【作者】 翟百强；

【导师】 罗云波；

【作者基本信息】 中国农业大学 ， 食品生物技术， 2018， 博士

【摘要】 能量代谢失衡会诱发如肥胖症、Ⅱ型糖尿病、非酒精性脂肪肝、心血管等多种疾病,这些疾病也成为全球面临的一个重要且严峻的公共健康问题。由于棕色脂肪(BAT)在减少机体白色脂肪、改善胰岛素敏感性等多方面的显著效果,使BAT成为大健康领域的热门研究。BAT中含有丰富的线粒体,线粒体内膜上的解耦联蛋白通过产热作用促进能量消耗,进而调控糖代谢稳态,加大甘油三酯的吸收代谢。通过有效手段激活机体棕色脂肪并改善机体能量代谢科学依据充分,本文是通过利用物理激活、药物激活、食品激活三种不同手段,探讨了每种方式激活BAT对能量代谢的影响,主要研究结果如下:1、通过物理方法有效激活小鼠BAT。在进行冷暴露和BAT摘除实验发现,调节葡萄糖及脂质代谢的成纤维细胞生长因子FGF21的mRNA的表达在冷应激中上调,冷暴露8h最大化,血液中的FGF21水平有显著升高,在整个实验阶段保持较高水平。白色脂肪棕色化的相关基因CD137的表达量和脂肪组织的组织学的结果进一步提示,FGF21与白色脂肪棕色化的现象成正相关性。实验还发现,在冷暴露前期,激活BAT有效加大甘油三酯的快速消耗,冷暴露后期,白色脂肪棕色化程度提高,呈现持续BAT激活的现象。通过小鼠的BAT摘除实验发现,减少BAT的小鼠在冷暴露环境仍然保持促进白色脂肪棕色化的特性,这进一步暗示米色脂肪细胞的形成可能受到白色脂肪在冷诱导压力期间交感神经输入的控制。2、通过血管紧张素转换酶抑制剂(ACEI)成品药福辛普利有效激活小鼠BAT。采用处理高脂饮食诱导肥胖(DIO)小鼠的实验发现,ACEI可以显著地提高BAT线粒体内膜上的解耦联蛋白Ucp1以及氧化磷酸化相关基因的表达量。ACEI处理高脂饮食诱导的肥胖小鼠可以有效地提高小鼠糖代谢、胰岛素敏感性和能量代谢水平,抑制小鼠肥胖的发生。3、食品中有效功能活性成分激活小鼠BAT。分别采用天然食品大蒜中功能活性成分蒜氨酸及大蒜素处理DIO小鼠实验发现,蒜氨酸和大蒜素均可以有效改善DIO小鼠的葡萄糖利用率,提高胰岛素敏感性,抑制DIO小鼠脂肪肝发生。通过蒜氨酸和大蒜素对DIO小鼠的自发运动量、能量摄入量、采用远红外扫描仪热图像、正电子发射计算机断层显像(PET-CT)等综合统计和比较发现,大蒜素可以有效激活DIO小鼠的BAT活性,能量代谢指标差异性显著。通过以上物理、药物、食品的处理方法,对激活机体BAT,进而提高能量代谢、降低肥胖、提高胰岛素敏感性等代谢障碍相关的疾病干预提供一个崭新的思路。更多还原

【Abstract】 The imbalance of the energy metabolism,which has become an increasingly important and serious public health concern worldwide,is a major risk factor for many diseases,such as obesity,type II diabetes,nonalcoholic fatty liver disease,and cardiovascular disease,etc.The brown adipose tissue(BAT)plays an important role in modulating energy balance of healh field due to its ability to enhance energy expenditure in a manner of uncoupling proteins dependent mitochondrial membrane potential reduction.Therefore,taking advantage of BAT activation to burn extra triglycerides is an attractive and effective way to improve energy metabolism balance.In the current research,we investigated the effects of three different methods,including physical,chemical and functional food activation,on BAT functions,the major findings are as follows:1.From the physical activation aspect,the mice were treated with 4℃ cold temperature.We found that the mRNA expression of FGF21 in BAT was significantly up-regulated upon 8 hours of cold exposure.Consistently,serum FGF21 levels also significantly increased upon 8 hours of cold exposure and kept in high levels during the entire experimental periods.In addition,the expression of beige cell mark CD 137 together with the histological results showed a strong positive correlation between FGF21 and BAT formation.Moreover,we found that at early time point of the cold exposure,the mobilization of triglyceride by BAT is the major phenotype,whereas at late stage of the cold exposure,it changed into sustained BAT activation.The results from BAT removal experiment further revealed that the mice without BAT still had the ability of beige formation,which indicated that beige cell formation was mainly controlled by neurological input.2.For chemical BAT activation,the diet induced obesity(DIO)mice were treated with Fosinopril,a third-generation drug of angiotensin-converting enzyme inhibitor(ACEI).We found that ACEI treatment could significantly activate BAT by up-regulation of BAT specific gene UCP1 and fatty acid oxidation related gene expression.In addition,ACEI significantly increased the resting metabolic rate,energy expenditure and heat production in DIO mice.Moreover,ACEI treatment prominently reduced adiposity,improved lipid metabolism,accelerated glucose homeostasis and alleviated insulin resistance in DIO mice.3.To explore the BAT activation ability of functional food ingredients,the DIO mice were treated with garlic extracts,alliin and allicin.We found alliin had no significant effects on BAT function.However,the allicin treatment significantly increased glucose expenditure and improved insulin sensitivity,leading to an efficient reduction in fasting plasma glucose level and effective protection for fatty liver.Through the alliin and allicin on spontaneous activity of mice DIO,energy intake,using infrared thermal image scanner,positron emission computed tomography imaging(PET-CT),and other comprehensive statistics and comparison,further validated the BAT activation by allicin.Taken together,multi-dimentional experiments including phisical,chemical and functional food ingredients treatments were performed on animal models in the current study.We found these methods could significantly activate BAT,thus improving energy metabolism,reducing adiposity,increasing insulin sensitivity and alleviating fatty liver.We believe the current study paves new ways to treat the metabolic diseases caused by the imbalance of energy metabolism.更多还原