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Significance Autophagy impairment is a major hallmark of aging, and any intervention that enhances autophagy is of potential interest to delay aging. However, it was described that the hypothalamus is a brain area with a key role on whole-body aging. In the present study, we show that an endogenous molecule produced by the hypothalamus, the neuropeptide Y (NPY), stimulates autophagy in rodent hypothalamus. Because both hypothalamic autophagy and NPY levels decrease with age, a better understanding of hypothalamic neuronal autophagy regulation by NPY may provide new putative therapeutic strategies to ameliorate age-related deteriorations and delay aging.
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... Our findings correlate with previous studies suggesting the involvement of the NPY system in the aging process, particularly in the brain of mammals [36], and in association with neurodegenerative diseases through the activation of several mechanisms [7]. Cui and colleagues [28] reported that NPY was downregulated by aging in multiple brain regions, such as the cortex, hypothalamus, striatum, and spinal cord, while Michalkiewicz [8] showed improved resistance to stress exerted by the positive modulation of hemodynamic parameters and increased mean lifespan in transgenic rats overexpressing NPY [8] probably due to the modulation of the autophagy cascade in the CNS [37,38]. During caloric restriction, NPY levels increase in the hypothalamus, suggesting a role of NPY in autophagy modulation in hypothalamic neurons but also on whole-body aging (37). ...
... Cui and colleagues [28] reported that NPY was downregulated by aging in multiple brain regions, such as the cortex, hypothalamus, striatum, and spinal cord, while Michalkiewicz [8] showed improved resistance to stress exerted by the positive modulation of hemodynamic parameters and increased mean lifespan in transgenic rats overexpressing NPY [8] probably due to the modulation of the autophagy cascade in the CNS [37,38]. During caloric restriction, NPY levels increase in the hypothalamus, suggesting a role of NPY in autophagy modulation in hypothalamic neurons but also on whole-body aging (37). It has been shown that NPY receptor antagonists slowed the autophagic response to caloric restriction. ...
... It has been shown that NPY receptor antagonists slowed the autophagic response to caloric restriction. Moreover, NPY enhanced autophagy in rodent hypothalamic neurons by stimulating Y1 or Y5 receptors through the combined activation of different pathways including class I phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinase (ERK), and protein kinase A (PKA) [37]. ...
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NPY is among the most abundant neuropeptides in vertebrate brain and is primarily involved in the regulation of food intake. The NPY system is also associated with the aging process showing beneficial effects on neuronal survival via autophagy modulation. Here, we explore the age-related regulation of NPY in the brain and foregut of the shortest- and longest-lived fish species, Nothobranchius furzeri and Danio rerio, respectively. These two research models, despite some similarities, display profound biological differences making them attractive vertebrates to elucidate the mechanisms underlying the regulation of neuropeptide synthesis and function. It is noteworthy that in both fish species only Npya has been identified, while in the other teleosts two classes of NPY (Npya and Npyb) have been annotated. Our findings document that in both species: i) NPY is centrally regulated; ii) NPY levels increase in the brain during aging; iii) NPY is localized in the enteroendocrine cells as well as in the myenteric plexus and drastically decreases in old animals. According to our data, the age-related regulation in the gut resembles that described in other vertebrate species while the increased levels in the brain offer the unique possibility to explore the role of NPY in model organisms to develop future experimental and translatable approaches.
... Recently, it has been shown that NPY can modulate autophagy in hypothalamic neurons [31]. Autophagy is a bulk protein degradation process that functions as a cellular quality control system to remove damaged proteins or organelles [32], and it also regulates inflammasome [33] and innate immune responses [34,35]. ...
... Analysis at 24 h suggests a slight impairment of the p62/SQSTM1 autophagic degradation pathway by NPY. It should be recognized that our observations in human macrophages are inconsistent with the previous report showing that NPY enhances autophagic flux by stimulating the p62 degradation pathway in hypothalamic neurons [31]. Although the p62 accumulates in NPY-treated macrophages, the effect is reversed quickly, so that p62 levels were decreased below that observed in the untreated control cells at 36 h, thus suggesting NPY to exert a stimulatory effect on autophagosome formation in macrophages. ...
