The role of NPY in metabolic homeostasis: implications for obesity therapy

Neuropeptide Y (NPY) is a 36 amino acid amidated peptide which has now emerged as an important regulator of feeding behaviour. Upon intracerebroventricular (icv.) administration, NPY produces a pronounced feeding response in a variety of species. The actions of NPY are believed to be mediated by a family of receptor subtypes named Y1 - y6. Recent studies suggest that the Y1 and Y5 receptor subtypes are intimately involved in NPY induced feeding. This review presents preclinical data obtained with receptor subtype selective agonists and antagonists as well as findings from knockout mice. These new data suggest that NPY receptor antagonists may become an additional option for treating human obesity.     

神经肽Y与脂肪细胞增殖分化的研究进展

神经肽Y（NPY）在中枢和外周神经系统的神经组织中合成,除了调节食欲和能量的平衡,还具有许多重要功能。本文对NPY通过其受体介导,作用于脂肪细胞,促进脂肪细胞增殖和分化的机制研究情况作一简要的概述。     

Lewis Y寡糖在小鼠胚泡表面的表达受α1,2-岩藻糖基转移酶基因的反馈调控

目的探讨胚泡的LewisY寡糖合成关键酶α1,2岩藻糖基转移酶基因FUT1及α1,3岩藻糖基转移酶基因FUT4的表达和其表面LewisY寡糖抗原表达间的关系。方法以寡糖特异性单克隆抗体封闭体外培养的胚泡表面LewisY抗原,应用RTPCR和间接免疫荧光方法检测胚泡的LewisY寡糖合成关键酶α1,2岩藻糖基转移酶基因FUT1和α1,3岩藻糖基转移酶基因FUT4及其表面LewisY抗原的表达。结果在胚泡表面LewisY寡糖被抗体封闭后,其FUT1的表达迅速升高,FUT4的表达则未见明显变化,而胚泡表面的LewisY寡糖在除去抗体后一直到再培养约21h后才重新出现,在约30h几乎全部复现。结论着床前胚泡表面的LewisY寡糖的表达主要受胚泡α1,2岩藻糖基转移酶FUT1的反馈调节。     

Central Neuropeptide Y Modulates Binge-Like Ethanol Drinking in C57BL/6J Mice via Y1 and Y2 Receptors

Frequent binge drinking has been linked to heart disease, high blood pressure, type 2 diabetes, and the development of ethanol dependence. Thus, identifying pharmaceutical targets to treat binge drinking is of paramount importance. Here we employed a mouse model of binge-like ethanol drinking to study the role of neuropeptide Y (NPY). To this end, the present set of studies utilized pharmacological manipulation of NPY signaling, immunoreactivity (IR) mapping of NPY and NPY receptors, and electrophysiological recordings from slice preparations of the amygdala. The results indicated that central infusion of NPY, a NPY Y1 receptor (Y1R) agonist, and a Y2R antagonist significantly blunted binge-like ethanol drinking in C57BL/6J mice (that achieved blood ethanol levels >80 mg/dl in control conditions). Binge-like ethanol drinking reduced NPY and Y1R IR in the central nucleus of the amygdala (CeA), and 24 h of ethanol abstinence after a history of binge-like drinking promoted increases of Y1R and Y2R IR. Electrophysiological recordings of slice preparations from the CeA showed that binge-like ethanol drinking augmented the ability of NPY to inhibit GABAergic transmission. Thus, binge-like ethanol drinking in C57BL/6J mice promoted alterations of NPY signaling in the CeA, and administration of exogenous NPY compounds protected against binge-like drinking. The current data suggest that Y1R agonists and Y2R antagonists may be useful for curbing and/or preventing binge drinking, protecting vulnerable individuals from progressing to the point of ethanol dependence.     

