Effects Of Neuropeptide Y Research Articles

Intracellular mechanisms coupled to NPY Y2 and Y5 receptor activation and lipid accumulation in murine adipocytes

The formation of adipose tissue is a process that includes the pre-adipocyte proliferation and differentiation to adipocytes that are cells specialized in lipid accumulation. The adipocyte differentiation is a process driven by the coordinated expression of various transcription factors, such as peroxisome proliferator-activated receptor (PPAR-γ). Neuropeptide Y (NPY) induces adipocyte proliferation and differentiation but the NPY receptors and the intracellular pathways involved in these processes are still not clear. In the present work we studied the role of NPY receptors and the intracellular pathways involved in the stimulatory effect of NPY on lipid accumulation. The murine pre-adipocyte cell line, 3T3-L1, was used as a cell model. Adipogenesis was evaluated by quantifying lipid accumulation by Oil red-O assay and by analyzing PPAR-γ expression using the Western blotting assay. Adipocytes were incubated with NPY (100nM) and a decrease on lipid accumulation and PPAR-γ expression was observed in the presence of NPY Y(2) receptor antagonist (BIIE0246, 1μM) or NPY Y(5) antagonist. Furthermore, NPY Y(2) (NPY(3-36), 100nM) or NPY Y(5) (NPY(19-23)(GLY(1), Ser(3), Gln(4), Thr(6), Ala(31), Aib(32), Gln(34)) PP, 100nM) receptor agonists increased lipid accumulation and PPAR-γ expression. We further investigate the intracellular pathways associated with NPY Y(2) and NPY Y(5) receptor activation. Our results show NPY induces PPAR-γ expression and lipid accumulation through NPY Y(2) and NPY Y(5) receptors activation. PKC and PLC inhibitors inhibit lipid accumulation induced by NPY Y(5) receptor agonist. Moreover, our results suggest that lipid accumulation induced by NPY Y(2) receptor activation occurs through PKA, MAPK and PI3K pathways. In conclusion, this study contributes to a step forward on the knowledge of intracellular mechanisms associated with NPY receptors activation on adipocytes and contributes to a better understanding and the development of new therapeutic targets for obesity treatment.

Stimulatory effects of neuropeptide Y on the growth of orange-spotted grouper (Epinephelus coioides)

Neuropeptide Y (NPY) is a member of the pancreatic polypeptide family which is a potent orexigenic peptide known to date in mammals and teleost. This study was carried out to investigate the effects of NPY on food intake and growth of orange-spotted grouper (Epinephelus coioides). Synthetic grouper NPY (gNPY) was given orally at the dose of 0.5, 1.0 and 2.0μg/g feed for 50days, results showed that NPY treatment (1.0 and 2.0μg/g feed) significantly increased growth rate, weight gain, feed conversion efficiency (FCE) and pituitary growth hormone (GH) mRNA level than the control group (p<0.05). Furthermore, high level secretion of gNPY was expressed and purified in the Pichia pastoris expression system. The bioactivity of recombinant gNPY was confirmed by its ability to up-regulate GH mRNA expression in vivo and in vitro and down-regulate preprosomatostatin I (PSSI) mRNA expression in vivo. These results demonstrate that NPY has stimulatory effects on food intake as well as growth of grouper as in other teleost fish, also indicate that recombinant gNPY from P. pastoris has the same bioactivity as synthetic gNPY and has the potential to be used as a feed additive for both research and aquatic application.

Structural and functional characterization of neuropeptide Y in a primitive teleost, the Japanese eel (Anguilla japonica)

