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

Sousa-Ferreira, Lígia; Garrido, M.; Nascimento-Ferreira, Isabel; Nóbrega, Clévio; Santos-Carvalho, Ana; Álvaro, Ana Rita; Rosmaninho‐Salgado, Joana; Kaster, Manuella P.; Kügler, Sebastian; Almeida, Luís Pereira de

doi:10.1371/journal.pone.0022333

Cited by 47 publications

(42 citation statements)

References 95 publications

(127 reference statements)

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“…The NPY serum levels observed in our normal rats are similar to those found in other studies in rats (32) and slightly higher than those observed in humans (35,36). We propose that the decrease in serum NPY levels observed in BDL rats may be due to reduced secretion of NPY by the neural tissue of the central and peripheral nervous system (38).…”

Section: Discussionsupporting

confidence: 89%

Neuropeptide Y inhibits biliary hyperplasia of cholestatic rats by paracrine and autocrine mechanisms

DeMorrow

Meng

Venter

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Biliary homeostasis is regulated by several factors through autocrine/paracrine signaling. NPY inhibits cholangiocarcinoma growth; however, no information exists regarding the autocrine/paracrine role of NPY on biliary hyperplasia during cholestasis. The aims of this study were to determine: 1) the expression of NPY and Y 1-Y5 in cholangiocytes and 2) the paracrine/autocrine effects of NPY on cholangiocyte proliferation. Normal or bile duct ligation (BDL) rats were treated with NPY, neutralizing anti-NPY antibody, or vehicle for 7 days. NPY and NPY receptor (NPYR) expression was assessed in liver sections and isolated cholangiocytes. NPY secretion was assessed in serum and bile from normal and BDL rats, as well as supernatants from normal and BDL cholangiocytes and normal rat cholangiocyte cell line [intrahepatic normal cholangiocyte culture (NRICC)]. We evaluated intrahepatic bile ductal mass (IBDM) in liver sections and proliferation in cholangiocytes. With the use of NRICC, the effects of NPY or anti-NPY antibody on cholangiocyte proliferation were determined. The expression of NPY and all NPYR were increased after BDL. NPY levels were lower in serum and cholangiocyte supernatant from BDL compared with normal rats. NPY secretion from NRICC was detected at both the basolateral and apical domains. Chronic NPY treatment decreased proliferating cellular nuclear antigen (PCNA) expression and IBDM in BDL rats. Administration of anti-NPY antibody to BDL rats increased cholangiocyte proliferation and IBDM. NPY treatment of NRICC decreased PCNA expression and increased the cell cycle arrest, whereas treatment with anti-NPY antibody increased proliferation. Therapies targeting NPY-mediated signaling may prove beneficial for the treatment of cholangiopathies. biliary epithelium; neurotransmitters; proliferation; cell cycle CHOLANGIOCYTES ARE THE TARGET cells in cholangiopathies such as primary biliary cirrhosis and primary sclerosing cholangitis (4).During the course of these diseases and in many other forms of liver injury, a balance between cholangiocyte proliferation and loss is critical for the maintenance of the homeostasis of biliary mass (4). Effort has gone into identifying the factors regulating biliary loss/proliferation to identify potential therapeutic targets for the maintenance of biliary mass during liver diseases.Biliary mass is coordinately regulated by a number of growth factors and hormones during normal and cholestatic states by both autocrine and paracrine signaling (5, 12, 13, 23, 28). After bile duct ligation (BDL), cholangiocytes secrete increased amounts of growth factors such as vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) stimulating biliary proliferation (12, 13). Conversely, proliferating cholangiocytes secrete increased amounts of serotonin (23) and melatonin (28) that inhibit cholangiocyte proliferation. Serotonin and melatonin may be secreted by cholangiocytes to prevent overt biliary proliferation in response to cholestasis.Neuropeptide Y (NPY) is a neurotransm...