13-甲基十四烷酸对H2O2诱导SH-SY5Y神经细胞损伤的保护作用

目的：探讨13-甲基十四烷酸（13-MTD）对过氧化氢（H2O2）诱导SH-SY5Y神经细胞损伤的影响。方法：采用体外细胞培养的方法,建立SH-SY5Y神经细胞H2O2损伤模型。光镜观察细胞形态,SRB法检测细胞存活率,AO/EB双重染色法检测细胞凋亡,MTT法检测线粒体活性。结果：与正常对照组相比,H2O2损伤模型组细胞出现明显病理改变,细胞存活率、线粒体活性均显著下降（P〈0.01）,细胞凋亡率显著升高（P〈0.01）;13-MTD10、20、40μg/mL可显著提高细胞存活率（P〈0.01）;13-MTD5、10、20μg/mL可显著下调细胞凋亡率（P〈0.01）;13-MTD5、10、20、40μg/mL可显著提高细胞MTT代谢率（P〈0.01）;且存在一定量效差异（P〈0.05,P〈0.01）。结论：不同剂量的13-MTD对H2O2诱导的SH-SY5Y神经细胞氧化损伤具有保护作用。     

红参水提物对Aβ_(25-35)诱导SH-SY5Y细胞凋亡的保护作用

目的 探讨红参水提物对Aβ25-35诱导人神经瘤母细胞SH-SY5Y细胞凋亡的保护作用.方法 用Aβ25-35处理SH-SY5Y细胞,模拟阿尔茨海默病患者脑内神经元的病理损伤模型,以不同浓度的红参水提物进行干预;用倒置显微镜观察其形态学的变化;MTT法测定细胞的存活率;流式细胞技术检测细胞的凋亡率以及线粒体膜电位的变化.结果 50 μmol·L-1Aβ25-35诱导SH-SY5Y细胞72 h后,细胞变圆、聚集,其存活率为39.26%土3.16%、凋亡率为37.30%±0.69%,线粒体红绿荧光强度比值为0.45±0.10;而Aβ25-35诱导的SH-SY5Y细胞与不同浓度(1、5、10 mg·ml-1)红参水提物同时孵育后,明显减少了细胞损伤,升高了细胞存活率、降低了凋亡率,并升高了线粒体红绿荧光强度比值.结论 红参水提物对Aβ25-35诱导的SH-SY5Y细胞凋亡有显著的保护作用.     

Neuropeptide Y receptors as targets for anti-obesity drug development: perspective and current status

Neuropeptide Y is a widely distributed neuropeptide that elicits a plethora of physiological effects via interaction with six different receptors (Y₁–y₆). Recent attention has focused on the role of neuropeptide Y in the regulation of energy homeostasis. Neuropeptide Y stimulates food intake, inhibits energy expenditure, increases body weight and increases anabolic hormone levels by activating the neuropeptide Y Y₁ and Y₅ receptors in the hypothalamus. Based on these findings, several neuropeptide Y Y₁ and Y₅ receptor antagonists have been developed recently as potential anti-obesity agents. In addition, mice lacking neuropeptide Y, the neuropeptide Y Y₁ receptor or the neuropeptide Y Y₅ receptor have been generated. The data obtained to date with these newly developed tools suggests that neuropeptide Y receptor antagonists, particularly neuropeptide Y Y₁ receptor antagonists, may be useful anti-obesity agents. However, the redundancy of the neurochemical systems regulating energy homeostasis may limit the effect of ablating a single pathway. In addition, patients in whom the starvation response is activated, such as formerly obese patients who have lost weight or patients with complete or partial leptin deficiency, may be the best candidates for treatment with a neuropeptide Y receptor antagonist.     

P2Y12受体基因多态性在中国人群中的分布和对氯吡格雷疗效的影响

目的:探讨P2Y12受体C34T和G52T基因多态性在中国汉族健康人群与冠心病患者中的分布特点,并进一步分析对氯吡格雷药物疗效的影响.方法:采用聚合酶链反应一限制性片段长度多态性(PCR-RFLP)方法检测190例冠心病患者和240例健康对照组的P2Y12受体C34T和G52T基因多态性,选取健康受试者18例(6例P2Y12 CC34/GG52,6例P2Y12 TT34/GG52和6例P2Y12 CC34/TT52),测定服甩氯吡格雷前后血小板聚集率.结果:P2Y12受体C34T和G52T基因突变频率在中国健康人群和冠心病患者中分别是24.2%,12.1%和21.1%,10.5%,但2个位点突变频率在2组人群中无明显差异(P>0.05).在3种P2Y12单倍型之间,服用氯吡格雷前后血小板聚集率无明显差异(P>0.05).结论:P2Y12受体C34T和G52T基因多态性在中国汉族健康人群和冠心病患者中分布无明显差异,并且对氯吡格雷抗血小板聚集率的疗效无明显影响.     