In the present study, the first full-length cDNA encoding Neuropeptide Y (NPY) was cloned from the brain of Japanese eel (Anguilla japonica). The open reading frame of Japanese eel NPY gene is 294bp in length, encoding a precursor protein of 97 amino acids, which contains a 36-amino-acid mature peptide. Sequence analysis showed that the Japanese eel NPY peptide is similar to that of other species. Real-time PCR revealed that NPY in Japanese eel is mainly expressed in the brain, especially in the hypothalamus and the optic tectum thalamus. The effect of a negative energy balance on NPY gene expression was examined subsequently. The mRNA level of NPY in the hypothalamus and the optic tectum thalamus showed a pronounced increase after 4days of food deprivation. The biological activities of Japanese eel NPY were further investigated in vivo and in vitro. Intraperitoneal injection of the NPY peptide into Japanese eel could potently elevate the expression of the mammalian gonadotropin-releasing hormone (mGnRH) in hypothalamus and the follicle-stimulating hormone beta (FSHβ), the luteinizing hormone beta (LHβ) and growth hormone (GH) in pituitary. In static incubation studies, the stimulatory effects of NPY on mGnRH expression in hypothalamic fragments and on FSHβ, LHβ and GH expression in pituitary cells were also observed. However, in vivo and in vitro studies showed that NPY exhibits an inhibitory action on the expression of thyroid-stimulating hormone beta (TSHβ) in pituitary. The results indicate that NPY is involved in the regulation of multiple physiological processes in Japanese eel.

Potential players in the hood

Pharmacologic treatment of cardiac arrhythmias has been mostly confined to drugs that alter the electrical function of the myocytes of the heart. In fact, big players in this market have been the adrenergic blocking agents. By virtue of modulation of autonomic tone, this class of drugs can be helpful. However in the case of atrial fibrillation (Af), most current agents are not that helpful and the course of Af is little changed. It is possible that other players in the neighbor “hood” of cells may gain importance. In the paper of Mao et al. [1], autonomic modulation takes on an additional meaning in that in this study, it is the modulation of atrial neural networks, namely those of the fat pads, that these authors believe promote Af. This is consistent with their ideas that autonomic nerve stimulation or autonomic denervation modulates autonomic activity in physiologic and/or pathophysiologic functions. Notably, the experiments of Mao et al. were completed using naive control animals and not animals susceptible to persistent Af. In fact, the longest Af duration noted was 33 min in the presence of acetylcholine (Ach), which was used to mimic the neurotransmitter released with stimulation of the left and right ganglionated plexi (GPs). It is not known whether the same outcomes would occur in animals with highly remodeled or even aged atria as well as if remodeled GPs had been used. The mechanism of remodeling of the Af substrate by atrial neural networks was not explored in this study and thus remains unknown. We know that disease-associated disruptions of adrenergic/cholinergic signaling would be a form of functional denervation and if these paths serve to maintain the adult cardiac phenotype (and if functional and anatomic denervation have equivalent effects) then that could lead to additional myocyte remodeling. There are clear examples in the literature that Af produced by rapid atrial pacing, and VT, Vf and sudden death are associated with heterogeneous atrial innervation in the form of nerve sprouting [2]. Atrial cell electrical [3–6] or autonomic remodeling [7] may be just a reflection of an altered antagonism between the parasympathetic and sympathetic controls of the atria. It is known that vagal input can inhibit sympathetic neurotransmission via (Ach) receptors on the sympathetic nerve terminals. Sympathetic stimulation can produce long-lived vagal inhibition. This latter effect is thought to be caused by neuropeptideY (NPY) which colocalizes with Norepinephrine in sympathetic nerve terminals. NPY effects are varied showing both acute and chronic effects on cardiac cells. Using myocardial neuronal cocultures, labs have now defined some aspects of how neurons first impact the cardiac phenoptype [8–10]. One of us has studied intensely how sustained sympathetic innervation regulates ion channel expression and autonomic responsiveness and how some of these effects can be ascribed to NPY acting as a trophic factor [11, 12]. Mao et al. suggest that another peptide, VIP, may play a role. VIP effects are less well defined. It is released with Ach but causes a marked increase in HR. Whether it too has trophic effects is not known. Obviously more needs to be done here using cardiac tissues. This study was supported by grant HL 66140 from the National Heart Lung and Blood Institute, Bethesda, MD, USA. P. A. Boyden : R. B. Robinson Department of Pharmacology, Center for Molecular Therapeutics, Columbia University, New York, NY 10032, USA

Neuropeptide Y potentiates beta-adrenergic stimulation of lipolysis in 3T3-L1 adipocytes

