高脂饮食对大鼠下丘脑前增食欲素原及CRH表达的影响

目的观察高脂饮食摄入对大鼠下丘脑前增食欲素原增食欲素受体1、2及促肾上腺皮质激素释放激素（cRH）表达的影响。方法高脂饮食喂养3周后,观察高脂饮食摄入前后大鼠下丘脑及前增食欲素原、增食欲素受体1、2mRNA表达;观察CRHmRNA表达水平变化。结果高脂饮食摄入后大鼠前增食欲素原mRNA表达降低（P〈0．05）;两组组间增食欲素受体1和受体2mRNA表达,差异均无统计学意义（P〉0．05）。高脂饮食摄入后下丘脑CRH表达无明显增加。结论高脂饮食诱导大鼠过度摄食的机制可能与下丘脑CRH、增食欲素等食欲调节因子表达失调,对摄食行为失控制有关。     

咖啡豆提取物对肥胖大鼠血清瘦素、脂联素水平及脂联素受体表达水平的影响

目的 研究咖啡豆提取物对高脂饮食肥胖大鼠的瘦素(Leptin,LP)、脂联素(APN)及脂联素受体表达的影响。方法 给予高脂饲料建立SD大鼠肥胖模型,灌胃给予咖啡豆提取物(800,267,133 mg·kg^-1),连续6周。测量大鼠体质量及脂体比,测定大鼠血浆总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、血清LP、APN;检测肝组织脂联素受体表达。结果 与正常对照组相比,给予高脂饲料6周的大鼠体质量明显增加(P<0.01),提示SD大鼠肥胖模型建立。与模型组比较,咖啡豆提取物给药后大鼠体质量、脂体比和LP水平下降(P<0.01或P<0.05),血清APN水平、APN受体的mRNA和蛋白表达显著增加(P<0.01或P<0.05)。结论 咖啡豆提取物对高脂饮食肥胖大鼠的体质量具有改善作用,作用机制可能是升高血清APN水平,降低LP水平及上调肝脏脂联素受体的mRNA和蛋白表达。     

糖尿病性肥胖大鼠模型的建立及西布曲明对其治疗作用的研究

目的:研究链脲佐菌素(STZ)联合高营养饲料诱导的大鼠糖尿病性肥胖模型的特点,以及盐酸西布曲明对此种模型的治疗作用。方法:先用小剂量STZ(25mg/kg)尾静脉注射诱导大鼠产生糖尿病,再用高营养饲料喂养4个月建立糖尿病性肥胖模型。盐酸西布曲明4mg/kg灌胃治疗17d,给药期间定时测定体重及摄食量,15d时测定糖耐量,实验终点时测定体重、内脏脂肪及右比目鱼肌重量;取血分离血清测定血脂、血糖和血清胰岛素水平,并计算胰岛素抵抗指数。结果:模型组大鼠体重、内脏脂肪重量及系数均显著升高,而右比目鱼肌系数显著降低;空腹血糖、血胰岛素水平显著升高,并出现糖耐量异常及胰岛素抵抗;TG水平显著升高,而高密度脂蛋白胆固醇(HDL-C)水平显著降低。盐酸西布曲明可减轻糖尿病肥胖大鼠的体重、内脏脂肪含量和系数,改善高胰岛素血症和胰岛素抵抗,降低血TG水平,同时升高HDL-C水平。对右比目鱼肌系数,血糖、总胆固醇和低密度脂蛋白胆固醇(LDL-C)水平,以及糖耐量无明显影响。结论:STZ联合高营养饲料可成功诱导糖尿病性肥胖的大鼠模型,盐酸西布曲明对大鼠糖尿病肥胖具有一定的治疗作用。     

