we report that the expression of hypothalamic NOR1 was remarkably decreased in mildly obese beta-endorphin-deficient mice and obese db/db mice with the leptin receptor mutation, compared with age-matched wild-type mice, whereas there were no genotypic differences in the expression of hypothalamic Nur77 or Nurr1 in these animals. The injection of NOR1 siRNA oligonucleotide into the third cerebral ventricle significantly suppressed food intake and body weight in mice. On the other hand, the decreases in hypothalamic NOR1 expression were not found in non-obese 5-HT2C receptor-deficient mice. Moreover, systemic administration of m-chlorophenylpiperazine (mCPP), a 5-HT2C/1B receptor agonist, had no effect on hypothalamic NOR1 expression, while suppressing food intake in beta-endorphin-deficient mice. These findings suggest that 5-HT2C receptor-independent proopiomelanocortin-derived peptides regulate the expression of hypothalamic NOR1, which is a novel modulator of feeding behavior and energy balance.
Asunto(s)
Proteínas de Unión al ADN/biosíntesis , Hiperfagia/metabolismo , Hipotálamo/metabolismo , Proteínas del Tejido Nervioso/biosíntesis , Proopiomelanocortina/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Receptores de Esteroides/biosíntesis , Receptores de Hormona Tiroidea/biosíntesis , Animales , Proteínas de Unión al ADN/genética , Ingestión de Alimentos , Metabolismo Energético , Hiperfagia/genética , Masculino , Ratones , Ratones Mutantes , Proteínas del Tejido Nervioso/genética , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Piperazinas/farmacología , ARN Interferente Pequeño/genética , Receptor de Serotonina 5-HT2C/genética , Receptores de Esteroides/genética , Receptores de Hormona Tiroidea/genética , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/farmacología , Factores de Transcripción/biosíntesis , betaendorfina/deficiencia , betaendorfina/genéticaRESUMEN
Serotonin (5-hydroxytryptamine; 5-HT) 2C receptors and the downstream melanocortin pathway are suggested to mediate the anorexic effects of m-chlorophenylpiperazine (mCPP) and fenfluramine. We previously reported that fluvoxamine, a selective serotonin reuptake inhibitor, together with pharmacological inactivation of 5-HT2C receptors exert feeding suppression through activation of 5-HT1B receptors in mice. Here, we report that fluvoxamine exerted anorexic effects in 5-HT2C receptor mutant mice with heterozygous mutation of beta-endorphin gene (2CREnd mice), whereas fluvoxamine had no effect on food intake in age-matched wild-type mice and 5-HT2C receptor mutant mice, which are associated with decreases in hypothalamic proopiomelanocortin (POMC) expression. mCPP suppressed food intake in 5-HT2C receptor mutant mice, 2CREnd mice and age-matched wild-type mice. These results suggest that fluvoxamine-induced feeding suppression requires a perturbation of 5-HT2C receptor and beta-endorphin signalling plus functional hypothalamic POMC activity, whereas mCPP-induced feeding suppression does not always require functional 5-HT2C receptor, beta-endorphin, and POMC activity in mice.