Recently, we have shown that neuropeptide Y (NPY) is produced and upregulated in visceral adipose tissue of an early-life programmed rat model of central obesity. Moreover, we have demonstrated that NPY promotes proliferation of adipocyte precursor cells and contributes to the pathogenesis of obesity. However, the role of NPY in regulating adipocyte metabolism is poorly understood. The present study was designed to examine the effects of NPY on adipocyte metabolic function using 3T3-L1 adipocytes as an in vitro cell model system. We found that although it did not affect basal lipolysis, NPY potentiated isoproterenol (a β-adrenergic receptor agonist) stimulated lipolysis. Furthermore, this potentiation occurred upstream of adenylyl cyclase, since NPY did not enhance forskolin (an activator of adenylyl cyclase) stimulated lipolysis. In addition, NPY also augmented isoproterenol-stimulated phosphorylation of hormone sensitive lipase. In contrast, NPY did not alter the expression of several key lipolytic and lipogenic enzymes/proteins. Taken together, our results revealed a novel cross talk between the NPY and β-adrenergic signaling pathways in regulating lipolysis. Thus, the present findings add a new dimension to the dynamic role NPY plays in regulating energy balance.

Intracellular Nitric Oxide Mediates Neuroproliferative Effect of Neuropeptide Y on Postnatal Hippocampal Precursor Cells

Neuropeptide Y (NPY) is widely expressed in the central and peripheral nervous systems and is proliferative for a range of cells types in vitro. NPY plays a key role in regulating adult hippocampal neurogenesis in vivo under both basal and pathological conditions, although the underlying mechanisms are largely unknown. We have investigated the role of nitric oxide (NO) on the neurogenic effects of NPY. Using postnatal rat hippocampal cultures, we show that the proliferative effect of NPY on nestin(+) precursor cells is NO-dependent. As well as the involvement of neuronal nitric-oxide synthase, the proliferative effect is mediated via an NO/cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (PKG) and extracellular signal-regulated kinase (ERK) 1/2 signaling pathway. We show that NPY-mediated intracellular NO signaling results in an increase in neuroproliferation. By contrast, extracellular NO had an opposite, inhibitory effect on proliferation. The importance of the NO-cGMP-PKG signaling pathway in ERK1/2 activation was confirmed using Western blotting. This work unites two significant modulators of hippocampal neurogenesis within a common signaling framework and provides a mechanism for the independent extra- and intracellular regulation of postnatal neural precursors by NO.

NPY intraperitoneal injections produce antidepressant-like effects and downregulate BDNF in the rat hypothalamus.

Several studies have documented an involvement of Neuropeptide Y (NPY) in stress-related disorders. Stress-related disorders are also characterized by changes in brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), neurotrophins implicated in the survival and function of neurons. Thus the aim of this study was to investigate whether an NPY intraperitoneal treatment has antidepressant-like effects in rats subjected to a classical stress paradigm, the Forced Swim Test (FST), in association with changes in local brain neurotrophin production. Rats were intraperitoneally injected with either NPY (60 μg/kg) or a vehicle for three consecutive days between two FST sessions and then tested for time spent (or delay onset) in immobile posture. Moreover, we measured by enzyme-linked immunosorbent assay (ELISA) neurotrophin levels in the hypothalamus and corticosterone levels in plasma. The data showed that NPY induced a significant delay in the onset and a significant reduction in the duration of the immobility posture in FST. We also found that NPY decreased BDNF levels in the hypothalamus and corticosterone levels in plasma. Immobility posture in FST can be reduced by antidepressant drugs. Thus, our data show an antidepressant-like effect of NPY associated with changes in BDNF levels in the hypothalamus and reduced activity of hypothalamic-pituitary-adrenal (HPA) axis. These findings, while confirming the involvement of the NPY system in stress-related disorders, suggest that a less invasive route of administration, such as an intraperitoneal injection, may be instrumental in coping with stressful events in animal models and perhaps in humans.