利拉鲁肽对肥胖大鼠体质量、血脂水平和下丘脑炎症通路的影响研究

目的:研究利拉鲁肽对肥胖大鼠体质量和血清中总胆固醇(TC)、甘油三酯(TG)水平及下丘脑炎症通路的影响。方法:取大鼠分别用基础饲料和高脂饲料喂养8周后,分为正常对照组、肥胖组、肥胖-利拉鲁肽组。正常对照组和肥胖组大鼠腹腔注射0.9%氯化钠注射液,肥胖-利拉鲁肽组大鼠腹腔注射利拉鲁肽100μg/kg,每日2次,连续8周。末次给药后隔夜禁食处死大鼠,称体质量,检测各组大鼠给药前和末次给药后血清中TC、TG水平和下丘脑细胞核因子κB(NF-κB)mRNA及细胞因子信号转导抑制因子3(SOCS-3)蛋白的表达。结果:与正常对照组比较,肥胖组大鼠体质量和血清中TC、TG水平及下丘脑NF-κB mRNA、SOCS-3蛋白表达水平均明显升高(P<0.01);与肥胖组比较,肥胖-利拉鲁肽组大鼠体质量和血清中TC、TG水平及下丘脑NF-κB mRNA、SOCS-3蛋白表达水平均较明显降低(P<0.01)。结论:利拉鲁肽能显著改善高脂诱导肥胖大鼠的体质量增加、血脂紊乱,其机制可能涉及下丘脑炎症调节通路的改善。     

盐酸西布曲明对营养性肥胖大鼠的减肥作用

目的 :研究盐酸西布曲明对营养性肥胖大鼠的减肥作用。方法 :给刚断乳的SD大鼠饲喂营养性饲料 ,7wk后养成营养性肥胖模型 ,分组给药 ,连续 6wk。结果 :盐酸西布曲明 9.0、3.0、1.0mg·kg-1灌胃给药 ,能明显降低肥胖大鼠体重、Lee's指数和脂肪重量 ,降低血清甘油三酯水平 ,抑制脂肪细胞增大 ,但对肥胖大鼠空肠绒毛的密度和肠绒毛直径无明显影响。结论 :盐酸西布曲明灌胃给药对营养性肥胖大鼠有显著的减肥降脂作用。     

罗格列酮对糖耐量受损大鼠血清脂联素和肝脏脂联素受体表达的影响

目的探讨罗格列酮对糖耐量受损大鼠血清脂联素和肝脏脂联素受体-1表达的影响。方法60只Wistar雄性大鼠随机分为对照组(普通饲料喂养)和高脂组(高脂饲料喂养)。每周记录体质量变化,每2周作1次糖耐量试验;用HOMA胰岛素抵抗指数评价胰岛素抵抗程度,用反转录聚合酶链反应和蛋白印迹法分别测定脂联素受体1 mRNA和蛋白在肝脏的表达,成模后用罗格列酮干预4周。结果①12周时高脂组有18只大鼠成模,其2 h血糖均值达到了糖耐量受损的诊断标准,空腹血糖高于对照组(P<0.05),但未达到空腹血糖受损的诊断标准;②成模组大鼠体质量明显增加,空腹胰岛素和HOMA-IR指数高于对照组(P<0.05);③罗格列酮干预4周后血清脂联素水平较模型组升高(P<0.05),肝脏组织脂联素受体1 mRNA和蛋白的表达与模型组相比差异无统计学意义(P>0.05)。结论脂联素表达的下降在高脂饮食导致的胰岛素抵抗的发生中起着重要作用,罗格列酮可升高血清脂联素水平,但不影响肝脏脂联素受体-1的表达。     

营养性肥胖大鼠体内血糖及胰岛素的变化

目的研究营养性肥胖大鼠血糖、血脂及胰岛素的变化。方法建立高脂饮食诱导的营养性肥胖大鼠模型,微型血糖仪测血糖,生化酶法测定血清血脂及化学发光免疫分析法测定血清胰岛素水平。结果大鼠饲养8周后,高脂膳食诱导大鼠出现营养性肥胖;肥胖组大鼠体质量、体质指数、胰岛素、血糖、三酰甘油(TG)、胆固醇(TC)、低密度脂蛋白(LDL-C)高于正常对照组(P<0.05)。结论高脂膳食成功诱导营养性肥胖大鼠模型,具有血糖、血脂、胰岛素显著升高等特点,提示在肥胖组大鼠有胰岛素抵抗存在。     

