节食和运动对肥胖小鼠的干预作用及IRE1在果蜗糖脂代谢中的调控功能
文献类型：学位论文
| 作者 | 黄萍 |
| 学位类别 | 博士 |
| 答辩日期 | 2011-05 |
| 授予单位 | 中国科学院上海生命科学研究院营养科学研究所 |
| 授予地点 | 中国科学院上海生命科学研究院 |
| 导师 | 刘勇 |
| 关键词 | 高脂诱导肥胖 节食 运动 肌醇酶1 糖脂代谢 |
| 其他题名 | Intervention effects of calorie restriction and exercise in obese mice & mediation functions of IRE1 in glucose-lipid metabolism of drosophila |
| 学位专业 | 生物化学与分子生物学 |
| 中文摘要 | 第一章 在过去的20年里，肥胖症已成为威胁人类健康的主要问题。肥胖症与一系列疾病相关，包括胰岛素抵抗、2型糖尿病、心血管疾病、神经性退行性疾病及某些癌症。现代社会的生活方式使人处于一个极易增加体重的状态，尤其是脂肪组织的增加，导致了肥胖症的发生，所以改变生活方式被认为是十分有效干预手段。在这项研究中，我们直接比较了节食和耐力运动以及两者结合在一起后对高脂诱导肥胖小鼠模型的脂肪组织和胰岛素抵抗的影响。用multivariate linear regression analysis对表征葡萄糖耐受实验结果的AUC和代谢指标及肝脏和白色脂肪组织中的前炎症因子基因的表达进行了相关性分析，进一步评估节食和耐力运动在这两大外周组织中的作用。研究发现，节食能显著地改善高脂诱导的肥胖症，极显著地防止高脂诱导的代谢紊乱症的发生。当节食和耐力运动结合在一起进行干预能进一步降低高脂诱导产生的肥胖和胰岛素抵抗。节食和耐力运动都能抑制白色脂肪组织中炎症因子的表达，当两种干预方式结合在一起，显示出叠加效应，但是节食和耐力耐力运动对肝脏中炎症因子的表达没有显著的抑制作用。进一步数据分析表明，高脂诱导的肥胖症及其相关代谢紊乱病症与白色脂肪细胞中炎症因子的表达呈正相关关系，远高于与肝脏中炎症因子的表达的相关性。这些研究结果表明节食和耐力运动对饮食诱导的肥胖症的干预效果虽然有所不同，但共同机制之一就是抑制了白色脂肪组织中炎症因子的表达，暗示了白色脂肪组织中炎症因子的表达是治疗胰岛素抵抗的重要靶点。 第二章 IRE1是最重要最保守的内质网应激感受分子。我们发现在野生型的W1118果蝇中，饥饿能诱导dIRE1发生磷酸化，提示dIRE1在代谢方面有重要的生理功能。因此，我们通过Gal4-UAS系统获得了全身和脂肪体dIRE1基因抑制果蝇。全身和脂肪体dIRE1基因抑制果蝇都表现出对饥饿的敏感，急剧下降的甘油三酯和糖原水平。用葡萄糖，甘油和丙酮酸钠进行补偿实验，结果不能逆转dIRE1基因抑制果蝇对饥饿的敏感性。同时，我们发现在dIRE1基因抑制果蝇中，胰岛素样肽3和Akt分子的磷酸化显著下降。这些结果暗示dIRE1可能通过调控胰岛素样肽3和Akt来调控糖脂代谢。 |
| 索取号 | D2011-122 |
| 英文摘要 | Part I In the last 20 years, obesity has become a public health problem. Obesity is related with various diseases, particularly insulin resistance, type 2 diabetes, cardiovascular disease, Neurodegenerative disease and certain of cancer. Sustained increase in body mass, particularly fat mass result in obesity that increase metabolic syndrome risks in modern life. Lifestyle modifications are known to effectively attenuate obesity and improve metabolic syndrome. Here we directly compare the effects of calorie restriction （CR） and endurance exercise in a mouse model of diet-induced obesity and insulin resistance. To further evaluate the effects of CR and endurance exercise on the two important peripheral tissues, adipose tissues and liver, we performed multivariate linear regression analysis on AUC of the glucose tolerance test and each of the metabolic parameters and pro-inflammation gene expression in adipose tissues and liver. Results demonstrate exercise significantly attenuated high-fat diet-induced obesity. CR dramatically prevented high-fat diet-induced metabolic abnomalities. A combination of CR and endurance exercise further reduced obesity and insulin resistance under the condition of high-fat diet. CR and endurance exercise each potently suppressed the expression of inflammatory cytokines in white adipose tissues with additive effects when combined, but the effects of diet and exercise interventions in the liver were moderate to minimal. Our studies suggest although the effects of CR and exercise on the diet-induced obesity have differences, they share the same mechanize that is to suppress the expression of pro-inflammatory cytokines and targeting the expression of pro-inflammatory cytokines in white adipose tissues presents a viable therapeutic option for the prevention of insulin resistance. PartII IRE1 is the most conserved and important ER stress sensor. Here, we found the starvation can induced phosphorylation of IRE1 in wild type drosophila (w1118).To investigate the physiological role of Drosophila IRE1 (dIRE1), we generated dIRE1 knockdown flies using Gal4-UAS system. Reduced dIRE1 in whole body and fat body decreased survival under starvation conditions. Under starvation condition, disruption of dIRE1 significantly decreased triglyceride level and glycogen level in drosophila. Glucose, glycerol and pyruvate can not rescue the sensitive to starvation in dIRE1 knockdown flies. The phosphorylation of Akt and expression of insulin-like peptide 3 dramatically decreased in dIRE1 deficiency flies. These data suggest that dIRE1 regulation of lipid and glucose metabolism through mediating the synthesis of insulin-like peptide and phosphorylation of Akt. |
| 语种 | 中文 |
| 公开日期 | 2015-12-24 |
| 源URL | [http://202.127.25.144/handle/331004/320]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所_糖脂代谢与调控研究组 |
| 推荐引用方式 GB/T 7714 | 黄萍. 节食和运动对肥胖小鼠的干预作用及IRE1在果蜗糖脂代谢中的调控功能[D]. 中国科学院上海生命科学研究院. 中国科学院上海生命科学研究院营养科学研究所. 2011. |
入库方式： OAI收割
来源：上海营养与健康研究所
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