利拉鲁肽对高脂诱导肥胖大鼠脂肪组织内质网应激作用的研究

发布时间：2018-03-18 06:47

  本文选题：肥胖　切入点：利拉鲁肽　出处：《郑州大学》2014年硕士论文　论文类型：学位论文

【摘要】：背景 肥胖及超重人口的比例逐年增加，肥胖引发的多种代谢性疾病早已引起学者的注意，但是减肥似乎是世界性的难题，肥胖的相关疾病如代谢综合征、2型糖尿病、冠心病、高脂血症、非酒精性脂肪肝等则随着肥胖人口的增加而逐年增加，肥胖如何引发这么多代谢性疾病？现认为可能与肥胖诱发肝脏、胰腺、心血管、脂肪组织出现细胞应激及炎症信号通路激活有关，其中内质网应激占有重要地位。有关利拉鲁肽减轻体重已成为大家的共识，关于其减轻体重的机制研究则层出不穷，有摄食减少学说，有减缓胃肠蠕动等，但内质网应激对其减轻体重的影响则鲜有报道。 目的 利用高脂饮食建立大鼠肥胖模型，同时应用胰高血糖素样肽-1（GLP-1）受体激动剂利拉鲁肽进行干预，探讨利拉鲁肽对高脂饮食诱导肥胖大鼠体重的影响及脂肪组织内质网应激相关分子类PKR的内质网激酶（pancreatic ERkinase，PERK）；肌醇需求激酶1-α（inositol-requiring kinase1-α，IRE1-α）；C/EBP同源蛋白（C/EBP homologous protein， CHOP）；葡萄糖转运蛋白78（glucose-regulated protein78,GRP78）表达的变化。 材料与方法 5周龄雄性清洁级SD大鼠48只，适应性喂养1周后，，随机分为基础饲料组（normal diet control，NC，n=8），高脂饲料组（high fat diet，HF，n=40）。8周后，将HF组体重大于NC组体重x+1.96s的大鼠选择为饮食诱导肥胖组（dietinduced obesity，DIO），NC组继续基础饲料喂养。DIO组大鼠继续高脂饮食，并被随机分为两组，DIOLIRA组腹腔注射利拉鲁肽100μg/kg，DIOSALINE组腹腔注射等量生理盐水，2次/天，共8周。实验期间，实验动物均自由摄食、饮水，温度20℃-24℃，相对湿度40%-60%，明暗周期为12h/12h。每天记录进食量，每周测定大鼠体重。16周末，隔夜禁食称重处死大鼠，取肾周及睾周脂肪组织，迅速置于液氮中保存待测。RT-PCR测脂肪组织中类PKR的内质网激酶（PERK）、肌醇需求激酶1-α（IRE1-α）、C/EBP同源蛋白（CHOP）mRNA表达，Western blot测葡萄糖转运蛋白78（GRP78）蛋白的表达。 结果 8周末，猪油高脂饲料饲养的HF组中共筛选出DIO大鼠17只，肥胖发生率为42.5%；16周末，DIOLIRA组体重及脂体比显著高于NC组，而低于DIOSALINE组（P＜0.01）；与NC组比较，DIOSALINE与DIOLIRA组大鼠脂肪组织PERK、IRE1-α、CHOP mRNA表达、GRP78蛋白均显著升高（P＜0.01）；而DIOLIRA组上述指标表达明显低于DIOSALINE组（P＜0.01）。提示利拉鲁肽能部分缓解体重、脂体比及脂肪组织内质网应激因子PERK、IRE1-α、CHOP mRNA及GRP78蛋白表达。 结论 1.本实验以高脂饮食成功诱导大鼠肥胖模型； 2.高脂饮食可通过上调脂肪组织内质网应激标志因子PERK、IRE1-αCHOP mRNA、GRP78的表达诱导肥胖及内质网应激； 3. GLP-1类似利拉鲁肽干预能减轻高脂诱导肥胖大鼠体重、脂体比及脂肪组织内质网应激标志因子PERK、IRE1-α、CHOP mRNA及GRP78蛋白表达。
[Abstract]:Background. The proportion of obese and overweight population is increasing year by year. Many metabolic diseases caused by obesity have long attracted the attention of scholars, but weight loss seems to be a worldwide problem. Obesity related diseases such as metabolic syndrome type 2 diabetes, coronary heart disease, Hyperlipidemia, non-alcoholic fatty liver and so on with the increase in the number of obese people and increasing year by year, obesity how to cause so many metabolic diseases? It is thought that obesity may be related to the activation of cellular stress and inflammatory signaling pathway in liver, pancreas, cardiovascular and adipose tissue, in which endoplasmic reticulum stress plays an important role. There are many studies on the mechanism of weight loss, such as the theory of food intake reduction and the decrease of gastrointestinal peristalsis. However, the effects of endoplasmic reticulum stress on weight loss are rarely reported. Purpose. The obesity model of rats was established by high-fat diet, and the rat obesity model was induced by the intervention of the glucagon like peptide-1 (GLP-1) receptor agonist, Lilaru peptide, at the same time. To investigate the effect of rilalutide on the body weight of obese rats induced by high fat diet and the changes of endoplasmic reticulum kinase pancreatic ERkinase1 (PERKN) associated with endoplasmic reticulum stress (PKR) in adipose tissue, and the expression of inositol-demanding kinase-1- 伪 (IRE1- 伪) C / EBP homologous protein (CHOPN), glucose-regulated protein 78GRP78 (glucose-regulated protein 78GRP78) in adipose tissue. Materials and methods. 48 5-week-old male SD rats of clean grade were randomly divided into normal diet control group (normal diet control group) and high fat dietate group (40. 8 weeks later) after adaptive feeding for 1 week. Rats in HF group and NC group were selected as dietinduced obesity group (dietinduced obesityn) group, NC group continued basic diet feeding, DIO group rats continued to maintain high fat diet, the rats in HF group were more than NC group in body weight x 1.96 s. The rats were randomly divided into two groups: the control group was injected with 100 渭 g / kg rialurutide 100 渭 g / kg DIOSALINE intraperitoneally for 8 weeks. During the experiment, the animals were fed freely, drank water and the temperature was 20 鈩

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