Neuropeptide Y (NPY) inhibits spontaneous contraction of the mouse atrium by possible activation of the NPY1 receptor

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INHIBITORY EFFECT OF NEUROPEPTIDE Y ON STIMULATED RENIN SECRETION OF AWAKE RATS

1. (1-36)-NPY is a vasoconstrictor peptide widely distributed in sympathetic nerve terminals. This peptide exerts an inhibitory action on renin release induced by various stimuli. Post-synaptic neuropeptide Y (NPY) receptors show a high affinity for (1-36)-NPY as well as for the agonist (Pro34)-NPY, while presynaptic receptors bind preferentially (13-36)-NPY. 2. This study was undertaken to assess whether the NPY induced renin suppression in awake normotensive rats infused with the beta-adrenoceptor stimulant isoproterenol is mediated by activation of pre- or post-synaptic receptors. 3. Non-pressor doses of (1-36)-NPY and (Pro34)-NPY markedly attenuated the renin secretion triggered by isoproterenol whereas (13-36)-NPY had no effect. This suggests that the effect of NPY on renin release is due to the stimulation of post-synaptic receptors. However it remains unknown whether NPY acts directly on juxtaglomerular cells or indirectly by modifying intraglomerular haemodynamics.     

Synthesis and Neuropeptide Y Y1 Receptor Antagonistic Activity of N,N-Disubstituted ω-Guanidino- and ω-Aminoalkanoic Acid Amides

Potent arpromidine-type histamine H₂ receptor agonists such as BU-E-76 (He 90481) were among the first non-peptides reported to display weak neuropeptide Y (NPY) Y₁ receptor antagonist activity. In search of new chemical leads for the development of more potent NPY antagonists, a series of N,N-disubstituted ω-guanidino and ω-aminoalkanoic acid amides were synthesized on the basis of structure-activity relationships and molecular modeling studies of arpromidine and related imidazolylpropylguanidines. In one group of compounds the imidazole ring was retained whereas in the second group it was replaced with a phenol group representing a putative mimic of Tyr³⁶ in NPY. Although the substitution patterns have not yet been optimized, the title compounds are NPY Y₁ antagonists in human erythroleukemia (HEL) cells (Ca²⁺ assay) achieving pKB values in the range of 6.3–6.6. For representative new substances tested in the isolated guinea pig right atrium histamine H₂ receptor agonism could not be found. In the N-(diphenylalkyl)amide series, compounds with a trimethylene chain were more active Y₁ antagonists than the ethylene homologs. Concerning the spacer in the ω-amino or ω-guanidinoalkanoyl portion, the best activity was found in compounds with a four- or five-membered alkyl chain or a 1,4-cyclohexylene group. Surprisingly, in contrast to the phenol series, in the imidazole series the compounds with a side chain amino group turned out to be considerably more potent than the corresponding strongly basic guanidines. Thus, the structure-activity relationships appear to be different for the diphenylalkylamide NPY antagonists with one or two basic groups.     

Discovery of a Novel Class of Bicyclo[3.1.0]hexanylpiperazines as Noncompetitive Neuropeptide Y Y1 Antagonists

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Preparation of fluorescent nonpeptidic neuropeptide Y receptor ligands: analogues of the quinazoline-type anti-obesity Y5 antagonist CGP 71683A

