本文選題：肥胖　切入點(diǎn)：利拉魯肽　出處：《鄭州大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：背景 肥胖及超重人口的比例逐年增加，肥胖引發(fā)的多種代謝性疾病早已引起學(xué)者的注意，但是減肥似乎是世界性的難題，肥胖的相關(guān)疾病如代謝綜合征、2型糖尿病、冠心病、高脂血癥、非酒精性脂肪肝等則隨著肥胖人口的增加而逐年增加，肥胖如何引發(fā)這么多代謝性疾病？現(xiàn)認(rèn)為可能與肥胖誘發(fā)肝臟、胰腺、心血管、脂肪組織出現(xiàn)細(xì)胞應(yīng)激及炎癥信號(hào)通路激活有關(guān)，其中內(nèi)質(zhì)網(wǎng)應(yīng)激占有重要地位。有關(guān)利拉魯肽減輕體重已成為大家的共識(shí)，關(guān)于其減輕體重的機(jī)制研究則層出不窮，有攝食減少學(xué)說，有減緩胃腸蠕動(dòng)等，但內(nèi)質(zhì)網(wǎng)應(yīng)激對(duì)其減輕體重的影響則鮮有報(bào)道。 目的 利用高脂飲食建立大鼠肥胖模型，同時(shí)應(yīng)用胰高血糖素樣肽-1（GLP-1）受體激動(dòng)劑利拉魯肽進(jìn)行干預(yù)，探討利拉魯肽對(duì)高脂飲食誘導(dǎo)肥胖大鼠體重的影響及脂肪組織內(nèi)質(zhì)網(wǎng)應(yīng)激相關(guān)分子類PKR的內(nèi)質(zhì)網(wǎng)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）；葡萄糖轉(zhuǎn)運(yùn)蛋白78（glucose-regulated protein78,GRP78）表達(dá)的變化。 材料與方法 5周齡雄性清潔級(jí)SD大鼠48只，適應(yīng)性喂養(yǎng)1周后，，隨機(jī)分為基礎(chǔ)飼料組（normal diet control，NC，n=8），高脂飼料組（high fat diet，HF，n=40）。8周后，將HF組體重大于NC組體重x+1.96s的大鼠選擇為飲食誘導(dǎo)肥胖組（dietinduced obesity，DIO），NC組繼續(xù)基礎(chǔ)飼料喂養(yǎng)。DIO組大鼠繼續(xù)高脂飲食，并被隨機(jī)分為兩組，DIOLIRA組腹腔注射利拉魯肽100μg/kg，DIOSALINE組腹腔注射等量生理鹽水，2次/天，共8周。實(shí)驗(yàn)期間，實(shí)驗(yàn)動(dòng)物均自由攝食、飲水，溫度20℃-24℃，相對(duì)濕度40%-60%，明暗周期為12h/12h。每天記錄進(jìn)食量，每周測(cè)定大鼠體重。16周末，隔夜禁食稱重處死大鼠，取腎周及睪周脂肪組織，迅速置于液氮中保存待測(cè)。RT-PCR測(cè)脂肪組織中類PKR的內(nèi)質(zhì)網(wǎng)激酶（PERK）、肌醇需求激酶1-α（IRE1-α）、C/EBP同源蛋白（CHOP）mRNA表達(dá)，Western blot測(cè)葡萄糖轉(zhuǎn)運(yùn)蛋白78（GRP78）蛋白的表達(dá)。 結(jié)果 8周末，豬油高脂飼料飼養(yǎng)的HF組中共篩選出DIO大鼠17只，肥胖發(fā)生率為42.5%；16周末，DIOLIRA組體重及脂體比顯著高于NC組，而低于DIOSALINE組（P＜0.01）；與NC組比較，DIOSALINE與DIOLIRA組大鼠脂肪組織PERK、IRE1-α、CHOP mRNA表達(dá)、GRP78蛋白均顯著升高（P＜0.01）；而DIOLIRA組上述指標(biāo)表達(dá)明顯低于DIOSALINE組（P＜0.01）。提示利拉魯肽能部分緩解體重、脂體比及脂肪組織內(nèi)質(zhì)網(wǎng)應(yīng)激因子PERK、IRE1-α、CHOP mRNA及GRP78蛋白表達(dá)。 結(jié)論 1.本實(shí)驗(yàn)以高脂飲食成功誘導(dǎo)大鼠肥胖模型； 2.高脂飲食可通過上調(diào)脂肪組織內(nèi)質(zhì)網(wǎng)應(yīng)激標(biāo)志因子PERK、IRE1-αCHOP mRNA、GRP78的表達(dá)誘導(dǎo)肥胖及內(nèi)質(zhì)網(wǎng)應(yīng)激； 3. GLP-1類似利拉魯肽干預(yù)能減輕高脂誘導(dǎo)肥胖大鼠體重、脂體比及脂肪組織內(nèi)質(zhì)網(wǎng)應(yīng)激標(biāo)志因子PERK、IRE1-α、CHOP mRNA及GRP78蛋白表達(dá)。
[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- 偽 (IRE1- 偽) 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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