title: Moderate long-term modulation of neuropeptide Y in hypothalamic arcuate nucleus induces energy balance alterations in adult rats.
abstract: Neuropeptide Y (NPY) produced by arcuate nucleus (ARC) neurons has a strong orexigenic effect on target neurons. Hypothalamic NPY levels undergo wide-ranging oscillations during the circadian cycle and in response to fasting and peripheral hormones (from 0.25 to 10-fold change). The aim of the present study was to evaluate the impact of a moderate long-term modulation of NPY within the ARC neurons on food consumption, body weight gain and hypothalamic neuropeptides. We achieved a physiological overexpression (3.6-fold increase) and down-regulation (0.5-fold decrease) of NPY in the rat ARC by injection of AAV vectors expressing NPY and synthetic microRNA that target the NPY, respectively. Our work shows that a moderate overexpression of NPY was sufficient to induce diurnal over-feeding, sustained body weight gain and severe obesity in adult rats. Additionally, the circulating levels of leptin were elevated but the immunoreactivity (ir) of ARC neuropeptides was not in accordance (POMC-ir was unchanged and AGRP-ir increased), suggesting a disruption in the ability of ARC neurons to response to peripheral metabolic alterations. Furthermore, a dysfunction in adipocytes phenotype was observed in these obese rats. In addition, moderate down-regulation of NPY did not affect basal feeding or normal body weight gain but the response to food deprivation was compromised since fasting-induced hyperphagia was inhibited and fasting-induced decrease in locomotor activity was absent.These results highlight the importance of the physiological ARC NPY levels oscillations on feeding regulation, fasting response and body weight preservation, and are important for the design of therapeutic interventions for obesity that include the NPY.
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Lígia
authors.initials: L
authors.lastname: Sousa-Ferreira
authors.forename: Manuel
authors.initials: M
authors.lastname: Garrido
authors.forename: Isabel
authors.initials: I
authors.lastname: Nascimento-Ferreira
authors.forename: Clévio
authors.initials: C
authors.lastname: Nobrega
authors.forename: Ana
authors.initials: A
authors.lastname: Santos-Carvalho
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Alvaro
authors.forename: Joana
authors.initials: J
authors.lastname: Rosmaninho-Salgado
authors.forename: Manuella
authors.initials: M
authors.lastname: Kaster
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kügler
authors.forename: Luís Pereira
authors.initials: LP
authors.lastname: de Almeida
authors.forename: Claudia
authors.initials: C
authors.lastname: Cavadas
mesh_terms: D017667:Adipocytes / Q000166:cytology; D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D048429:Cell Size; D000229:Dependovirus / Q000235:genetics; D015536:Down-Regulation; D004435:Eating / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D005215:Fasting / Q000378:metabolism; D025461:Feedback, Physiological; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D006963:Hyperphagia / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D009478:Neuropeptide Y / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000097:blood; D047495:PPAR gamma / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015430:Weight Gain / Q000235:genetics
chemical_list: D035683:MicroRNAs; D009478:Neuropeptide Y; D047495:PPAR gamma