As part of a programme to develop fluorescence-based methods for the study of the interactions between G-protein coupled receptors (GPCRs) and their ligands the preparation of low molecular weight fluorescence-labelled neuropeptide Y (NPY) Y(5) antagonists is reported. The naphthylsulfonyl group in the potent quinazoline-type NPY Y(5) receptor antagonist CGP 71683A was replaced with a dansyl, nitrobenzoxadiazole (NBD) or acridine-9-carbonyl group. In radioligand binding studies on human Y(5) receptor expressing HEC-1B cells the substances labelled with acridine (K(i) 311 nM) and NBD (K(i) > 1000 nM) proved to be moderately active or inactive, respectively. By contrast, a K(i) value of 49 nM was found for the dansyl analogue compared to 2 nM for CGP 71683A. No binding to Y(1) receptors (SK-N-MC cells, displacement of [(3)H]propionyl-NPY) was detected for the new compounds at concentrations 相似文献   

重度烧伤患者血浆NPY表达及其与抑郁状态的关系

目的探讨重度烧伤患者血浆神经肽Y(NPY)水平变化及其与抑郁的相关关系。方法采用竞争抑制酶联免疫分析法测定病程不同的重度烧伤患者血浆NPY水平。采用抑郁自评量表(self-rating Depression Scale,SDS)评估烧伤患者抑郁状况。结果病程<1个月、1-4个月、>4个月的患者的血浆NPY水平分别为[(0.41±0.14)pg/ml vs.(0.26±0.09)pg/mL vs(0.41±0.42)pg/mL],随着病程的发展,烧伤患者血浆NPY表达呈下降趋势(rs=-0.399,P=0.001)。抑郁组血浆NPY表达高于无抑郁组,但差异无统计学意义[(0.32±0.31)pg/mL vs.(0.30±0.29)pg/mL,F=0.044,P=0.836]。结论烧伤患者神经肽Y表达与烧伤应激相关,并参与了患者烧伤后并发抑郁的病理过程。     

氟桂利嗪治疗偏头痛及对血浆神经肽Y的影响

目的 :观察氟桂利嗪治疗偏头痛的疗效及其对血浆神经肽Y (NPY)水平的影响。方法 :选择偏头痛病人 6 0例 ,随机分为 2组 ,分别予氟桂利嗪和普萘洛尔治疗 ,观察 2组疗效。并分别测定治疗前后血浆NPY水平 ,做统计学分析。结果 :2组比较 ,氟桂利嗪组与普萘洛尔组偏头痛控制率 (5 4 % ,2 1% )及总有效率 (93% ,71% )的差异有显著意义(均P <0 .0 5 )。治疗后 ,氟桂利嗪组NPY水平降低了 (32± 5 3)ng·L- 1,经t检验 ,差异有显著意义 (P<0 .0 5 ) ,而普萘洛尔组差异无显著意义 (P >0 .0 5 )。结论 :氟桂利嗪治疗偏头痛有效 ,且治疗后血浆神经肽水平降低 ,提示氟桂利嗪可有解除血管痉挛的作用     

男性不育160例Y染色体基因微缺失分析

目的 探索男性不育与Y染色体基因微缺失之间的关系.方法 采用PCR技术,针对124例严重少精子症(A组)、36例无精子症(B组)与41例已正常生育的男性(C组)进行AZFa、AZFb、AZFe 3个区域共12个序列标签位点的微缺失分析.结果 A组中发现Y染色体微缺失24例,B组发现12例,而C组未发现Y染色体微缺失.此研究中发现微缺失形式有两种,分别是AZFa+ AZFb+ AZFc区的全缺失和AZFc区的单独缺失.结论 Y染色体微缺失与精子发生障碍导致的不育有一定的联系.     

Neuropeptide Y administration into the third ventricle does not increase sucrose or ethanol self-administration but does affect the cortical EEG and increases food intake

