Moderate Long-Term Modulation of Neuropeptide Y in Hypothalamic Arcuate Nucleus Induces Energy Balance Alterations in Adult Rats

PLOS ONE, Jul 2011

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.

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Moderate Long-Term Modulation of Neuropeptide Y in Hypothalamic Arcuate Nucleus Induces Energy Balance Alterations in Adult Rats

et al. (2011) Moderate Long-Term Modulation of Neuropeptide Y in Hypothalamic Arcuate Nucleus Induces Energy Balance Alterations in Adult Rats. PLoS ONE 6(7): e22333. doi:10.1371/journal.pone.0022333 Moderate Long-Term Modulation of Neuropeptide Y in Hypothalamic Arcuate Nucleus Induces Energy Balance Alterations in Adult Rats Lgia Sousa-Ferreira 0 Manuel Garrido 0 Isabel Nascimento-Ferreira 0 Cle vio Nobrega 0 Ana Santos- Carvalho 0 Ana Rita A lvaro 0 Joana Rosmaninho-Salgado 0 Manuella Kaster 0 Sebastian Ku gler 0 Lus 0 Pereira de Almeida 0 Claudia Cavadas 0 Daniel Tome, Paris Institute of Technology for Life, Food and Environmental Sciences, France 0 1 Center for Neuroscience and Cell Biology, University of Coimbra , Coimbra , Portugal , 2 Department of Neurology, Viral Vectors Laboratory, University Medicine Go ttingen , Go ttingen, Germany , 3 Department of Biology and Environment, University of Tra s-os-Montes and Alto Douro, Vila Real, Portugal, 4 Faculty of Pharmacy, University of Coimbra , Coimbra , Portugal 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 fastinginduced 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. - Funding: This work was supported by the Portuguese Foundation for Science and Technology, FEDER and COMPETE [PTDC/SAU-FCF/099082/2008; PTDC/SAUFCF/70384/2006; PTDC/SAU/NEU/73119/2006; SFRH/BD/30608/2006; SFRH/BD/29479/2006; SFRH/BPD/62945/2009; SFRH/BD/45311/2008, SFRH/BPD/49079/2008; SFRH/BPD/46086/2008; SFRH/BPD/31547/2006]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Obesity and overweight are an increasing health problem associated with the risk to develop life threatening conditions such as diabetes, cardiovascular disease and cancer. The main cause of obesity in the western society is the elevated consumption of high caloric aliments and beverages, as well as decreased physical activity. Food intake and body weight gain are centrally regulated by the hypothalamus, where arcuate nucleus (ARC) neurons have a key role sensing and integrating peripheral signals of nutrition to downstream circuits [1,2]. ARC neurons are divided into two distinct populations acting together to regulate feeding behavior: the orexigenic NPY/AGRP (Neuropeptide Y/Agouti-Related Protein) neurons and the anorexigenic POMC/CART (ProOpioMelanocortin/Cocaine-and-Amphetamine-Regulated-Transcript) neurons. Most of the hypothalamic NPY-expressing neurons are located in the ARC and project to different areas of the hypothalamus, including the paraventricular nucleus (PVN), dorsomedial hypothalamus (DMH), ventromedial hypothalamus (VMH) and lateral hypothalamic area (LH) [3]. Other sources contribute to the hypothalamic levels of NPY, such as a moderate number of NPYexpressing neurons in the DMH [4,5]. NPY receptors are widely distributed in hypothalamic nuclei and, in particular those receiving NPY projections [6,7]. Within the hypothalamus, NPY acts on down-stream target neurons, including neurons in the PVN and LH, to produce feeding response [6,8,9]. In physiological conditions, NPY neurons located in the ARC are controlled by multiple neural and peripheral signals. These signals includ (...truncated)


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Lígia Sousa-Ferreira, Manuel Garrido, Isabel Nascimento-Ferreira, Clévio Nobrega, Ana Santos-Carvalho, Ana Rita Álvaro, Joana Rosmaninho-Salgado, Manuella Kaster, Sebastian Kügler, Luís Pereira de Almeida, Claudia Cavadas. Moderate Long-Term Modulation of Neuropeptide Y in Hypothalamic Arcuate Nucleus Induces Energy Balance Alterations in Adult Rats, PLOS ONE, 2011, Volume 6, Issue 7, DOI: 10.1371/journal.pone.0022333