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研究生:張芸綺
研究生(外文):Yun-Chi Chang
論文名稱:探討可溶性環氧化物水解酶在高脂飲食誘導小鼠的代謝及大腦功能扮演之角色
論文名稱(外文):The Role of Soluble Epoxide Hydrolase in High Fat Diet-induced Metabolism and Brain Function in Mice
指導教授:林惠菁林惠菁引用關係
指導教授(外文):Hui-Ching Lin
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:英文
論文頁數:69
中文關鍵詞:高脂飲食肥胖海馬迴記憶長期增益效應環氧化物水解酶
外文關鍵詞:High fat dietObesityHippocampusMemoryLong-term potentiationSoluble epoxide hydrolase
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高脂飲食(high fat diet, HFD)不僅導致肥胖,更是造成代謝異常和大腦中胰島素阻抗性(insulin resistance)及發炎反應的主要成因,同時伴隨著大腦胰島素的訊息傳遞路徑如insulin receptor substrate-1 (IRS-1), protein kinase B (Akt)和glycogen synthase kinase-3β (GSK-3β)的異常表現。此外,HFD也可能導致記憶功能障礙及海馬迴中記憶形成機制的突觸可塑性(synaptic plasticity)長期增益效應(long-term potentiation, LTP)的受損。而環氧化物水解酶(soluble epoxide hydrolase, sEH)是一種酵素,會代謝具有抗發炎特性的環氧二十碳三烯酸(epoxyeicosatrienoic acids, EETs),先前研究顯示TPPU是一種sEH的抑制劑,能夠有效抑制sEH並提升EETs的含量達到抗發炎的效果,而我們先前研究也發現TPPU具有促進突觸可塑性中LTP的現象。然而,抑制sEH是否能改善因HFD所造成的代謝異常、大腦中胰島素阻抗性、記憶及突觸可塑性LTP的受損仍是不清楚的。在本篇研究,利用8週大雄性的sEH基因剔除(sEH-KO)小鼠、及利用鼻腔滴注給予sEH的抑制劑TPPU兩種方式,去探討對於餵食12週HFD後小鼠的改善效果。在代謝指標方面,結果顯示sEH的基因缺失能夠改善口服葡萄糖耐受測試(oral glucose tolerance test, OGTT)中HFD所造成的高血糖,及homeostasis model assessment-insulin resistance (HOMA-IR) index測量出的高胰島素抗性,也能去降低和發炎反應相關的基因如tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β)及IL-6的mRNA表現。同時也發現HFD確實會造成海馬迴中sEH 活性的顯著增加。在腦部胰島素訊息傳遞路徑中,在sEH-KO小鼠身上發現能夠去降低因HFD所造成IRS-1在serine位點的高度磷酸化表現,並提升下游路徑AKT和GSK-3β的磷酸化表現。在記憶功能及突觸可塑性LTP方面,在動物行為和電生理實驗中發現sEH的基因缺失也能夠去改善因HFD所導致的記憶功能障礙及LTP受損情形,也發現sEH的基因缺失能夠改善HFD所導致α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)的次單元glutamate A1 (GluA1) 磷酸化下降的現象。在另一方面,透過鼻腔滴注TPPU同樣也能夠去抑制sEH activity及改善HFD所造成在代謝及記憶上的不良影響。綜合上述,本篇研究顯示sEH的缺失或抑制能夠改善HFD所造成的代謝異常、大腦中胰島素阻抗性和記憶及突觸可塑性LTP的受損情形。
High fat diet (HFD) is a common cause of obesity accompanied by not only metabolic syndrome, but also brain insulin resistance and inflammation that altered brain insulin signaling such as insulin receptor substrate-1 (IRS-1), protein kinase B (Akt) and glycogen synthase kinase-3β (GSK-3β). Moreover, HFD may also increase the risk of impaired memory and hippocampal long-term potentiation (LTP) which forms of synaptic plasticity and plays an important role in the formation of memories. Additionally, soluble epoxide hydrolase (sEH) is an enzyme that metabolizes epoxyeicosatrienoic acids (EETs) which possess anti-inflammatory properties. Previous studies have shown that TPPU, a sEH inhibitor, has potential to increase the availability of EETs and facilitate synaptic plasticity LTP. However, whether HFD-induced metabolic disorder, brain insulin resistance, memory impairment and synaptic plasticity deficits could be recovered through reducing sEH is still unclear. In this study, 8-week-old male sEH-KO mice and intranasal TPPU treatment were used to investigate the improvement effect after feeding 12-week HFD. First, as for the metabolic aspects, HFD induced increased glucose level in oral glucose tolerance test (OGTT), homeostasis model assessment-insulin resistance (HOMA-IR) index and mRNA expression of inflammation-related genes including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and IL-6 were reversed in sEH-KO mice. We found that sEH activity was elevated in HFD-fed mice compared with ND-fed mice. The results also indicated that the increased serine phosphorylation of IRS-1, the decreased phosphorylation of Akt and GSK-3β induced by HFD were rescued by genetic deletion of sEH. In addition, sEH deletion improved memory and hippocampal LTP impairment caused by HFD in behavioral tests and electrophysiology. We also found HFD-induced decreased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit glutamate-A1 (GluA1) phosphorylation in hippocampus was reversed in sEH-KO mice. Similarly, HFD-induced elevated sEH activity, metabolic makers, brain insulin resistance, memory impairment and the impaired hippocampal LTP and decreased phosphorylation of GluA1 were also recovered by TPPU treatment. Taken together, this study suggests that reducing sEH might have potential to improve the HFD-induced metabolic disorder, brain insulin resistance, memory impairment and synaptic plasticity deficits.
CONTENTS