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Neuropeptide Y (NPY) is an abundantly expressed peptide capable of modulating innate and adaptive immune responses and regulating chemotaxis and cytokine secretion by macrophages. Abnormal regulation of NPY is involved in the development of atherosclerosis. The inflammatory infiltrate within atherosclerotic plaque is characterized by accumulation of macrophages, which are subject to reprogram their phenotypes in response to environmental signals. Macrophage number and phenotype influence plaque fate. Here, we investigated the effect of NPY on the changes in phenotype and functions of human macrophages, from the pro-inflammatory phenotype M1 to the reparative M2, indicative of atherosclerosis regression or stabilization. Human monocytes were differentiated in vitro into macrophages with M-CSF (M0) and polarized towards an M1 phenotype with IFN-γ plus LPS M(IFN-γ/LPS) or M2 with IL-10 (M IL-10) and further challenged with NPY (10−7–10−9 M) for 8–36 h. Cell phenotype and functions were analyzed by immunofluorescence and immunochemical analyses. NPY affected macrophage surface markers and secretome profile expression, thus shifting macrophages toward an M2-like phenotype. NPY also prevented the impairment of endocytosis triggered by the oxysterol 7-keto-cholesterol (7KC) and prevented 7KC-induced foam cell formation by reducing the lipid droplet accumulation in M0 macrophages. NPY-treated M0 macrophages enhanced the autophagosome formation by upregulating the cell content of the autophagy markers LC3-II and p62-SQSTM1, increased activation of the anti-oxidative transcription factor NRF2 (NF-E2-related factor 2), and subsequently induced its target gene HMOX1 that encodes heme oxygenase-1. Our findings indicate that NPY has a cytoprotective effect with respect to the progression of the inflammatory pathway, both enhancing p62/SQSTM1-dependent autophagy and the NRF2–antioxidant signaling pathway in macrophages. NPY signaling may have a crucial role in tissue homeostasis in host inflammatory responses through the regulation of macrophage balance and functions within atherosclerosis.
... Aveleira and collaborators showed that NPY not only induces autophagy, increasing the number of autophagosomes, but also increases autophagic flux in hypothalamic neurons [72,73]. In both hypothalamic neuronal in vitro models, rat hypothalamic neural cell primary cultures, and a mouse hypothalamic cell line, NPY1R (neuropeptide Y receptor Y1), NPY2R, or NPY5R antagonists were able to block autopha-gy induction. ...
... In both hypothalamic neuronal in vitro models, rat hypothalamic neural cell primary cultures, and a mouse hypothalamic cell line, NPY1R (neuropeptide Y receptor Y1), NPY2R, or NPY5R antagonists were able to block autopha-gy induction. Therefore, their results show that NPY induces autophagic flux through NPY1R and NPY5R activation, and this involves a concerted action of the PI3K, MAPK1/3, and PKA pathways [73]. ...
Article
Neuropeptide Y (NPY), a 36 amino acid peptide, is widely expressed in the mammalian brain. Changes in NPY levels in different brain regions and plasma have been described in several neurodegenerative diseases, including Alzheimer’s disease, Parkinson's disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, and Machado-Joseph disease. The changes in NPY levels may reflect the attempt to set up an endogenous neuroprotective mechanism to counteract the degenerative process. Accumulating evidence indicates that NPY can function as an anti- apoptotic, anti-inflammatory, and pro-phagocytic agent, which may be used effectively to halt or to slow down the progression of the disease. In this review, we will focus on the neuroprotective roles of NPY in several neuropathological conditions, with a particular focus on the anti- inflammatory properties of NPY.
... Neuropeptide Y (NPY) is an abundantly distributed neuropeptide in the mammalian brain and has been implicated in neuroprotection through inhibiting neuron death and excitotoxicity (Smialowska et al., 2009;Santos-Carvalho et al., 2013), increasing neuronal trophic support (Croce et al., 2013), stimulating the process of autophagy (Aveleira et al., 2015), and regulating transmission between cerebellar interneurons (Dubois et al., 2012). To date, five NPY receptors (NPY1R, NPY2R, NPY4R, NPY5R, and NPY6R) have been found in the mammalian brain; however, NPY6R has not been reported to be functional in the human brain (Diaz-delCastillo et al., 2018). ...
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Recently, NPY overexpression has been proposed to alleviate motor deficits and neuropathy in Machado-Joseph disease (MJD) mouse models, indicating its neuroprotective role in the pathogenesis of MJD. We aimed to evaluate the association between SNPs in NPY and its receptors and the susceptibility of MJD in the Chinese population. Moreover, we investigated whether these SNPs modulate the age at onset (AO) of MJD. In total, 527 MJD patients and 487 healthy controls were enrolled in the study, and four specific selected SNPs (rs16139, rs3037354, rs2234759, and rs11100494) in NPY and its receptor genes were genotyped. In this study, the genotypic frequency using the dominant model and the allelic distribution of rs11100494 in NPY5R revealed a significant difference between the MJD and control group during the first-stage analysis ( P = 0.048 and P = 0.024, respectively). After we expanded the sample size, significant differences were observed between the two groups using the dominant model in genotypic and allelic distribution ( P = 0.034, P = 0.046, and P = 0.016, respectively). No significant differences in genotypic and allelic distribution were found between the MJD and control groups for the other three SNPs. All selected SNPs had no significant effect on the AO of MJD. The association of rs11100494 in the NPY5R gene and susceptibility of MJD suggested that the NPY system might be implicated in the pathogenesis of MJD. Our study demonstrated the existence of other genetic modifiers in MJD, along with CAG expansion and known genetic modifier factors, which might lead to a better understanding of MJD pathogenesis.
