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棕榈酰肉碱酰基转移酶1c的功能研究
Alternative TitleStudy on the role of Carnitine palmitoyltransferase-1c
高学飞
Subtype博士
Thesis Advisor吴东海
2009-04-23
Degree Grantor中国科学院研究生院
Place of Conferral广州生物院
Degree Name博士
Degree Discipline生物化学与分子生物学
KeywordCPT1c基因敲除 葡萄糖耐受 葡萄糖异生 葡萄糖摄取 下丘脑
AbstractCPT1c是最新发现的脑特异表达的CPT1家族的新成员。CPT1c基因敲除小鼠易感高脂饮食诱导的肥胖。然而,CPT1c缺失造成小鼠上述表型的潜在机制以及CPT1c是否参与高脂饮食诱导的胰岛素抵抗的发生发展过程并不清楚。为研究CPT1c在高脂饮食诱导的胰岛素抵抗发生中的作用,我们构建了CPT1c基因敲除小鼠(CPT1c KO)并对小鼠进行正常饲粮(SC)和高脂饲粮(HFD)的喂养,喂养过程中对小鼠的血糖等指标每周进行检测。经过8周喂养后,我们发现HFD CPT1c KO相对于野生型对照出现了更为严重的胰岛素抵抗,且该表型的出现并不依赖于相对肥胖的发生。HFD 组CPT1c KO葡萄糖耐受性的降低主要由于肝脏葡萄糖异生的增加以及骨骼肌葡萄糖摄取的减少所致。这些生理效应伴随着肝脏及骨骼肌内脂肪酸氧化能力的降低、氧化代谢基因表达的下调以及三甘油酯累积的增加。此外,高脂饮食状态下CPT1c KO小鼠出现了下丘脑特异的Cpt1a、Cpt1b表达增高以及CPT1活性的上升,而高脂喂养小鼠血液中游离脂酸的升高可能就是下丘脑CPT1活性代偿性增高的诱发因素。此外,基因芯片分析结果分析显示:相对于野生小鼠,HFD CPT1c KO全脑中即刻早期基因家族(IEGs)的几个主要成员的表达水平显著下降。这些结果进一步确认了中枢CPT1c在整体能量稳态维持中的重要作用,肝脏糖异生的增加以及骨骼及葡萄糖摄取能力的降低是CPT1c基因敲除小鼠易感高脂饮食诱导胰岛素抵抗的组织水平的决定机制。
Other AbstractCPT1c is a novel isoform in the CPT1 family, with a brain specific expression. CPT1c knockout (KO) mice are more susceptible to high-fat diet (HFD) -induced obesity. However, the underling mechanism of this phenotype and possible involvement of CPT1c in the development of dietary induced insulin resistance are unclear. To assess the potential role of CPT1c in the regulation of whole-body glucose homeostasis, we generated CPT1c KO mice and challenged them with HFD or standard chow (SC). The glucose homeostasis of each group was assessed weekly. After 8 weeks HFD feeding, CPT1c KO mice developed a phenotype of more severe insulin resistance compared with wild-type controls. The increased susceptibility of CPT1c KO mice to HFD induced insulin resistance is independent of obesity. Impaired glucose tolerance in CPT1c KO mice was attributable to both elevated hepatic gluconeogenesis and decreased glucose uptake in skeletal muscle. These effects correlated with decreased hepatic and intramuscular fatty acid oxidation and oxidative genes expression plus elevated triacylglycerol content in these tissues. Interestingly, Cpt1c deletion caused a specific elevation of hypothalamic Cpt1a and Cpt1b isoform expression and activity. We demonstrated that elevated plasma non-esterified fatty acid (NEFA) concentration is one mechanism via which this compensatory effect is induced. In addition, our microarray analysis identified several immediate early genes (IEGs) to be down-regulated in CNS of CPT1c KO mice on HFD. These results further establish the role of CPT1c in controlling whole body glucose homeostasis. We identify changes in hepatic and skeletal muscle glucose metabolism as important mechanisms determining the phenotype of CPT1c KO mice.
Subject Area生物化学与分子生物学
Pages100
Language中文
Document Type学位论文
Identifierhttp://ir.foo.ac.cn/handle/2SETSVCV/924
Collection中国科学院广州生物医药与健康研究院
Affiliation中国科学院广州生物医药与健康研究院
First Author AffilicationGUANGZHOU INSTITUTES OF BIOMEDICINE AND HEALTH,CHINESE ACADEMY OF SCIENCES
Recommended Citation
GB/T 7714
高学飞. 棕榈酰肉碱酰基转移酶1c的功能研究[D]. 广州生物院. 中国科学院研究生院,2009.
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