慢性脑缺血大鼠睡眠障碍的机制探讨

目的:研究慢性脑缺血及睡眠剥夺(sleep deprivation,SD)后大鼠下丘脑食欲素原mRNA的表达变化,初步探讨慢性脑缺血大鼠睡眠障碍的可能机制。方法:采用改良式双侧颈总动脉永久性结扎法制作大鼠慢性脑缺血模型,造模3周后大鼠进入慢性脑缺血期,再施以睡眠剥夺刺激。睡眠剥夺用小平台水环境法(flower pots tetchnique),分SD12h与SD3d两大组。存活大鼠随机分为空白组、假手术组、模型组、空白SD12h组、假手术SD12h组、模型SD12h、空白SD3d组、假手术SD3d组、模型SD3d组(n=4),用荧光定量PCR方法检测慢性脑缺血大鼠及睡眠剥夺后大鼠下丘脑食欲素原mRNA的表达变化。结果:与假手术组相比,模型SD12h组、SD3d各组下丘脑的食欲素原mRNA表达均上升(P<0.01);与空白组相比,模型组大鼠下丘脑的食欲素原mRNA表达下降(95%可信区间为(0.10,1.29)),而模型SD12h组、空白SD3d组及模型SD3d组表达均上升(95%可信区间为分别为(-6.46,-1.05)、(-12.63,-0.77)、(-8.93,-0.07))。模型SD12h与假手术SD12h组相比下丘脑食欲素原mRNA表达增加(P<0.01),SD3d各组间虽无统计学意义,但有上升的趋势。结论:食欲素与睡眠之间有密切的关系,慢性脑缺血大鼠睡眠障碍的可能机制之一——模型改变了食欲素的表达。     

替米沙坦对OLETF大鼠脂肪细胞因子网膜素、视黄醇结合蛋白4及内脂素的影响

目的：研究血管紧张素Ⅱl型(AT1)受体阻滞剂替米沙坦对改善OLETF大鼠胰岛素抵抗(IR)的作用及其机制。方法：肥胖自发2型糖尿病雄性OLETF大鼠47只,高脂喂养22周诱导建立胰岛素抵抗大鼠模型。随机分为5组,胰岛素抵抗对照组（OLETF）大鼠给予高脂饮食,替米沙坦组(L)高脂饮食加替米沙坦,二甲双胍组（MET）高脂饮食加二甲双胍,吡格列酮组（P）高脂饮食加吡格列酮,低剂量替米沙坦组(VL) 高脂饮食加低剂量替米沙坦,干预26周后测定空腹血糖、空腹胰岛素、游离脂肪酸、血脂、网膜素、视黄醇结合蛋白4、内脂素水平。结果：替米沙坦具有改善OLETF自发胰岛素抵抗大鼠的胰岛素抵抗和糖、脂代谢的作用,药物干预组与胰岛素抵抗对照组比较,血清网膜素表达水平明显升高(F=6.888,P<0.001), 血清视黄醇结合蛋白4表达水平明显降低(F=7.236,P<0.001),血清内脂素表达水平明显降低(F=4.165,P=0.003),血脂水平和胰岛素抵抗得到明显改善。结论：替米沙坦可能通过提高血清网膜素表达、降低血清视黄醇结合蛋白4及内脂素表达,调节血脂水平,改善胰岛素抵抗。     

罗格列酮对高脂血症大鼠心肌脂联素系统的调节作用

目的探讨罗格列酮对高脂血症大鼠心肌脂联素及其受体表达的影响,阐述过氧化物酶体增殖物激活受体γ(PPARγ)激动药心肌保护的新机制。方法28只WKY大鼠随机分为普通饲料组、高脂饲料组和罗格列酮(4mg·kg-1.d-1)组。24wk处死动物,采用全自动生化分析仪测定血脂,HE和Masson染色观察心肌形态学变化、测定心肌肥厚指数和平均心肌细胞直径,ELISA、RT-PCR和免疫组化法测定心肌脂联素及脂联素受体1和2(AdipoR1和AdipoR2)的表达。结果罗格列酮显著抑制高脂饮食引起的血脂升高和体重增加、抑制细胞内脂质沉积及心肌细胞肥大、增加心肌组织局部脂联素水平及其受体1基因和蛋白的表达。结论罗格列酮通过改善脂质代谢、增加心肌局部脂联素水平及其AdipoR1基因和蛋白的表达拮抗高脂血症所致心肌损害,从而发挥心肌保护作用。     

