补肾排毒合剂对慢性肾衰竭大鼠瘦素受体及神经肽Y在脑组织表达的影响

目的:探讨补肾排毒合剂改善慢性肾衰竭营养不良的作用机制.方法:60例大鼠分为正常对照组、慢性肾衰竭组和肾衰竭补肾排毒合剂治疗组,并取大鼠脑组织,采用免疫组化技术,检测瘦素受体(Ob-R)和神经肽Y(NPY)的蛋白表达.结果:慢性肾衰竭后下丘脑组织Ob-R 表达增强,NPY的表达降低;经补肾排毒合剂治疗后,下丘脑组织Ob-R的表达有所减少,NPY的表达有所恢复(P＜0.05).结论:补肾排毒合剂可能通过调节Ob-R及NPY的活性而改善慢性肾衰竭营养不良.     

瘦素/阿片促黑素细胞皮质素原/神经肽Y信号在胃转流术治疗2型糖尿病中的作用

目的 探讨瘦素(Leptin)、神经肽Y(NPY)、阿片促黑素细胞皮质素原(POMC)信号通路在胃转流手术治疗2型糖尿病中的作用及机制.方法采用20只成年SD雄性大鼠成功建立2型糖尿病大鼠模型,随机分为糖尿病非手术对照组(NO组,n=10)和糖尿病手术组[Roux-en-Y胃旁路术(RYGB)组,n=10],另外再选10只正常大鼠作为正常对照组(NC组),对手术组实施胃转流手术,分别于术前、术后检测各组大鼠血糖(GLU)、总胆固醇(TCH)及甘油三酯(TG)、Leptin水平,每天定时监测大鼠饮水量、饮食量以及体质量的变化,术后第4周取大鼠下丘脑,检测下丘脑中NPY、POMC mRNA的表达水平.结果术后第4周,RYGB组大鼠血糖、血脂以及进食、水量已接近正常水平,Leptin和NPY mRNA水平分别由术前的(4.58±0.37)μg/L、1.89 ±0.24降低到(3.10±0.38) μg/L、0.95±0.19(P＜0.01),而POMC mRNA水平则由术前的0.78±0.26升高至1.70±0.31(P＜0.01).结论 胃转流手术可以改善2型糖尿病的血糖水平,Leptin可能通过NPY、POMC神经元信号调节2型糖尿病的能量代谢平衡,提示Leptin与下丘脑NPY、POMC调节通路可能在胃转流手术后2型糖尿病病情缓解过程中发挥重要作用.     

长期迷走神经电刺激对肥胖鼠摄食和体重的影响

目的观察膈下迷走神经刺激(vagal nerves stimulation,VNS)对肥胖鼠摄食、体重、摄食神经肽的影响。方法将18只雄性营养性肥胖鼠(dietary induced obesity,DIO)随机分3组:对照组、假手术组、VNS组。VNS组大鼠体内植入自主研发的闭环芯片并高脂饲养90天,芯片电刺激膈下迷走神经;假手术组体内植入不工作的芯片;对照组不做手术。术后每天测量所有动物体重、日进食量。90天后处死所有动物,分离并称重双侧附睾脂肪垫。反转录PCR法(RT-PCR)半定量检测摄食神经肽:重组人刺鼠色蛋白相关蛋白(AgRP)、神经肽Y(NPY)、可卡因-苯丙胺调节转录因子编码的肽(CART)、阿片促黑色素原(POMC)的含量。结果 VNS组大鼠体重增加量[(124.3±15.5)g vs.(263.1±16.8)g,P=0.013],总摄食量[(1998.7±37.2)g vs.(3312.6±40.9)g,P=0.021]以及附睾脂肪垫重量[(15.9±2.3)g vs.(22.7±2.6)g,P=0.035]明显低于假手术组。VNS组大鼠下丘脑促摄食神经肽AgRP(P=0.027)、NPY的含量(P=0.019)低于假手术组,而抑制摄食的神经肽POMC高于假手术组(P=0.011)。结论 膈下迷走神经电刺激可显著减少大鼠摄食量,减轻体重。     