Neuropeptide Y modulates calcium channels in hamster submandibular ganglion neurons

It is established that neuropeptide Y (NPY) is a transmitter of parasympathetic secretory impulses in submandibular gland. The neuropeptides substance P, vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) are likely mediators of secretory parasympathetic responses of the gland. Previously, we have shown that substance P, VIP and CGRP modulate voltage-dependent Ca2+ channels (VDCCs) in hamster submandibular ganglion (SMG) neurons. In this study, we attempt to characterize the effect of NPY on VDCCs current using Ba2+ (IBa) in SMG neurons. Application of NPY caused both facilitation and inhibition of L-type and N/P/Q-type IBa, respectively. Intracellular dialysis of the Gαs-protein antibody attenuated the NPY-induced facilitation of IBa. The adenylate cyclase (AC) inhibitor, as well as protein kinase A (PKA) inhibitor attenuated the NPY-induced facilitation of IBa. Intracellular dialysis of the Gαi-protein antibody attenuated the NPY-induced inhibition of IBa. Application of a strong depolarizing voltage prepulse attenuated the NPY-induced inhibition of IBa. These results indicate that NPY facilitates L-type VDCCs via Gαs-protein involving AC and PKA. On the other hand, NPY also inhibits N/P/Q-type VDCCs via Gαi-protein βγ subunits in the SMG neurons.

Altered profile of basket cell afferent synapses in hyper‐excitable dentate gyrus revealed by optogenetic and two‐pathway stimulations

Cholecystokinin (CCK-) positive basket cells form a distinct class of inhibitory GABAergic interneurons, proposed to act as fine-tuning devices of hippocampal gamma-frequency (30-90 Hz) oscillations, which can convert into higher frequency seizure activity. Therefore, CCK-basket cells may play an important role in regulation of hyper-excitability and seizures in the hippocampus. In normal conditions, the endogenous excitability regulator neuropeptide Y (NPY) has been shown to modulate afferent inputs onto dentate gyrus CCK-basket cells, providing a possible novel mechanism for excitability control in the hippocampus. Using GAD65-GFP mice for CCK-basket cell identification, and whole-cell patch-clamp recordings, we explored whether the effect of NPY on afferent synapses to CCK-basket cells is modified in the hyper-excitable dentate gyrus. To induce a hyper-excitable state, recurrent seizures were evoked by electrical stimulation of the hippocampus using the well-characterized rapid kindling protocol. The frequency of spontaneous and miniature excitatory and inhibitory post-synaptic currents recorded in CCK-basket cells was decreased by NPY. The excitatory post-synaptic currents evoked in CCK-basket cells by optogenetic activation of principal neurons were also decreased in amplitude. Interestingly, we observed an increased proportion of spontaneous inhibitory post-synaptic currents with slower rise times, indicating that NPY may inhibit gamma aminobutyric acid release preferentially in peri-somatic synapses. These findings indicate that increased levels and release of NPY observed after seizures can modulate afferent inputs to CCK-basket cells, and therefore alter their impact on the oscillatory network activity and excitability in the hippocampus.

The Vicious Cycle of Leptin-Insulin Resistance Predicts Impaired Glucose Metabolism in Obese Adults with Obstructive Sleep Apnea