The effect of clomipramine on wake/sleep and orexinergic expression in rats

We have previously found that neonatal treatment with clomipramine (CLI) induced a decrease in brain orexins during the juvenile period and that these changes were reversed at adulthood. This study investigated the effect of CLI on the orexinergic component and sleep/wake states. Two groups of adult male rats were conducted for 48-h polysomnographic recording. One group of rats was treated with CLI (20 mg/kg every 12 h), and a second group was treated with equivolume of saline (SAL) simultaneously after the first 24 h of polysomnographic recording. Rats were killed 2 h after the third dose of treatment. Brain tissues were collected for radioimmunoassay quantification of orexins and real-time PCR analysis of prepro-orexin and orexin receptor mRNA. The CLI group had significantly shorter rapid eye movement (REM) sleep and longer REM latency compared with both the baseline day and the SAL group and had significantly less active wake and more quiet wake. Compared with the control rats, the CLI rats had significantly higher mRNA expression of prepro-orexin in the hypothalamus and the frontal cortex, but not in the hippocampus. The CLI rats also had significantly less orexin B in the hypothalamus than the control rats. These results suggest that suppression of active wake and orexin B by CLI may be a factor responsible for CLI-induced depression and that the increase of prepro-orexin mRNA may be a sign of increased brain orexins found in this model.     

疏肝和胃汤对抑郁模型大鼠血清、下丘脑中Orexin-A、CCK水平及下丘脑室旁核中OX1-R、CCK-AR表达的影响

目的：观察疏肝和胃汤对抑郁模型大鼠行为学、胃排空和血清、下丘脑中食欲素-A （orexin-A）、胆囊收缩素（cholecystokinin,CCK）水平及下丘脑室旁核（paraventricular nucleus,PVN）中食欲素1型受体（orexin receptor type 1,OX1-R）和胆囊收缩素A型受体（cholecystokinin receptor type A,CCK-AR）表达的影响,探讨疏肝和胃汤改善抑郁模型大鼠胃排空延迟的作用机制。方法：将115只SD大鼠随机分为空白组19只,造模组96只。以慢性不可预知性应激制作抑郁模型,造模5周后,筛选出行为学表现及体质量相近的85只大鼠,分为模型组、疏肝和胃汤低剂量组、中剂量组、高剂量组、氟西汀组。空白组与模型组给予生理盐水;疏肝和胃汤低、中、高剂量组分别按3.67,7.34,14.68 g·（kg·d）^-1给药;氟西汀组按1.58 mg·（kg·d）^-1给药,连续给药7 d,每天2次。采用糖水消耗实验和新奇摄食抑制实验评价大鼠行为学;比色法检测大鼠甲基橙胃残留率,计算胃排空率;ELISA法检测血清、下丘脑中orexin-A和CCK的含量;RT-PCR法检测下丘脑prepro-orexin、CCK、OX1-R及CCK-AR mRNA的表达;免疫荧光法检测下丘脑室旁核中OX1-R与CCK-AR的表达。结果：抑郁模型大鼠糖水偏好率下降（P<0.05）,进食潜伏期延长（P<0.01）,胃排空率降低（P<0.05,或P<0.01）,与模型组比较,疏肝和胃汤可改善糖水偏好率（P<0.05,或P<0.01）,缩短进食潜伏期（P<0.05）,升高胃排空率（P<0.05）;抑郁模型大鼠血清、下丘脑中orexin-A含量下降,CCK含量升高（P<0.01）,疏肝和胃汤升高orexin-A含量,降低CCK含量（P<0.05,或P<0.01）;抑郁模型大鼠下丘脑中prepro-orexin、OX1-R mRNA表达下降,CCK、CCK-AR mRNA表达升高（P<0.01）;疏肝和胃汤升高Prepro-Orexin、OX1-R mRNA的表达,降低CCK、CCK-AR mRNA的表达（P<0.01或P<0.05）;抑郁模型大鼠下丘脑室旁核中OX1-R表达下降,CCK-AR表达升高（P<0.05,或P<0.01）,疏肝和胃汤升高OX1-R的表达,降低CCK-AR表达（P<0.01或P<0.05）。结论：抑郁模型大鼠的胃排空延迟可能与orexin、CCK及其受体的异常改变有关;疏肝和胃汤可能通过调节orexin、CCK及其受体,从而改善抑郁模型大鼠胃排空延迟。     