... This NPY dependent stimulation of autophagy is mediated by NPY receptors Y1 and Y5 through the PI3K, MAPK/ERK and PKA pathways. NPY expres sion in the hypothalamus of aged mice is reduced [121]. The marked accumulation of p62 in POMC neurons indicates that these cells exhibit increased sensitivity to an age related decrease in autophagy, which in old mice leads to an increase in the hypothalamic level of POMC and a decrease in α MSH. ...
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The hypothalamus is the most important integrator of functions of the autonomous, endocrine, somatic nervous systems; it is involved in the regulation of rhythmic processes and systemic aging. Putative hypothalamic nuclei responsible for the implementation of the developmental program of aging include the suprachiasmatic nucleus and the median group of nuclei, including the arcuate, ventromedial, and dorsomedial nuclei. Hypothalamic aging is accompanied by an excitation-inhibition imbalance due to dysregulation of the GABAergic system, decreased frequency of neuronal firing, impaired calcium metabolism, elevated nitric oxide production, decreased autophagy, and disturbed intracellular signaling, in particular Sirt1, mTOR, NF κB, AMPK, P53, and FoxO. Also, an important role in hypothalamic aging belongs to specialized ependymal cells, tanycytes, as manifested in the disruption of tanycyte neuron relationships and impaired barrier function of these cells. Hypothalamic neural stem cells, located mainly in the region of the middle hypothalamic nuclei, secrete exosomal microRNA also responsible for anti aging effects of stem cells. The pool of hypothalamic neural stem cells, as well as microRNA production therein, decline with age.
... Autophagy is an important process for tissue homeostasis, and a loss of autophagy leads to neurodegeneration, even in the absence of any disease-associated mutant protein [78]. NPY can stimulate autophagy in mouse and rat hypothalamic neural cells by activating Y1R and Y5R [79]. Additionally, an A1-40 mouse model treated with exogenous NPY demonstrated reduced oxidative stress, and mitochondrial dysfunction, via blockade of NO production and reduced lipid peroxidation [80,81]. ...
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Neuropeptide Y (NPY), one of the most abundant neuropeptides in the body, is widely expressed in the central and peripheral nervous systems and acts on the cardiovascular, digestive, endocrine, and nervous systems. NPY affects the nutritional and inflammatory microenvironments through its interaction with immune cells, brain-derived trophic factor (BDNF), and angiogenesis promotion to maintain body homeostasis. Additionally, NPY has great potential for therapeutic applications against various diseases, especially as an adjuvant therapy for stem cells. In this review, we discuss the research progress regarding NPY, as well as the current evidence for the regulation of NPY in each microenvironment, and provide prospects for further research on related diseases.
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Neuropeptide Y (NPY), a sympathetic neurotransmitter, is involved in various physiological functions, and its dysregulation is implicated in several neurodegenerative diseases. Glutamate excitotoxicity, endoplasmic reticulum (ER) stress, and oxidative stress are the common mechanisms associated with numerous neurodegenerative illnesses. The present study aimed to elucidate the protective effects of NPY against glutamate toxicity and tunicamycin-induced ER stress in the human neuroblastoma SH-SY5Y cell line. We exposed the SH-SY5Y cells to glutamate and tunicamycin for two different time points and analyzed the protective effects of NPY at different concentrations. The protective effects of NPY treatments were assessed by cell viability assay, and the signalling pathway changes were evaluated by biochemical techniques such as Western blotting and immunofluorescence assays. Our results showed that treatment of SH-SY5Y cells with NPY significantly increased the viability of the cells in both glutamate toxicity and ER stress conditions. NPY treatments significantly attenuated the glutamate-induced pro-apoptotic activation of ERK1/2 and JNK/BAD pathways. The protective effects of NPY were further evident against tunicamycin-induced ER stress. NPY treatments significantly suppressed the ER stress activation by downregulating BiP, phospho-eIF2α, and CHOP expression. In addition, NPY alleviated the Akt/FoxO3a pathway in acute oxidative conditions caused by glutamate and tunicamycin in SH-SY5Y cells. Our results demonstrated that NPY is neuroprotective against glutamate-induced cell toxicity and tunicamycin-induced ER stress through anti-apoptotic actions.
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