le tt e r t o t H e e d it o r S is an overlooked area of metabolic processes and an important modulator of endocrine function. Despite a large body of evidence suggesting that obstructive sleep apnea (OSA) is an independent risk factor for type 2 diabetes, the underlying pathogenesis of impaired glucose metabolism (IGM) in OSA remains less well understood. The recent fi ndings of Papaioannou and colleagues showed no clinically signifi cant abnormalities of appetite regulating hormones in OSA that would suggest a cause for IGM.1 While the study provides an important insight into the phenotypic spectrum of OSA, it also raises questions related to possible yet unexplored more complex pathomechanisms linking appetite hormones with IGM in OSA. From a pathophysiological point of view, insulin resistance (IR) and beta-cell dysfunction both play a role in the development of IGM. While research has documented that OSA can contribute to IR independent of obesity, there is a paucity of information on leptin resistance-related IR in OSA that may potentially impair glucose homeostasis. Leptin is a wellknown adipose tissue-derived hormone that binds to receptors in the brain and inhibits expression of neuropeptide Y (NPY). Most obese humans produce large quantities of leptin but are insensitive to its effects. The suggested mechanisms underlying leptin resistance include defective leptin receptors and/or post-receptor signal transduction, reduced numbers of leptin receptors, interactions between leptin and plasma circulating factors, and other factors that override the leptin satiety signal. It is plausible that OSA-stress-related release of NPY from sympathetic nerves and activation of its Y2 receptors in the adipose tissue might stimulate fat angiogenesis and the proliferation and differentiation of new adipocytes, resulting in abdominal obesity, while closing a vicious cycle of increasing leptin-insulin resistance. Considering different receptor-mediated effects of NPY, the plasma level of NPY might not necessarily be the best parameter to assess NPY effects in peripheral tissues. In our study,2 we demonstrated that OSA is associated with specifi c cytokines that refl ect link between OSA and glucose metabolism. Specifi cally, nocturnal oxyhemoglobin desaturations in OSA were closely associated with interleukin-6 (IL-6) production in obese women with IGM, but not in controls with normal glucose metabolism matched individually for sex, age, adiposity, and apnea-hypopnea index. Moreover, cross-sectional data from our study showed additional close associations of IL-6 with leptin-to-leptin receptor ratio and markers of adiposity only in IGM. These fi ndings support the role that IL-6 plays in obesity and extend it to possible pathophysiological processes linking obesity to IGM via leptin resistance and hypoxic stress in OSA. Further prospective studies are needed to explore the dynamic interactions among appetite regulating hormones, their receptors, and glucose homeostasis in OSA to develop novel interventions to prevent metabolic sequelae of OSA.

Neuropeptide Y promotes neurogenesis and protection against methamphetamine-induced toxicity in mouse dentate gyrus-derived neurosphere cultures

Methamphetamine (METH) is a psychostimulant drug of abuse that causes severe brain damage. However, the mechanisms responsible for these effects are poorly understood, particularly regarding the impact of METH on hippocampal neurogenesis. Moreover, neuropeptide Y (NPY) is known to be neuroprotective under several pathological conditions. Here, we investigated the effect of METH on dentate gyrus (DG) neurogenesis, regarding cell death, proliferation and differentiation, as well as the role of NPY by itself and against METH-induced toxicity. DG-derived neurosphere cultures were used to evaluate the effect of METH or NPY on cell death, proliferation or neuronal differentiation. Moreover, the role of NPY and its receptors (Y1, Y2 and Y5) was investigated under conditions of METH-induced DG cell death. METH-induced cell death by both apoptosis and necrosis at concentrations above 10 nM, without affecting cell proliferation. Furthermore, at a non-toxic concentration (1 nM), METH decreased neuronal differentiation. NPY's protective effect was mainly due to the reduction of glutamate release, and it also increased DG cell proliferation and neuronal differentiation via Y1 receptors. In addition, while the activation of Y1 or Y2 receptors was able to prevent METH-induced cell death, the Y1 subtype alone was responsible for blocking the decrease in neuronal differentiation induced by the drug. Taken together, METH negatively affects DG cell viability and neurogenesis, and NPY is revealed to be a promising protective tool against the deleterious effects of METH on hippocampal neurogenesis.

NPY suppressed development of experimental autoimmune encephalomyelitis in Dark Agouti rats by disrupting costimulatory molecule interactions

Neuropeptide Y (NPY) suppressed clinical experimental autoimmune encephalomyelitis (EAE) and reduced numbers of CD28+, CD11b+ and CD80+ cells among spinal cord infiltrating cells at the peak of disease in Dark Agouti rat strain. Suppression of EAE was accompanied by the reduced expression of costimulatory CD80 and CD86 molecules on ED1+ macrophages and OX62+ dendritic cells in draining lymph nodes during the inductive phase of EAE. An inhibitor of dipeptidyl peptidase 4, an enzyme which terminates the action of NPY on Y1 receptor subtype, did not sustain the suppressive effect of NPY on the EAE development, suggesting involvement of Y2 and Y5 receptors.

