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oai:repository.ajou.ac.kr:201003/130212024-10-11T02:21:24Zcom_201003_14372com_201003_14368col_201003_14374

Protective effect of TM-25659, known as TAZ activator, on high-fat diet-induced insulin resistance in C57BL/6J mice TAZ 활성제로 알려진, TM-25659가 고지방 식이로 유도된 인슐린 저항성 마우스에 미치는 효과 정, 종갑 이, 관우 대학원 의생명과학과 200724304 정, 종갑 TAZ TM-25659 insulin resistance FGF21 AMPK PART 1. TM-25659-induced activation of FGF21 level decreases insulin resistance and inflammation in skeletal muscle via GCN2 pathways 1 Ⅰ. INTRODUCTION 2 Ⅱ. MATERIALS AND METHODS 8 A. MATERIALS 9 B. METHODS 10 1. Preparation of PA 10 2. Cell culture 10 3. Immunoblot analysis 11 4. RNA isolation and quantitative real-time polymerase chain reaction (PCR) 12 5. siRNAs 13 6. Uptake of 2-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino-2-deoxyglucose (2-NBDG) 14 7. Animal experiments 14 8. FGF21 secretion 15 9. IL-1β assay 15 10. Statistical analysis 15 Ⅲ. RESULTS 16 A. TM-25659 restored PA-induced insulin resistance and inflammation in skeletal muscle cells 17 B. TM-25659 increased FGF21 levels by GCN2 pathways in skeletal muscle cells 22 C. Effects of TM-25659 reduced insulin resistance and inflammation in skeletal muscle cells treated with or without FGF21 siRNA 27 D. TM-25659 prevented HF-diet induced obesity 31 E. TM-25659 restored the insulin signaling pathways in DIO mice skeletal muscle 33 F. TM-25659 lowered the muscle pro-inflammatory cytokine levels in DIO mice 35 G. TM-25659 regulates expression of both FGF21 mRNA and protein in DIO mice skeletal muscles 37 Ⅳ. DISCUSSION 38 Ⅴ. CONCLUSION 42 PART 2. Protective effects of TM-25659 on high-fat diet-induced insulin resistance in liver via AMPK pathways 44 Ⅰ. INTRODUCTION 45 Ⅱ. MATERIALS AND METHODS 52 A. MATERIALS 53 B. METHODS 54 1. Preparation of PA 54 2. Cell culture 54 3. Immunoblot analysis 54 4. RNA isolation and quantitative real-time polymerase chain reaction (PCR) 55 5. Animal experiments 56 6. Insulin tolerance tests 57 7. Glucose tolerance tests 57 8. Statistical analysis 57 Ⅲ. RESULTS 58 A. TM-25659 restored PA-induced reduction of insulin signaling pathway and induction of in flammation in HepG2 cells 59 B. TM-25659 increased AMPK and ACC phosphorylation in HepG2 cells 62 C. TM-25659 reduced PA-induced reduction of insulin signaling pathway in HepG2 cells 65 D. TM-25659 reduced PA-induced reduction of inflammation in HepG2 cells 67 E. TM-25659 improved glucose homeostasis and insulin sensitivity in DIO mice 69 F. TM-25659 restored the insulin signaling pathways in DIO mice liver 71 G. TM-25659 lowered the serum and liver pro-inflammatory cytokine levels in DIO mice 73 H. TM-25659 activated AMPK pathways in DIO mice liver 77 I. TM-25659 repressed serum lipid levels in HF-diet fed mice 79 J. TM-25659 prevented HF-diet induced hepatic steatosis 81 K. TM-25659 reduced expression of lipogenic genes but increased expression of fatty acid oxidation genes in HF diet-fed mice 83 Ⅳ. DISCUSSION 85 Ⅴ. CONCLUSION 88 REFERENCES 90 국문요약 108 Doctor 2016-11-27T23:06:05Z 2016-11-27T23:06:05Z 2016 2016 Thesis Theses http://repository.ajou.ac.kr/handle/201003/13021 http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000021474 000000021474 en application/pdf