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Role of microbe-derived extracellular vesicles in glucose metabolism

당 대사에서 박테리아 유래 세포밖 소포체의 역할

최영우 (Youngwoo Choi)

원문보기

  • 발행기관 포항공과대학교 일반대학원
  • 지도교수류성호
  • 발행년도2016
  • 학위수여년월2016. 2
  • 학위명박사
  • 학과 및 전공일반대학원 생명과학과
  • 본문언어영어
  • 저작권포항공과대학교 논문은 저작권에 의해 보호받습니다.
초록 moremore
Gut microbiota interact with their host and affect its homeostatic functions. This interaction and the composition of the microbiota are implicated in the pathogenesis of type 2 diabetes (T2D), which is characterized by chronic inflammation and insulin resistance. Recently, extracellular vesicles (E...
Gut microbiota interact with their host and affect its homeostatic functions. This interaction and the composition of the microbiota are implicated in the pathogenesis of type 2 diabetes (T2D), which is characterized by chronic inflammation and insulin resistance. Recently, extracellular vesicles (EVs) have been shown to play roles in intracellular communication in some pathological and physiological conditions including tumors and immune response, but the precise role of these EVs in host metabolism is not clear. To identify diabetes-related EVs, metagenomic data analysis of stool EVs derived from regular diet (RD)- and high-fat diet (HFD)-fed mice was performed. Interestingly, 16S ribosomal DNA sequencing indicated that several EVs exhibited changes in composition after the mice were administered with HFD. These EVs were used to treat myotubes to evaluate effects of EVs on metabolic cells. Specifically, Pseudomonas panacis-derived EVs (PpEVs) inhibited insulin function, which is responsible for increasing glucose uptake into cells. In addition, PpEVs were administered to mice via the oral route to investigate their effect on host glucose metabolism. It was observed that PpEV-treated mice, when fed with a regular diet, showed a diabetic phenotype including impaired glucose tolerance and insulin resistance. The insulin resistance was due to inhibition of Akt phosphorylation, which has been shown to be involved in the insulin signaling pathway. Thus, these data suggest that microbe-derived EVs may play a role in the development of insulin resistance in diabetes. To further investigate the diverse effects of EVs on glucose homeostasis, Akkermansia muciniphila-derived EVs (AmEVs) were isolated and compared with Escherichia coli-derived EVs (EcEVs) that are known to be pathogenic. These EVs had similar physical characteristics such as shape and size, but exhibited distinct protein contents and functions. AmEVs increased GLUT4 translocation on the cell surface by activation of AMP-activated protein kinase (AMPK), which is responsible for glucose uptake in myotubes, whereas EcEVs did not stimulate the myotubes. Moreover, AmEV treatment improved body weight gain, glucose tolerance, and hyperinsulinemia in HFD-induced diabetic mice in an AMPK-dependent manner. Thus, AmEVs had a protective effect on improvement of insulin sensitivity. Taken together, these results suggest that EVs from gut microbioita can affect host cells by controlling phosphorylation of intracellular signaling molecules involved in glucose uptake. Therefore, gut microbe-derived EVs play a significant role in regulation of host glucose metabolism.
목차 moremore
1. General introduction 1
1-1. Introduction 2
1-2. References 5
...
1. General introduction 1
1-1. Introduction 2
1-2. References 5
1-3. Figures 10

2. Pseudomonas panacis-derived extracellular vesicles impair glucose metabolism in skeletal muscle 13
2-1. Introduction 14
2-2. Materials and Methods 16
2-3. Results 22
2-4. Discussion 26
2-5. References 29
2-6. Figures and Tables 33

3. Akkermansia muciniphila-derived extracellular vesicles affect glucose homeostasis through activation of AMPK 45
3-1. Introduction 46
3-2. Materials and Methods 47
3-3. Results 51
3-4. Discussion 54
3-5. References 56
3-6. Figures 60

4. Summary in Korean 67

5. Acknowledgement 69

6. Curriculum Vitae 71