SIRT6通过在肌肉组织和脂肪组织中发挥不同功能调节机体的代谢稳态
发布时间：2018-07-24 11:45
【摘要】：2型糖尿病和肥胖已经成为当今社会危害人类健康的常见代谢疾病,二者都是由于机体内糖脂代谢紊乱所导致的,但是其发病的最根本机制至今还尚未明确,临床上也没有能够治愈的方法。因此,探究2型糖尿病和肥胖的发病机制,并研发出安全有效的治疗方案,是代谢领域亟需解决的问题。肌肉组织和脂肪组织在机体的能量代谢中都起着重要作用,它们既是机体最重要的产热组织,又是机体糖脂代谢的关键器官。SIRT6是一种依赖于NAD+的去乙酰化酶,已经被证实参与机体的多种代谢调控,但是关于其在肌肉组织和脂肪组织中的特异性作用,至今尚未明确。而鉴定SIRT6在这两种组织中的调控作用将有利于为2型糖尿病和肥胖寻找治疗靶点。我们分别构建了肌肉组织特异性敲除SIRT6的小鼠模型和脂肪组织特异性敲除SIRT6的小鼠模型。我们采用肌肉组织特异性敲除SIRT6的小鼠进行了生理特征分析、代谢笼检测和运动耐力测试等一系列实验,并检测了代谢相关蛋白和基因的表达水平,同时还在C2C12成肌细胞中验证了 SIRT6在肌肉组织中的功能;我们采用脂肪组织特异性敲除SIRT6的小鼠进行了生理特征分析、氧耗测试、刺激诱导产热等一系列实验,还分离了脂肪原代细胞并诱导其分化,验证SIRT6对脂肪组织的特异性调控,同时我们还探索了 SIRT6调控脂肪组织产热的具体分子机制。通过研究我们发现,肌肉组织特异性敲除SIRT6的小鼠机体的葡萄糖耐受性和胰岛素敏感性受损,整体能量输出减少,并且运动中的耐力减弱,原因是SIRT6的缺失降低了AMPK的活性,从而使其下游基因的表达量减少,导致骨骼肌细胞中葡萄糖和脂肪酸的摄入、脂肪酸氧化和线粒体氧化磷酸化作用被减弱,进而导致了机体的代谢紊乱;脂肪组织特异性敲除SIRT6的小鼠表现出明显的肥胖,其棕色脂肪呈现“白色化”,血糖明显升高,并伴随胰岛素抵抗和脂肪肝,整个机体氧耗减少,体温降低,并且β-肾上腺素激动剂和冷刺激诱导的白色脂肪“棕色化”作用也明显减弱。而SIRT6影响脂肪组织产热的根本机制是SIRT6能够与pATF2形成复合物而结合在产热关键调节因子PGClα的启动子区,从而影响PGC1α和其下游产热基因以及线粒体基因的表达,最终影响机体的能量输出。我们的研究揭示了 SIRT6在肌肉组织和脂肪组织中通过发挥特异性作用,影响机体的糖脂代谢稳态和能量平衡,为2型糖尿病和肥胖的治疗提供了潜在的靶点。
[Abstract]:Type 2 diabetes mellitus and obesity have become the common metabolic diseases endangering human health. Both of them are caused by the disorder of glucose and lipid metabolism in the body, but the most basic mechanism of their pathogenesis has not been clarified. There is no cure clinically. Therefore, to explore the pathogenesis of type 2 diabetes and obesity and to develop safe and effective treatment is an urgent problem in the field of metabolism. Both muscle and adipose tissue play an important role in energy metabolism. They are not only the most important heat-producing tissue, but also the key organ of glycolipid metabolism. SIRT6 is a deacetylase dependent on NAD. It has been proved to be involved in a variety of metabolic regulation, but its specific role in muscle and adipose tissue has not been clarified. Identifying the regulatory role of SIRT6 in these two tissues will be helpful in finding therapeutic targets for type 2 diabetes and obesity. We constructed the mouse model of muscle-tissue specific knockout (SIRT6) and adipose tissue specific knockout (SIRT6). We used muscle-specific knockout SIRT6 mice to carry out a series of experiments, such as physiological characteristics analysis, metabolic cage test and exercise endurance test, and detected the expression level of metabolism-related proteins and genes. At the same time, the function of SIRT6 in muscle tissue was verified in C2C12 myoblasts. We used adipose tissue specific knockout SIRT6 mice for a series of experiments, such as physiological characteristics analysis, oxygen consumption test, stimulation induced heat production and so on. The primary adipocytes were isolated and induced to differentiate to verify the specific regulation of SIRT6 on adipose tissue. At the same time, we also explored the specific molecular mechanism of adipose tissue heat production regulated by SIRT6. We found that the glucose tolerance and insulin sensitivity of muscle-specific knockout SIRT6 mice were impaired, the overall energy output was reduced, and endurance during exercise was decreased, because the absence of SIRT6 reduced the activity of AMPK. Therefore, the expression of downstream genes was reduced, and the uptake of glucose and fatty acids in skeletal muscle cells, the oxidation of fatty acids and oxidative phosphorylation of mitochondria were weakened, which resulted in the metabolic disorder of the body. The mice with adipose tissue specific knockout of SIRT6 showed obvious obesity, their brown fat was "white", their blood glucose was significantly increased, and accompanied by insulin resistance and fatty liver, the whole body decreased oxygen consumption and hypothermia. 尾-adrenaline agonists and cold-stimulated white fat browning was also significantly weakened. However, the fundamental mechanism of SIRT6 affecting adipose tissue heat production is that SIRT6 can form complex with pATF2 and bind to the promoter region of PGCl 伪, which affects the expression of PGC1 伪, its downstream heat production gene and mitochondrial gene. Ultimately affect the body's energy output. Our study revealed that SIRT6 plays a specific role in muscle and adipose tissue, which affects the homeostasis and energy balance of glucose and lipid metabolism, and provides a potential target for the treatment of type 2 diabetes and obesity.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R587.1;R589.2