肾衰养真胶囊对5/6肾切除慢性肾衰竭营养不良大鼠下丘脑神经肽Y mRNA表达的影响

目的：观察肾衰养真胶囊对5/6肾切除慢性肾衰竭（CRF）营养不良大鼠的改善作用和探讨其作用机制。方法：5/6肾切除同时予4%酪蛋白饮食制作CRF营养不良大鼠模型,观察其营养不良发生时间,符合CRF营养不良模型的随机分为正常组、模型组、肾衰养真胶囊组和开同组。药物干预4周后检测尿素氮、肌酐、白蛋白、血红蛋白、24h尿蛋白,动态观察摄食量及体重变化,灌胃4周后检测血浆神经肽Y（NPY）和下丘脑NPY mRNA表达水平。结果：CRF大鼠在术后10周末出现营养不良,与模型组比较,肾衰养真胶囊组大鼠摄食量、体重显著增高,白蛋白和血红蛋白显著升高,肾功能改善,肾衰养真胶囊可上调下丘脑NPY mRNA表达,降低血浆NPY水平。结论：肾衰养真胶囊可改善CRF营养不良其机制可能是通过上调下丘脑NPY mRNA表达及降低血浆NPY从而促进CRF营养不良大鼠摄食,增加体重。     

穴位埋线对单纯性肥胖症瘦素和胰岛素抵抗影响的研究

目的:探讨穴位埋线疗法对单纯性肥胖症瘦素和胰岛素抵抗的作用.方法:采用RT-PCR技术测定瘦素受体(OB-R)基因表达水平,放射免疫分析测定血清和下丘脑瘦素(Leptin)和胰岛素(INS)的含量.观察穴位埋线疗法治疗前后单纯性肥胖患者血清Leptin、INS、脂质水平的变化;还观察穴位埋线疗法治疗前后肥胖大鼠体重、Lee's 指数、体脂、血清和下丘脑瘦素和INS 的含量以及下丘脑OB-R基因表达的变化.结果:单纯性肥胖患者Leptin、INS、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白-胆固醇(LDL-C) 的含量均显著高于正常人水平;而高密度脂蛋白-胆固醇(HDL-C)却显著低于正常人水平,穴位埋线疗法治疗后患者Leptin、INS、TC、TG、LDL-C的含量均明显回降,而HDL-C含量却明显回升,这种变化与减肥疗效有关.肥胖大鼠体重、Lee's 指数、体脂及血清Leptin和INS 水平均显著高于正常大鼠,而下丘脑瘦素和INS水平及OB-R 基因表达水平均明显低于正常大鼠.穴位埋线疗法治疗取得良好减肥疗效的同时,肥胖大鼠血清瘦素和INS 均明显回降,而下丘脑瘦素和INS水平以及OB-R基因表达水平却明显升高.结论:穴位埋线疗法对肥胖机体中枢和外周Leptin和INS水平的良性调整作用以及促进下丘脑OB-R基因表达可能是穴位埋线疗法纠正瘦素和胰岛素抵抗以及异常的内分泌代谢的重要机制.     

温阳益气针灸方对单纯性肥胖症血脂代谢功能的影响

目的:分析温阳益气针灸方治疗单纯性肥胖对患者血脂代谢功能的影响。方法:选取笔者医院2016年10月-2018年3月收治的106例单纯性肥胖症患者,根据治疗方法不同分为对照组和观察组。对照组患者采用针刺方法治疗,观察组患者采用温阳益气针灸方治疗,分析两组患者治疗后的临床效果。结果:治疗后,观察组患者气虚质积分、肥胖度、体脂百分率、身体质量指数(BMI)、腹腔内脏脂肪面积(VFA)水平均低于对照组,差异有统计学意义(P0.05);观察组患者脂联素水平高于对照组,瘦素(Leptin)、神经肽Y(NPY)水平低于对照组,空腹血脂指标水平优于对照组,差异有统计学意义(P0.05)。结论:温阳益气针灸方治疗单纯性肥胖症可改善患者血脂代谢功能,降低肥胖度、体脂百分率、BMI及VFA水平。     