ABSTRACT IN CHINESE i
ABSTRACT IN ENGLISH iii
CONTENTS V
LIST OF FIGURES Vi

INTRODUCTION 1
MATERIALS AND METHODS 9
RESULTS 22
DISCUSSION 30
CONCLUSION 36
REFERENCES 37
FIGURES 45
SUPPLEMENTARY 67


List of Figures

Figure 1.Body weight was significant increased and food intake had no significant differences in HFD-induced mice 46
Figure 2. HFD-induced peripheral glucose intolerance and insulin resistance were reversed in sEH-KO mice 47
Figure 3. HFD-induced increased hippocampal inflammatory cytokines were reversed in sEH-KO mice 48
Figure 4. HFD increased sEH activity in hippocampus of mice 49
Figure 5. HFD-induced aberrant insulin signaling in hippocampus was reversed in sEH-KO mice 50
Figure 6. Deletion of sEH rescued HFD-induced memory impairment in Y-maze test 51
Figure 7. Deletion of sEH rescued HFD-induced memory impairment in modified Y-maze test 52
Figure 8. Deletion of sEH rescued HFD-induced memory impairment in novel object recognition test 53
Figure 9. Deletion of sEH rescued HFD-induced memory impairment in object location test 54
Figure 10. Impaired hippocampal LTP induced by HFD was reversed in sEH-KO mice 55
Figure 11. HFD-induced decreased phosphorylation of GluA1 in hippocampus was reversed in sEH-KO mice 56
Figure 12. HFD-induced glucose intolerance couldn’t be reverse with TPPU treatment 57
Figure 13. HFD-induced increased mRNA expression of hippocampal inflammatory cytokines were reversed with TPPU treatment 58
Figure 14. HFD-induced elevated sEH activity in hippocampus were reversed with TPPU treatment 59
Figure 15. HFD-induced aberrant insulin signaling in hippocampus was reversed with TPPU treatment 60
Figure 16. TPPU treatment rescued HFD-induced memory impairment in Y-maze test 61
Figure 17. TPPU treatment rescued HFD-induced memory impairment in modified Y-maze test 62
Figure 18. TPPU treatment rescued HFD-induced memory impairment in novel object recognition test 63
Figure 19. TPPU treatment rescued HFD-induced memory impairment in object location test 64
Figure 20. Impaired hippocampal LTP induced by HFD was reversed with TPPU treatment 65
Figure 21. HFD-induced decreased phosphorylation of GluA1 in hippocampus was reversed with TPPU treatment 66
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