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Section: Discussionsupporting

confidence: 89%

Neuropeptide Y inhibits biliary hyperplasia of cholestatic rats by paracrine and autocrine mechanisms

DeMorrow

Meng

Venter

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…To evaluate the effect of NPY on hypothalamic autophagy modulation in vivo, NPY was overexpressed in hypothalamic arcuate nucleus (ARC) by gene transfer using adeno-associated viral vectors (AAV), in male C57BL/6 mice. Mice were injected with AAV encoding either GFP (AAV-GFP, control group) or NPY (AAV-NPY), under a neuronal-specific promoter (36), by bilateral stereotaxic injection in each ARC. After 4 wk, hypothalamic NPYoverexpressing mice (AAV-NPY mice) brains displayed a stronger, widespread expression of NPY through the several hypothalamic areas, but still more pronounced in the ARC (Fig.…”

Section: Significancementioning

confidence: 99%

“…7B, we observed an increase of ∼70% of NPY immunoreactivity in the ARC in hypothalamic NPY-overexpressing mice compared with control mice (AAV-GFP; 172.5 ± 21.6% of control). We and others previously reported that hypothalamic NPY overexpression led to hyperphagia, increased body weight gain, and several serum alterations, consistent with obesity phenotypes, such as high glucose and high cholesterol (36). To avoid this type of effect that could potentially influence autophagy regulation (37,38), hypothalamic NPY-overexpressing mice were pair-fed, by giving the same daily amount of food that AAV-GFP mice consumed.…”

Section: Significancementioning

confidence: 99%

Neuropeptide Y stimulates autophagy in hypothalamic neurons

Aveleira

Botelho

Carmo‐Silva

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Aging is characterized by autophagy impairment that contributes to age-related disease aggravation. Moreover, it was described that the hypothalamus is a critical brain area for whole-body aging development and has impact on lifespan. Neuropeptide Y (NPY) is one of the major neuropeptides present in the hypothalamus, and it has been shown that, in aged animals, the hypothalamic NPY levels decrease. Because caloric restriction (CR) delays aging, at least in part, by stimulating autophagy, and also increases hypothalamic NPY levels, we hypothesized that NPY could have a relevant role on autophagy modulation in the hypothalamus. Therefore, the aim of this study was to investigate the role of NPY on autophagy in the hypothalamus. Using both hypothalamic neuronal in vitro models and mice overexpressing NPY in the hypothalamus, we observed that NPY stimulates autophagy in the hypothalamus. Mechanistically, in rodent hypothalamic neurons, NPY increases autophagy through the activation of NPY Y 1 and Y 5 receptors, and this effect is tightly associated with the concerted activation of PI3K, MEK/ERK, and PKA signaling pathways. Modulation of hypothalamic NPY levels may be considered a potential strategy to produce protective effects against hypothalamic impairments associated with age and to delay aging.ging is associated with accumulation of specific cellular proteins within neurons, a pathologic hallmark of many neurodegenerative diseases. Because average human life expectancy has increased, but also the prevalence of cognitive decline and dementia, aging research is now focused in finding strategies that increase both lifespan and healthspan.Autophagy is a highly regulated intracellular process involved in the turnover of most cellular constituents and in the maintenance of cellular homeostasis (1, 2). It is well described that basal autophagic activity decreases with age, contributing to the accumulation of altered macromolecules (3). In addition, autophagy impairment contributes to different aspects of aging phenotype and to aggravation of age-related diseases (4).Caloric restriction (CR), the reduced intake of calories without malnutrition, extends lifespan of many organisms, from yeast to mammals, and delays the progression of age-related diseases, at least in part, by stimulating autophagy (5-8). One major neuroendocrine effect of CR is the increase of neuropeptide Y (NPY) in the hypothalamus (9-12). The hypothalamus has a key role in the control of body homeostasis, neuroendocrine outputs, and feeding behavior. Recently, it was described that this brain area is critical for the development of whole-body aging and has impact on lifespan (13,14). In the hypothalamus, NPY is involved in the regulation of different physiological functions, such as regulation of food intake, body temperature, circadian rhythms, memory processing, and cognition (15-19). These diverse actions of NPY are mediated by G protein-coupled receptor subtypes named NPY Y 1 , Y 2 , Y 4 , and/or Y 5 (20, 21), all of which have been reported to be...