大鼠垂体瘤模型下丘脑中神经肽Y及其受体的表达变化

目的观察神经肽Y（NPY）及其受体在垂体腺瘤模型大鼠下丘脑中的表达，探讨下丘脑中NPY表达变化与垂体腺瘤形成的关系。方法雌性Wistar大鼠40只，摘除双侧卵巢后，通过腹腔注射雌激素的方法建立大鼠垂体腺瘤模型，在此基础上采用免疫组织化学和逆转录-聚合酶链反应（RT—PCR）的方法，研究大鼠下丘脑中NPY及其受体的表达。结果实验组大鼠符合垂体腺瘤的诊断标准；免疫组织化学和RT—PCR研究结果表明，在实验组大鼠下丘脑中NPY及其Y1受体（Y1R）的表达水平明显低于对照组。Y2受体（Y2R）在两组之间的表达水平差异无统计学意义（P〉0．05）。结论通过雌激素诱导Wistar大鼠，可以成功建立垂体腺瘤动物模型；实验组大鼠下丘脑中NPY及其Y1R表达下调可能与肿瘤发生有关。     

针药结合治疗高血压病106例

目的:探索提高治疗高血压疗效的方法及其作用机理.方法:将106例患者随机分成2组,治疗组(针刺加药物)53例,对照组(单纯药物)53例,观察治疗前后血压和血浆神经肽Y(NPY)的变化.结果:降压效果治疗组明显优于对照组(P＜0.05),且治疗组NPY含量明显降低.结论:中西医结合治疗高血压病有协同作用,能提高疗效,其作用机理可能是通过调节NPY实现的.     

Kisspeptin/kiss1 r系统在营养性肥胖雄性大鼠下丘脑弓状核的表达以及对下丘脑-垂体-睾丸轴的影响

目的:通过构建营养性肥胖雄性大鼠的模型,探讨下丘脑弓状核kisspeptin/kiss1r系统和促性腺激素释放激素(GnRH)的表达和作用,以及对下丘脑-垂体-睾丸轴(HPT)的影响。方法:孕14 d SD大鼠,其后代随机分为正常组和高能饲料组,构建营养性肥胖模型。将肥胖大鼠进一步分为对照组和实验组,实验组侧脑室注入kisspeptin。记录体重参数和内分泌激素的改变;免疫组化和Western印迹检测各组大鼠下丘脑弓状核中瘦素受体(LepR)、kisspeptin、kiss1r和GnRH的蛋白表达。qRT-PCR检测各组大鼠下丘脑弓状核GnRH mRNA的表达。结果:成功构建营养性肥胖大鼠,体重参数和内分泌激素改变明显。相比较正常组,对照组大鼠弓状核LepR、kisspeptin和GnRH表达减少,侧脑室注入kisspeptin后,实验组大鼠弓状核GnRH显著增加,血清LH和T水平显著升高,未见LepR和kiss1r的改变。结论:中枢注入kisspeptin可以显著改善由营养性肥胖引起的GnRH低表达,纠正HPT轴功能失调,进而改善生殖功能。     

二甲双胍对营养性肥胖大鼠附睾精子质量和睾丸抗氧化能力的影响

目的:观察二甲双胍对高脂饮食诱导的肥胖大鼠附睾精子质量和睾丸抗氧化能力的影响。方法:雄性SD大鼠分为正常对照组和造模组,造模组以高脂饲料喂养8周后,取24只肥胖大鼠随机分为模型对照组、二甲双胍组和普通饲料组,除模型对照组继续高脂饲料喂养外,其余3组普通饲料喂养。12周末,所有大鼠均禁食12 h后处死,检测Lee's指数、睾丸和附睾脏器指数,附睾精子浓度、精子活动率和a+b级精子百分率,睾丸组织匀浆中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)和丙二醛(MDA)含量。结果:Lee's指数模型对照组与其他3组比较显著升高(P<0.01),Lee's指数正常对照组较二甲双胍组升高(P<0.05)。睾丸、附睾、脏器指数模型对照组较其他3组显著降低(P<0.01)。精子浓度、精子活动率和a+b级精子百分率模型对照组与其他3组比较显著降低(P<0.05或P<0.01),正常对照组较二甲双胍组和普通饲料组精子浓度升高(P<0.05)。SOD含量(U/mg prot)模型对照组(90.92±4.06)较正常对照组(101.69±8.49)与二甲双胍组(102.04±10.67)降低(P<0.05)。GSH-Px含量(U)正常对照组(28.32±2.28)较模型对照组(23.49±1.08,P<0.01)、二甲双胍组(25.73±2.14,P<0.05)和普通饲料组(25.77±2.19,P<0.05)升高,模型对照组较二甲双胍组降低(P<0.05)。MDA含量(nmol/mg prot)模型对照组(2.68±0.76)较正常对照组(1.84±0.31,P<0.01)、二甲双胍组(1.88±0.33,P<0.01)和普通饲料组(2.14±0.35,P<0.05)升高。结论:二甲双胍治疗和饮食改善均可提高营养性肥胖大鼠精子质量,改善睾丸组织抗氧化能力。     

Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats

AMP-activated protein kinase (AMPK) acts as a cellular energy sensor, being activated during states of low energy charge. Hypothalamic AMPK activity is altered by hormonal and metabolic signals and mediates the feeding response. To determine the effect of diabetes on hypothalamic AMPK activity, we assayed this activity in streptozotocin (STZ)-induced diabetic rats. Compared with control rats, STZ-induced diabetic rats had significant hyperphagia and weight loss. Hypothalamic AMPK phosphorylation and alpha2-AMPK activity were higher and acetyl-CoA carboxylase activity was lower in diabetic rats than in control rats. Chronic insulin treatment or suppression of hypothalamic AMPK activity completely prevented diabetes-induced changes in food intake as well as in hypothalamic AMPK activity and mRNA expression of neuropeptide Y and proopiomelanocortin. Plasma leptin and insulin levels were profoundly decreased in diabetic rats. Intracerebroventricular administration of leptin and insulin reduced hyperphagia and the enhanced hypothalamic AMPK activity in diabetic rats. These data suggest that leptin and insulin deficiencies in diabetes lead to increased hypothalamic AMPK activity, which contributes to the development of diabetic hyperphagia.     

Induction of obesity and hyperleptinemia by central glucocorticoid infusion in the rat.

It has been claimed that factors favoring the development or maintenance of animal or human obesity may include increases in glucocorticoid production or hyperresponsiveness of the hypothalamic-pituitary-adrenal axis. In normal rats, glucocorticoids have been shown to be necessary for chronic intracerebroventricular infusion of neuropeptide Y to produce obesity and related abnormalities. Conversely, glucocorticoids inhibited the body weight-lowering effect of leptin. Such dual action of glucocorticoids may occur within the central nervous system, since both neuropeptide Y and leptin act within the hypothalamus. The aim of this study was to determine the effects of glucocorticoids (dexamethasone) given intracerebroventricularly to normal rats on body weight homeostasis and hypothalamic levels of neuropeptide Y and corticotropin-releasing hormone. Continuous central glucocorticoid infusion for 3 days resulted in marked sustained increases in food intake and body weight relative to saline-infused controls. The infusion abolished endogenous corticosterone output and produced hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia, three salient abnormalities of obesity syndromes. Central glucocorticoid infusion also produced a marked decrease in the expression of uncoupling protein (UCP)-1 and UCP-3 in brown adipose tissue and UCP-3 in muscle. Finally, chronic central glucocorticoid administration increased the hypothalamic levels of neuropeptide Y and decreased those of corticotropin-releasing hormone. When the same dose of glucocorticoids was administered peripherally, it resulted in decreases in food intake and body weight, in keeping with the decrease in hypothalamic neuropeptide Y levels. These results suggest that glucocorticoids induce an obesity syndrome in rodents by acting centrally and not peripherally.     