RATIONALE: Several studies have provided indirect evidence that neuropeptide Y (NPY) may play a role in the regulation of ethanol consumption. However, the direct effects of central NPY administration on ethanol drinking are unclear. OBJECTIVE: This study examined the effects of NPY on ethanol, sucrose, and food consumption as well as its concomitant effects on the cortical EEG. METHODS: Wistar rats were implanted with cortical recording electrodes and a cannula in the third ventricle after using a sucrose substitution procedure to establish ethanol self-administration. NPY (0-15 microg/3.0 microl) was infused into the third ventricle prior to drinking sessions, when 10% ethanol (10E), 2% sucrose (2S), 0.5% sucrose (0.5S), or food were available. Behavior and cortical EEG were monitored during the sessions. RESULTS: NPY had no effect on the intake of 10E, 2S, or 0.5S, but NPY (15 microg/3.0 microl) significantly increased food intake. Under baseline drinking conditions, EEG power in the 6-8 Hz range was significantly greater when 2S was consumed compared to 10E. NPY decreased power in the 8-16 Hz range, decreased peak frequency in the 6-8 Hz range, and increased peak frequency in the 32-50 Hz range when 10E or 2S was available. CONCLUSIONS: These data suggest that NPY administration into the third ventricle preferentially regulates feeding compared to ethanol or sucrose drinking. In addition, since NPY significantly altered the cortical EEG in the absence of effects on ethanol and sucrose consumption, these data may indicate that NPY's cortical EEG effects are more related to its sedative or anxiolytic properties, rather than any effect on consumption.     

银杏叶提取物对大鼠颅脑损伤后心肌病变的保护作用及神经肽Y基因表达的影响

目的观察银杏叶提取物(GBE)对大鼠颅脑损伤后心肌病变的保护作用及神经肽Y(NPY)基因表达的影响。方法采用液压冲击建立颅脑损伤模型和药物干预模型,行心导管插管测定左心室收缩压(LVSP),左心室舒张压末压(LVEDP)及左心室压力上升和下降最大速度(±dp/dtmax),同时测定血清肌酸磷酸激酶同工酶(CK-MB)含量的改变,并通过反转录-聚合酶链反应(RT-PCR)的方法研究大鼠颅脑损伤后心肌NPY基因的表达。结果与对照组大鼠比较,颅脑损伤组大鼠LVSP和±dp/dtmax明显下降(P<0.05),LVEDP明显升高(P<0.05),血清CK-MB含量明显升高(P<0.05),且心肌NPY基因的表达水平显著增加(P<0.05);与颅脑损伤组大鼠比较,GBE干预组大鼠LVSP和±dp/dtmax增加(P<0.05),LVEDP降低(P<0.05),血清CK-MB含量降低(P<0.05),且心肌NPY基因的表达水平减少(P<0.05)。心肌NPY基因的表达与血清CK-MB和LVEDP变化呈正相关(r值分别为0.988和0.957,P<0.05),与LVSP变化呈负相关(r=-0.960,P<0.05)。结论颅脑损伤可引起明显的心肌病变,GBE对大鼠颅脑损伤后心肌病变有保护作用,其作用可能与心肌NPY基因表达下调有关。     

Ca2+/CaM-CaN途径参与神经肽Y诱导的大鼠心肌细胞肥大

目的 :探讨Ca2 CaM依赖的钙调神经磷酸酶(CaN)途径在神经肽Y(NPY)诱导心肌细胞肥大中的作用。方法 :用NPY (10、10 0nmol·L-1)刺激WISTAR乳鼠心肌细胞 ,并用CaN特异性抑制剂环胞霉素A加以干预。应用3 H Leu掺入法测定心肌细胞蛋白质合成速率 ,用免疫印迹 (Western blot)和组织化学法分别测定心肌细胞内CaN α蛋白表达和CaN酶的活性。结果 :较高浓度NPY(10 0nmol·L-1)可明显增加心肌细胞3 H Leu掺入量(P <0 .0 5 ) ,加入CsA可阻断上述效应 ;NPY(10 0nmol·L-1)还可明显增加心肌细胞内CaN酶比活性 (P <0 .0 5 ) ,并刺激心肌细胞CaN α蛋白表达(P <0 .0 5 )。结论 :NPY可活化大鼠心肌细胞Ca2 CaM CaN途径 ,而CaN特异性抑制剂环胞霉素A可抑制NPY诱导的心肌肥大 ,说明Ca2 CaM依赖的钙调神经磷酸酶 (CaN)途径参与神经肽Y诱导的心肌细胞肥大效应。