Neuropeptide Y Protects Rat Cortical Neurons against β-Amyloid Toxicity and Re-establishes Synthesis and Release of Nerve Growth Factor

Neuropeptide Y (NPY) is a 36 amino acid peptide, widely distributed within central nervous system neurons. More recently, it has been shown that NPY is involved in Alzheimer's disease (AD), a disorder characterized by accumulation of amyloid β-peptide (Aβ) in neurons. In a previous study, we investigated the effect of NPY on neuronal damage by exposing SH-SY5Y cells (an established human derived neuroblastoma cell line) to Aβ's pathogenic fragment 25-35 (Aβ(25-35)). We found a NPY-neuroprotective action associated with changes in intracellular production of nerve growth factor (NGF), a member of the neurotrophin family. Since our results were encouraging, we decided to replicate our data using primary cortical neurons cultured in presence of Aβ(25-35), and investigated whether NPY had similar neuroprotective action. Moreover, since cortical neurons are able to produce and release NGF, we investigated whether the synthesis and release of NGF were modified in such experimental conditions. Our results showed that a preincubation with NPY counteracted the toxic effect of Aβ, as measured by increased cell viability. Moreover, NPY pretreatment had an effect on NGF since its intracellular synthesis was increased, release was normalized, and mRNA expression was downregulated. Notably, these effects on NGF were in the opposite direction of those produced by incubating the cells with Aβ alone. This study in primary cortical neurons supports the hypothesis that NPY may be a neuroprotective agent against β-amyloid neurotoxicity. These data also suggest that NPY may influence the synthesis and the release of NGF by cortical neurons.

Neuropeptide Y in the noradrenergic neurons induces the development of cardiometabolic diseases in a transgenic mouse model

Neuropeptide Y (NPY) is a neuropeptide widely expressed in the brain and a peptide transmitter of sympathetic nervous system (SNS) co-released with noradrenaline (NA) in prolonged stress. Association of a gain-of-function polymorphism in the human NPY gene with dyslipideamia, diabetes and vascular diseases suggests that increased NPY plays a role in the pathogenesis of the metabolic syndrome in humans. In the hypothalamus, NPY plays an established role in the regulation of body energy homeostasis. However, the effects of NPY elsewhere in the brain and in the SNS are less explored. In order to understand the role of NPY co-expressed with NA in the sympathetic nerves and brain noradrenergic neurons, a novel mouse model overexpressing NPY in noradrenergic neurons was generated. The mouse displays metabolic defects such as increased adiposity, hepatosteatosis, and impaired glucose tolerance as well as stress-related hypertension and increased susceptibility to vascular wall hypertrophy. The mouse phenotype closely reflects the findings of the several association studies with human NPY gene polymorphisms, and fits with the previous work on the effects of stress-induced NPY release on metabolism and vasculature. Thus, in addition of promoting feeding and obesity in the hypothalamus, NPY expressed in the noradrenergic neurons in the brain and in the SNS induces the development of cardiometabolic diseases.

Somatostatin and Neuropeptide-Y Differentially Inhibit Insulin Secretion

Glucose homeostasis is a tightly regulated process coordinated by insulin and glucagon secretion. In β-cells, G-protein coupled receptor (GPCR) activation facilitates the optimization of insulin secretion. Somatostatin (SST) and Neuropeptide-Y (NPY) inhibit insulin secretion through Gi activation; this inhibitory effect is mediated by the SSTR2/5 and Y1 receptors, respectively. Here, we questioned the mechanism by which SST and NPY attenuate insulin secretion. Two-photon excitation microscopy was utilized to measure the combined autofluorescence of NADH and NADPH (NAD(P)H, a cellular redox state indicator) upon SST or NPY application. Treatment with SST or NPY induces a supplementary increase in NAD(P)H autofluorescence at glucose levels ranging from 5-23 mM compared to untreated control, suggesting that the inhibitory effect of SST and NPY is not mediated through metabolic inhibition. We then tested the effect of these GPCR ligands on intracellular calcium ([Ca2+]i). At glucose concentrations above ∼7 mM, pancreatic islets display synchronous oscillations in [Ca2+]i, resulting in the pulsatile release of insulin. SST treatment decreases the [Ca2+]i oscillation frequency, while NPY has no effect; the oscillation amplitude is not altered in the presence of either ligand. Insulin secretion assays were performed at low (2.8 mM) and high (16.7 mM) glucose levels to determine the effect of SST and NPY on the Gi pathway. At both glucose concentrations, mSIRK, a Gβγ-activating peptide, significantly potentiates insulin secretion; treatment with mSIRK(L9A), which serves as a negative control for mSIRK, does not affect secretion. However, combination treatment with SST and mSIRK inhibits insulin secretion at high glucose compared to mSIRK alone. Insulin secretion is not altered with NPY and mSIRK treatment compared to mSIRK only. These data suggest that SST attenuates insulin secretion through inhibition of Gβγ acting on voltage-gated Ca2+ channels and/or phospholipase-C, while NPY inhibits insulin secretion through Gα.