电针肥胖大鼠后三里或三阴交穴对脂肪代谢指标的影响

目的 观察电针单纯性肥胖大鼠的单穴后三里或三阴交穴对脂肪代谢的调节作用,探讨电针单穴减肥效应.方法 实验前后分别测定各组大鼠（每组8只）的体重、体长、Lee指数以及血清胆固醇（total cholesterol,TC）、三酰甘油（甘油三酯,triglyceride,TG）的含量变化,同时计算Lee指数,观察治疗2个疗程后的数据,用SPSS11.5软件进行数据统计处理.结果 治疗组与模型对照组、治疗组与非经非穴对照组在体重、Lee指数、TC、TG的差异均有统计学意义（P＜0.05或P＜0.01）;治疗组与普通饲料对照组体重、Lee指数、TC、TG的差异均无统计学意义（P＞0.05）.结论 电针后三里或三阴交对单纯性肥胖大鼠的治疗均具有显著性疗效,在减肥和减轻体重方面具有良性地改善调节功能,能减少Lee指数、降低血清TC、TG的浓度水平,其作用机制可能与改善和调节TC、TG代谢紊乱有关.     

Neurobiologic changes in the hypothalamus associated with weight loss after gastric bypass

BACKGROUND: Effects of Roux-en-Y gastric bypass (RYGB) on hypothalamic food intake regulation have not been investigated. The hypothalamic arcuate nucleus (ARC) and the magnocellular (m) and parvocellular (p) parts of the paraventricular nucleus (PVN) regulate hunger and satiety, and are under control of the orexigenic neuropeptide Y (NPY), and the anorexigenic alpha-melanocyte stimulating hormone (alpha-MSH) and serotonin (5-HT). We hypothesized that after RYGB, weight loss is associated with hypothalamic down regulation of NPY and up regulation of 5-HT and alpha-MSH. STUDY DESIGN: Obesity was induced in 12 Sprague Dawley rats using a high-energy diet for 7 weeks, and then the rats were divided into three groups (n = 4/group): RYGB, sham-operated pair-fed (PF), and sham-operated ad libitum (obese control). Ten days after operation, immunohistochemical quantification of NPY, alpha-MSH, and 5-HT(1B)-receptors in ARC and PVN was performed. Data were analyzed using ANOVA and Tukey's test. RESULTS: Body weight decreased in RYGB (417 +/- 21 g; mean +/- SE) and in PF (436 +/- 14 g) rats 10 days after operation compared with obese control rats (484 +/- 15 g; p < 0.05 for each comparison). NPY in ARC, pPVN, and mPVN decreased by 43%, 43%, and 61%, respectively in RYGB and by 55%, 42%, and 71% in PF, respectively, compared with obese controls (p < 0.05 for each pairwise comparison). RYGB versus PF did not show differences. alpha-MSH in ARC, pPVN and mPVN increased by 35%, 175%, and 67%, respectively in RYGB and by 29%, 162%, and 116% in PF, respectively, compared with obese controls (each p < 0.05). In mPVN, alpha-MSH significantly decreased by 23% in RYGB versus PF (p < 0.05). 5-HT-(1B)-receptor in pPVN increased by 58% in RYGB and by 26% in PF, compared with obese controls (p < 0.05). Compared with obese controls, 5HT-(1B)-receptor in mPVN increased by 39% in RYGB (p < 0.05) and by 9% in PF (p > 0.05). An increase of 5-HT-(1B)-receptor in pPVN and mPVN occurred in RYGB versus PF (p < 0.05). CONCLUSIONS: Obese rats that undergo weight loss after RYGB demonstrate changes in hypothalamic down regulation of NPY and up regulation of alpha-MSH and serotonin.     

Implantable Gastric Stimulation Alters Expression of Oxytocin- and Orexin-Containing Neurons in the Hypothalamus of Rats