西布曲明对谷氨酸钠诱导的肥胖动物模型的影响

目的　评价西布曲明 (Sibutramine ,Meridia ,MR)对肥胖动物的减肥作用。方法　取刚出生d 1的大鼠 ,♀♂兼用 ,皮下注射谷氨酸钠 (MSG) 3mg·g-1·d-1,连续 5d ;以诱导动物产生肥胖。在造型后 2 1d ,将肥胖动物按体重随机均分为 5组 ,分别灌胃MR 2 0、4 0和 8 0mg·kg-1·d-1;安菲拉酮 6 0mg·kg-1·d-1,模型组和对照组则均给 0 5 %CMC10ml·kg-1·d-1,连续 2 8d。在实验结束时 ,取样检测各指标。结果　研究显示 ,MR可使MSG诱导的肥胖大鼠体重增加减慢 ,使其脂肪垫重量及其Lees指数减少 ,脂肪细胞直径变小 ,脂肪细胞数 (一个视野内 )增加 ,使MSG大鼠血清甘油三酯降低 ,使其在禁食状态下降低的血糖及胰岛素水平恢复正常。MR对MSG的作用主要是降低其TG水平 ,而对TC无明显作用。结论　试验结果显示MR具有调节和改善脂质代谢及明显的减肥作用     

氯丙咪嗪对大鼠增食素系统mRNA表达的影响

目的观察皮下注射氯丙咪嗪（CLI）对成年大鼠增食素（orexin）系统各成分mRNA表达的影响。方法 16只大鼠被随机分为两组,注射等量的CLI（20 mg/kg）和生理盐水3次。第3次注射后2h将大鼠断头处死,收集脑组织行半定量RT-PCR测定额叶皮层、海马、下丘脑orexin前体和orexin受体的mRNA。结果与生理盐水对照组相比,在额叶皮层、海马和下丘脑,CLI组的orexin前体和orexin2型受体（OX2R）mRNA表达显著减少;但orexin 1型受体（OX1R）mRNA在3个脑区的变化均不显著。结论 CLI抑制了大鼠脑内orexin前体和OX2RmRNA的表达。     

Sibutramine reduces feeding, body fat and improves insulin resistance in dietary-obese male Wistar rats independently of hypothalamic neuropeptide Y

We studied the effects of the novel noradrenaline and serotonin (5-HT) reuptake inhibitor sibutramine on feeding and body weight in a rat model of dietary obesity, and whether it interacts with hypothalamic neuropeptide Y (NPY) neurones. Chow-fed and dietary-obese (DIO) male Wistar rats were given sibutramine (3 mg kg(-1) day(-1) p.o.) or deionized water for 21 days. Sibutramine decreased food intake throughout the treatment period in both dietary-obese rats (P<0.0001) and lean rats (P<0.0001). Weight gain was reduced so that final body weight was 10% lower in dietary-obese (P<0.005) and 8% lower in lean (P<0.05) rats versus their untreated controls. Plasma leptin concentration was lower in sibutramine-treated dietary-obese rats (P<0.05), and in treated lean rats (P<0.05). Using the homeostasis model assessment (HOMA) as a measure of insulin resistance, untreated DIO rats were significantly more insulin resistant than controls (P<0.005), and this was corrected by sibutramine treatment (P<0.05). Neither hypothalamic NPY mRNA nor NPY peptide levels in a number of hypothalamic nuclei were significantly altered by sibutramine compared to untreated controls. The hypophagic and anti-obesity effects of sibutramine in dietary-obese Wistar rats appear not to be mediated by inhibition of ARC NPY neurones.     

Sibutramine: new preparation. Slight weight loss; but also a slight rise in blood pressure ..