Neuropeptide Y Reverses Chronic Stress-induced Baroreflex Hypersensitivity in Rats

Chronic stress, as a risk factor for cardiovascular diseases, has been reported to result in elevated plasma neuropeptide Y (NPY) and be highly associated with abnormal cardiac autonomic function. This study aimed to explore the effect of NPY on the chronic stress-induced abnormal baroreceptor reflex sensitivity (BRS). Seven types of recognized stressors were used to develop chronic stress rat model. Subcutaneously implanting ALZET mini-osmotic pumps containing NPY were used to evaluate the action of NPY on the stressed male rats. We found that chronic stress showed no influence on baseline systolic blood pressure (SBP) and heart rate (HR), whereas NPY (85 µg for 30 days) could elevate baseline SBP and induce bradycardia in rats intervened by various stimuli. NPY pretreatment could preserve chronic stress-induced decreases in left ventricular systolic pressure (LVSP) and the maximum rate of change in left ventricular pressure in the isovolumic contraction period (+dp/dt_max) but has shown no effect on left ventricular end diastolic pressure (LVEDP) and the maximum rate of change in left ventricular pressure in the isovolumic relaxation period (-dp/dt_max). Notably, chronic stress led to baroreflex oversensitivity indicated by the elevated ratio of Δheart rate (HR)/ Δmean arterial blood pressure (MABP) in rats followed by vasoconstrictor (phenylephrine, PE) or vasodilator (sodium nitroprusside, SNP) administration, which was almost completely reversed by NPY pretreatment. The expressions of substance P (SP) and gamma aminobutyric acid A receptor (GABA_AR) in nucleus tractus solitarius were increased in chronic stress rats, which were counteracted by NPY pretreatment. We conclude that chronic stress-induced baroreflex hypersensitivity could be blocked by NPY pretreatment. Furthermore, the altered expressions of neurotransmitters and receptors in the brainstem might contribute to this process.

The intriguing mission of neuropeptide Y in the immune system

For many years, the central nervous system and the immune system were considered two autonomous entities. However, extensive research in the field of neuroimmunomodulation during the past decades has demonstrated the presence of different neuropeptides and their respective receptors in the immune cells. More importantly, it has provided evidence for the direct effects of neuropeptides on the immune cell functions. Neuropeptide Y (NPY) is generally considered the most abundant peptide in the central and peripheral nervous system. However, it is also distinguished by exhibiting pleiotropic functions in many other physiological systems, including the immune system. NPY affects the functions of the cells of the adaptive and innate immunity. In this respect, NPY is known to modulate immune cell trafficking, T helper cell differentiation, cytokine secretion, natural killer cell activity, phagocytosis and the production of reactive oxygen species. The specific Y receptors have been found in immune cells, and their expression is amplified upon immune stimulation. Different Y receptor subtypes may mediate an opposite effect of NPY on the particular function, thus underlining its regulatory role. Since the immune cells are capable of producing NPY upon appropriate stimulation, this peptide can regulate immune cell functions in an autocrine/paracrine manner. NPY also has important implications in several immune-mediated disorders, which affirms the clear need for further investigation of its role in either the mechanisms of the disease development or its possible therapeutic capacity. This review summarises the key points of NPY's mission throughout the immune system.