Background: Implantable gastric stimulation (IGS) has been proposed as a therapeutic option for treating obese patients. We studied the underlying central mechanism behind the reduction of food intake and body weight by gastric electrical stimulation (GES), by studying the expression of anorexigenic and orexigenic-peptide containing neurons in the hypothalamus. Methods: Oxytocin antiserum, orexin antiserum and c-Fos protein-antiserum were used for immunostaining technique. Brain sections were obtained from the control rats and those with 2 hours of GES with parameters typically used in the treatment of obesity in humans. Results: A) 2-hr IGS increased the expression of oxytocin-immunoreactive (IR) neurons in the paraventricular nucleus (PVN, 23.7±1.8 vs 31.1±2.2, P<0.05) and the supraoptic nucleus (SON, 29.0±2.2 vs 39.7±2.5, P<0.01). However, the expression of orexinIR neurons in the lateral hypothalamic area (LHA) was decreased (27.8±2.6 vs 20.6±1.7, P<0.01). B) The expression of c-Fos positive neurons was increased in the PVN and SON with IGS. A coexistence of oxytocin-IR positive neurons and c-Fos-IR ones in the PVN and SON from the adjacent brain sections was observed, confirming the activation of OT-containing neurons in the PVN and SON following IGS. Conclusion: IGS increases the expression of hypothalamic neurons containing the anorexigenic neuropeptide, oxytocin, and decreases the expression of neurons containing the orexigenic neuropeptide, orexin. This central anorexigenic effect of GES may contribute to the reduced appetite and increased satiety in obese patients with IGS therapy.     

Adrenalectomy reverses obese phenotype and restores hypothalamic melanocortin tone in leptin-deficient ob/ob mice

In genetically obese leptin-deficient ob/ob mice, adrenalectomy reverses or attenuates the obese phenotype. Relative to lean controls, ob/ob mice also exhibit decreased hypothalamic proopiomelanocortin (POMC) mRNA and increased hypothalamic agouti-related peptide (AGRP) mRNA and neuropeptide Y (NPY) mRNA. It has been hypothesized that this profile of hypothalamic gene expression contributes to the obese phenotype caused by leptin deficiency. To assess if reversal of obese phenotype by adrenalectomy entails normalization of hypothalamic gene expression, male wild-type and ob/ob mice were adrenalectomized (with saline supplementation) or sham adrenalectomized at 2 months of age. Mice were sacrificed 2 weeks after adrenalectomy, during which time food intake and body weight were monitored daily. After sacrifice, hypothalamic gene expression was assessed by Northern blot analysis as well as in situ hybridization. In wild-type mice, adrenalectomy significantly decreased AGRP mRNA but did not significantly influence POMC or NPY mRNA. In ob/ob mice, adrenalectomy reduced the levels of plasma glucose, serum insulin and corticosterone, and food intake toward or below wild-type levels, and it restored hypothalamic POMC and AGRP mRNA but not NPY mRNA to wild-type levels. These studies suggest that adrenalectomy reverses or attenuates the obese phenotype in ob/ob mice, in part by restoring hypothalamic melanocortin tone toward wild-type levels. These studies also demonstrate that factors other than leptin may play a major role in regulating hypothalamic melanocortin function.     

Plasma Ghrelin Modulation in Gastric Band Operation and Sleeve Gastrectomy

BACKGROUND: Gastric band operation and sleeve gastrectomy are increasingly popular bariatric surgeries for weight loss. The purpose of this study is to investigate the changes in plasma ghrelin levels and hypothalamic ghrelin receptor expression with weight loss achieved through these surgeries. METHODS: Twenty-four high fat diet-induced obese rats were used to investigate the effects of gastric band and sleeve operation on Body Mass Index, fat mass, plasma ghrelin levels, and hypothalamic growth hormone secretagogue receptor 1a (GHS-R 1a) protein expression in hypothalamus. In comparison, data of patients who received laparoscopic adjustable gastric banding (LAGB) and laparoscopic sleeve gastrectomy (LSG) in our hospital in 2005 were also summarized. RESULTS: Body weights and fat mass decreased significantly in rats that received operation. Plasma ghrelin concentrations in the sleeve group were 0.4-fold of control rats and about 2-fold of control in the gastric band group. GHS-R1a protein expression in hypothalamus was 1.5-fold in the sleeve group compared with control group, while it was only 0.9-fold in the gastric band group. Clinical data showed that patients in the LSG group lost 60% excess body weights in 2 years follow-up. After operation, fasting plasma ghrelin concentrations in LAGB was significantly higher than the LSG group. CONCLUSION: Both LAGB and LSG can decrease patients' excess body weights and fat mass. Plasma ghrelin levels are down-regulated with LSG operation but up-regulated with LAGB operation. Hypothalamic GHS-R1a expression is elevated in sleeve gastrectomy.     