(1) The reference treatment for achieving weight loss by obese patients is a combination of dietary measures, exercise and behavioural interventions. There is currently no drug treatment with demonstrated efficacy on the morbidity or mortality associated with excess body weight. (2) Sibutramine, a serotonin- and noradrenaline-reuptake inhibitor structurally related to the amphetamines has been granted marketing authorisation in France for the treatment of obesity and excess body weight in patients with associated risk factors. (3) The clinical file on sibutramine contains no trial focusing on morbidity or mortality end points. (4) According to comparative clinical trials, weight loss during a 6-12 month course of sibutramine is, on average, between 3 and 9 kg greater than that on placebo. Patients regain weight after sibutramine cessation. (5) Sibutramine has little or no benefit on blood sugar or lipid parameters. (6) The main known adverse effect of sibutramine is increased blood pressure. Sibutramine also has amphetamine-like side effects. (7) In practice, sibutramine currently has no place in the management of obesity.     

A review of the metabolic effects of sibutramine

BACKGROUND: Obesity is associated with an increased incidence of diabetes, hypertension, dyslipidaemia and coronary artery disease. Current management strategies of obesity include lifestyle management strategies of obesity include lifestyle interventions and pharmaco therapy. Sibutramine is a drug with established efficacy in weight reduction and maintenance of weight loss. It reduces food intake and attenuates the fall in reduces food intake and attenuates the fall in metabolic rate associated with weight loss. OBJECTIVE: To review the metabolic effects associated with sibutramine use. METHODS: Relevant articles were identified through a Medline search (up to December 2004). RESULTS: Weight loss with sibutramine treatment is associated with improved insulin sensitivity and a fall in glycosylated haemoglobin levels in type 2 diabetic patients. In most trials sibutramine exerted favourable effects on lipids, especially exerted favourable effects on lipids, especially on high density lipoprotein (HDL) cholesterol and triglycerides, as well as on the total:HDL cholesterol ratio. Sibutramine also lowers serum uric acid concentrations. Furthermore, this drug seems to favourably influence adipocytokines; it reduces serum leptin and resistin levels and increases adiponectin levels. Sibutramine also exerts a beneficial effect on hyper androgenaemia in obese women with polycystic ovary syndrome. Preliminary findings also suggest that weight loss following treatment with sibutramine is useful in patients with non-alcoholic fatty liver disease (NAFLD). CONCLUSION: Weight loss following sibutramine administration is associated with several favourable metabolic effects.     

小鼠代谢综合征模型的特征及西布曲明的治疗作用研究

目的研究高脂饲料诱导C57BL/6 J小鼠形成代谢综合征(MS)模型的特点,以及盐酸西布曲明对MS小鼠的治疗作用。方法用含10%猪油、2%胆固醇及0.4%胆酸钠的高脂饲料喂养9 wk♂C57BL/6 J小鼠18.5 wk,然后用西布曲明8 mg.kg-1灌胃10 d。实验终点时测定体重、腹腔内脏脂肪及肝脏湿重和肝游离脂肪酸(FFA)含量;取血分离血清测定血脂、血糖和血清胰岛素水平,并计算胰岛素抵抗指数;肝组织进行HE染色和油红O染色,光镜下观察脂肪病变程度。结果模型组小鼠脂肪重量及系数、肝脏重量均明显升高,肝组织切片光镜下可见明显的脂肪病变;血总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)及低密度脂蛋白胆固醇(LDL-C)水平均升高,且以LDL-C升高最为明显;高胆固醇喂养使模型小鼠血甘油三酯(TG)水平降低。西布曲明可改善MS小鼠的中心性肥胖、高血糖、高胰岛素血症和胰岛素抵抗,并进一步降低MS小鼠的血TG水平;但是,西布曲明可增加肝FFA含量,对MS小鼠的肝脏湿重及肝脂肪病变无改善作用。结论高脂饲料长期喂养C57小鼠可成功建立类似人类MS表现的动物模型;西布曲明可改善MS小鼠的中心性肥胖、糖脂代谢异常、增加机体对胰岛素的敏感性,对MS有一定的治疗作用。