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“…It also regulates TRH directly and indirectly: directly by opposing ␣-MSH activation of CREB signaling in TRH neurons and reducing pro-TRH processing by PC2, and indirectly by reducing the production and release of ARC ␣-MSH. We focus on ARC-derived NPY because NPY is produced most abundantly in the ARC (19,41); these neurons innervate the PVN (3) and POMC neurons (6,8,9), and ARC NPY has well-documented effects on food intake and body weight (64). NPY derived from other neurons could have the same influence on POMC and TRH, which merits future investigation.…”

Section: E647 Npy Regulates Pomc Processingmentioning

confidence: 99%

“…A recent study revealed the importance of ARC NPY in regulating energy balance, as moderate manipulation of NPY specifically in the ARC altered food intake and promoted positive energy balance (64). NPY neurons within the ARC innervate hypothalamic neurons involved in energy balance control, including cells in the PVN that produce the anorectic thyrotropin-releasing hormone (TRH) as well as cells within the ARC that produce the anorectic ␣-melanocyte-stimulating hormone (␣-MSH) (3,6,8,9).…”

mentioning

confidence: 99%

Mechanisms by which the orexigen NPY regulates anorexigenic α-MSH and TRH

Cyr

Toorie

Steger

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Cyr NE, Toorie AM, Steger JS, Sochat MM, Hyner S, Perello M, Stuart R, Nillni EA. Mechanisms by which the orexigen NPY regulates anorexigenic ␣-MSH and TRH. Am J Physiol Endocrinol Metab 67: E640 -E650, 2013. First published January 15, 2013; doi:10.1152/ajpendo.00448.2012.-Protein posttranslational processing is a cellular mechanism fundamental to the generation of bioactive peptides, including the anorectic ␣-melanocyte-stimulating hormone (␣-MSH) and thyrotropin-releasing hormone (TRH) peptides produced in the hypothalamic arcuate (ARC) and paraventricular (PVN) nuclei, respectively. Neuropeptide Y (NPY) promotes positive energy balance in part by suppressing ␣-MSH and TRH. The mechanism by which NPY regulates ␣-MSH output, however, is not well understood. Our results reveal that NPY inhibited the posttranslational processing of ␣-MSH's inactive precursor proopiomelanocortin (POMC) by decreasing the prohormone convertase-2 (PC2). We also found that early growth response protein-1 (Egr-1) and NPY-Y1 receptors mediated the NPY-induced decrease in PC2. NPY given intra-PVN also decreased PC2 in PVN samples, suggesting a reduction in PC2-mediated pro-TRH processing. In addition, NPY attenuated the ␣-MSH-induced increase in TRH production by two mechanisms. First, NPY decreased ␣-MSH-induced CREB phosphorylation, which normally enhances TRH transcription. Second, NPY decreased the amount of ␣-MSH in the PVN. Collectively, these results underscore the significance of the interaction between NPY and ␣-MSH in the central regulation of energy balance and indicate that posttranslational processing is a mechanism that plays a specific role in this interaction.␣-melanocyte-stimulating hormone; early growth response protein-1; neuropeptide Y; proopiomelanocortin; thyrotropin-releasing hormone OBESITY IS A MAJOR HEALTH and socioeconomic concern that has reached epidemic proportions in developed nations. Despite efforts to abate the problem, cases of obesity continue to rise. Thus, it is imperative to better understand the physiological mechanisms controlling food intake and body weight.Neuropeptide Y (NPY) is a potent orexigen that has received attention as an antiobesity drug target (69). NPY is produced both centrally and peripherally. Although it is widely distributed throughout the brain, in situ hybridization studies reveal that NPY is most densely localized to the hypothalamic arcuate nucleus (ARC) (19,41). Hypothalamic NPY plays an important role in energy balance and responds to changes in energy status. For example, NPY increases during food deprivation and returns to baseline levels following refeeding in the hypothalamic ARC and paraventricular nucleus (PVN) (1, 2, 29).Hypothalamic NPY also responds to changes in energy status signals, as it decreases with elevated leptin or insulin levels and increases with elevated ghrelin, growth hormone, or glucocorticoid levels (69). In addition, rodent models of genetic obesity including the fa/fa Zucker rat as well as db/db and ob/ob mice demonstrate increased hypothalamic...

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

Cited by 47 publications

References 95 publications

Neuropeptide Y inhibits biliary hyperplasia of cholestatic rats by paracrine and autocrine mechanisms

Neuropeptide Y inhibits biliary hyperplasia of cholestatic rats by paracrine and autocrine mechanisms

Neuropeptide Y stimulates autophagy in hypothalamic neurons

Mechanisms by which the orexigen NPY regulates anorexigenic α-MSH and TRH

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