Neuropeptide Y and the development of cancer anorexia.

OBJECTIVE: The authors determined whether radioligand binding of neuropeptide Y (NPY) to hypothalamus taken from nonanorectic and anorectic tumor-bearing rats was altered as compared with similar tissue taken from freely-feeding and food-restricted control rats. SUMMARY BACKGROUND DATA: Previous results indicate that tumor-bearing rats exhibit a refractory feeding response to NPY, the most potent feeding stimulus known. Additional studies indicate that the concentration of NPY in the hypothalamus of anorectic tumor-bearing rats is decreased as compared with freely-feeding or food-restricted control rats. METHODS: Because these observations of decreased response to exogenous peptide in the presence of decreased endogenous levels suggest an alteration in hypothalamic NPY receptors, this study investigated binding of 125I-NPY to hypothalamic membranes of tumor-bearing and control rats. RESULTS: Determinations of receptor affinity for NPY (half maximal concentration for displacement) indicated a 20-fold decrease in affinity with the development of anorexia, which changed to an 80-fold decrease during severe anorexia. Receptor density, as indicated by specific binding, exhibited only a 30% decrease, even during severe anorexia. CONCLUSIONS: These results suggest major alterations in NPY receptor mechanisms in experimental cancer anorexia, with receptor affinity being decreased progressively as the rats become more anorectic. The absence of a compensatory up-regulation in receptor density in the presence of decreased endogenous NPY concentrations indicate dysfunction in receptor regulatory mechanisms. This receptor aberration may be the central nervous system basis for the etiology of cancer anorexia.     

Altered neuropeptide Y concentrations in specific hypothalamic regions of obese (fa/fa) Zucker rats. Possible relationship to obesity and neuroendocrine disturbances.

Neuropeptide Y (NPY) concentrations were measured by radioimmunoassay in eight microdissected hypothalamic regions of obese (fa/fa) and lean (Fa/?) Zucker rats. Freely fed obese rats showed significant (40-100%) increases in NPY concentrations in several regions, notably the paraventricular, ventromedial, and dorsomedial nuclei and the arcuate nucleus/median eminence, compared with lean rats. Hypothalamic NPY concentrations were not affected in either obese or lean rats by food restriction, which caused 25% weight loss over 3 wk. Refeeding to initial weight significantly increased NPY levels in the ventromedial and dorsomedial nuclei in lean rats but did not significantly alter NPY concentrations in any hypothalamic region in obese rats. These observations indicate fundamental differences in the regulation of hypothalamic NPY between obese and lean Zucker rats. NPY injected into the paraventricular nucleus and other regions causes hyperphagia, obesity, and increased secretion of insulin, glucagon, ACTH, and corticosterone. These behavioral and neuroendocrine abnormalities all occur in the obese Zucker syndrome and may be due to increased NPY-ergic activity in the hypothalamus.     

Appetite suppression and weight reduction by a centrally active aminosterol

The rise in obesity and its complications has generated enormous interest in the regulation of feeding and body weight. We show that a spermine metabolite of cholesterol (MSI-1436) decreases body weight, specifically fat, by suppressing feeding and preventing the reduction in energy expenditure, hormonal changes, and patterns of neuropeptide expression normally associated with weight loss. MSI-1436 enters the brain after peripheral injection and is more potent when injected into the cerebral ventricle (intracerebroventricular [ICV]). Systemic or ICV MSI-1436 administration induced similar patterns of Fos immunoreactivity in the brain, especially the paraventricular hypothalamic nucleus (PVN). This brain region integrates neural signals from hypothalamic and brain stem nuclei and regulates feeding behavior, autonomic function, and neuroendocrine function. Microinjection of MSI-1436 into the PVN potently suppressed feeding and reduced body weight for several days. Unlike caloric restriction, MSI-1436 decreased mRNA levels of agouti-related peptide and neuropeptide Y in the hypothalamus. These findings indicate that MSI-1436 acts in the brain to regulate food intake and energy expenditure, likely through suppression of orexigenic hypothalamic pathways.