[Abstract]:Type 2 diabetes mellitus and obesity have become the common metabolic diseases endangering human health. Both of them are caused by the disorder of glucose and lipid metabolism in the body, but the most basic mechanism of their pathogenesis has not been clarified. There is no cure clinically. Therefore, to explore the pathogenesis of type 2 diabetes and obesity and to develop safe and effective treatment is an urgent problem in the field of metabolism. Both muscle and adipose tissue play an important role in energy metabolism. They are not only the most important heat-producing tissue, but also the key organ of glycolipid metabolism. SIRT6 is a deacetylase dependent on NAD. It has been proved to be involved in a variety of metabolic regulation, but its specific role in muscle and adipose tissue has not been clarified. Identifying the regulatory role of SIRT6 in these two tissues will be helpful in finding therapeutic targets for type 2 diabetes and obesity. We constructed the mouse model of muscle-tissue specific knockout (SIRT6) and adipose tissue specific knockout (SIRT6). We used muscle-specific knockout SIRT6 mice to carry out a series of experiments, such as physiological characteristics analysis, metabolic cage test and exercise endurance test, and detected the expression level of metabolism-related proteins and genes. At the same time, the function of SIRT6 in muscle tissue was verified in C2C12 myoblasts. We used adipose tissue specific knockout SIRT6 mice for a series of experiments, such as physiological characteristics analysis, oxygen consumption test, stimulation induced heat production and so on. The primary adipocytes were isolated and induced to differentiate to verify the specific regulation of SIRT6 on adipose tissue. At the same time, we also explored the specific molecular mechanism of adipose tissue heat production regulated by SIRT6. We found that the glucose tolerance and insulin sensitivity of muscle-specific knockout SIRT6 mice were impaired, the overall energy output was reduced, and endurance during exercise was decreased, because the absence of SIRT6 reduced the activity of AMPK. Therefore, the expression of downstream genes was reduced, and the uptake of glucose and fatty acids in skeletal muscle cells, the oxidation of fatty acids and oxidative phosphorylation of mitochondria were weakened, which resulted in the metabolic disorder of the body. The mice with adipose tissue specific knockout of SIRT6 showed obvious obesity, their brown fat was "white", their blood glucose was significantly increased, and accompanied by insulin resistance and fatty liver, the whole body decreased oxygen consumption and hypothermia. 尾-adrenaline agonists and cold-stimulated white fat browning was also significantly weakened. However, the fundamental mechanism of SIRT6 affecting adipose tissue heat production is that SIRT6 can form complex with pATF2 and bind to the promoter region of PGCl 伪, which affects the expression of PGC1 伪, its downstream heat production gene and mitochondrial gene. Ultimately affect the body's energy output. Our study revealed that SIRT6 plays a specific role in muscle and adipose tissue, which affects the homeostasis and energy balance of glucose and lipid metabolism, and provides a potential target for the treatment of type 2 diabetes and obesity.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R587.1;R589.2
【相似文献】
相关期刊论文 前10条
1 ;脂肪组织中的钒[J];广东微量元素科学;2001年04期
2 李晓博,侯新国,陈丽;脂肪组织肾素-血管紧张素系统研究进展[J];国外医学.内分泌学分册;2004年03期
3 李青;马钰;;脂肪组织功能新发现[J];中华病理学杂志;2006年06期
4 周立红;张铁梅;;脂肪组织生物学功能的研究进展[J];国外医学(老年医学分册);2006年02期
5 樊荣;臧益民;;脂肪组织的功与过评述[J];心脏杂志;2008年03期
6 梁忠泉;袁昌隆;张宝贺;;脂肪组织的制片技巧[J];中国疗养医学;2009年06期
7 刘若冰;魏丽;;脂肪组织的内分泌功能研究进展[J];求医问药(下半月);2013年03期
8 丁明修;脂肪组织病理制片研究[J];临床与实验病理学杂志;1991年02期
9 韩北;;并非所有的脂肪都一样[J];心血管病防治知识;2009年01期
10 吴秀英;运动中的是非题测试[J];开卷有益(求医问药);2002年11期
相关会议论文 前10条
1 陈福伟;杨国宇;李宏基;郭豫杰;鲁维飞;;小鼠脂肪组织中孤啡肽及其受体基因表达的研究[A];全国动物生理生化第十一次学术交流会论文摘要汇编[C];2010年
2 邹晓防;;脂肪组织与创面愈合[A];第八届全国烧伤外科学年会论文汇编[C];2007年
3 孙q，
本文编号：2141273
本文链接：https://www.wllwen.com/shoufeilunwen/yxlbs/2141273.html
教材专著