Neuropeptide Y and extracellular signal-regulated kinase mediate injury-induced neuroregeneration in mouse olfactory epithelium

In the olfactory epithelium (OE), injury induces ATP release, and subsequent activation of P2 purinergic receptors by ATP promotes neuroregeneration by increasing basal progenitor cell proliferation. The molecular mechanisms underlying ATP-induced increases in OE neuroregeneration have not been established. In the present study, the roles of neuroproliferative factors neuropeptide Y (NPY) and fibroblast growth factor 2 (FGF2), and p44/42 extracellular signal-regulated kinase (ERK) on ATP-mediated increases of neuroregeneration in the OE were investigated. ATP increased basal progenitor cell proliferation in the OE via activation of P2 purinergic receptors in vitro and in vivo as monitored by incorporation of 5′-ethynyl-2′-deoxyuridine, a thymidine analog, into DNA, and proliferating cell nuclear antigen (PCNA) protein levels. ATP induced p44/42 ERK activation in globose basal cells (GBCs) but not horizontal basal cells (HBCs). ATP differentially regulated p44/42 ERK over time in the OE both in vitro and in vivo with transient inhibition (5–15min) followed by activation (30min–1h) of p44/42 ERK. In addition, ATP indirectly activated p44/42 ERK in the OE via ATP-induced NPY release and subsequent activation of NPY Y1 receptors in the basal cells. There were no synergistic effects of ATP and NPY or FGF2 on OE neuroregeneration. These data clearly have implications for the pharmacological modulation of neuroregeneration in the olfactory epithelium.

Neuropeptide Y (NPY) in the central nucleus of the amygdala (CeA) does not affect ethanol-reinforced responding in binge-drinking, nondependent rats

The central nucleus of the amygdala (CeA) has been implicated as having a significant role in mediating alcohol-drinking behavior. Neuropeptide Y (NPY) has been investigated as a potential pharmacotherapeutic due to its ability to attenuate ethanol intake, particularly when administered into the CeA. Previous research suggests, though the evidence is somewhat conflicting, that the efficacy of NPY is contingent upon genetic background and/or prior history of ethanol dependence in rats. However, studies looking at the effects of NPY in nonselected animals lacking a history of ethanol dependence have two factors that could impact the interpretation of the results: ethanol history/selection AND relatively low baseline ethanol intakes as compared to ethanol-dependent and/or genetically selected controls. The purpose of the present study was to generate higher baseline ethanol intakes upon which to examine the effects of NPY on ethanol and sucrose drinking in nonselected rats using a binge drinking model. Long Evans rats were trained to complete a single response requirement resulting in access to either 2% sucrose (Sucrose Group) or 2% sucrose/10% ethanol (Ethanol Group) for a 20-min drinking session. On treatment days, rats were bilaterally microinjected into the CeA with aCSF or one of three doses of NPY (0.25μg, 0.50μg, or 1.00μg/.5μL). Subjects in the Ethanol Group were consuming an average of 1.2g/kg of ethanol (yielding BELs of ~90mg%) during the 20min access period following aCSF treatments. The results revealed that NPY had no effect on either sucrose or ethanol consumption or on appetitive responding (latency to respond). Overall, the findings indicate that even a history of binge-like ethanol consumption is not sufficient to recruit CeA NPY activity, and are consistent with previous studies showing that the role of NPY in regulating ethanol reinforcement in the CeA may be contingent upon a prior history of ethanol dependence.

Reduced fear conditioning after viral vector mediated neuropeptide Y administration into the basolateral amygdala

Background Neuropeptide Y (NPY) is a 36-amino-acid peptide that is abundantly expressed in the central nervous system. It is involved in various physiological and pathophysiological processes, including energy homeostasis, pain and epilepsy, but also in anxiety and depression. Consistent findings have demonstrated an anxiolytic effect of NPY. The presence of different NPY receptors in the amygdala and the effects of NPY on anxiety raise the question, whether NPY and its receptors may influence acquisition and extinction of conditioned fear. Therefore, we investigated NPY and NPY receptor knockout mice in Pavlovian fear conditioning.