最近臨床研究發現食用果糖將導致胰島素抗性及高血壓。食用果糖將促進蛋白質果糖化及過氧化物的形成。在之前的研究中，我們發現抑制腦幹孤立束核過氧化物的產生，將會下降血壓。咖啡因在保護細胞膜對抗氧化物的破壞上，展現明顯抗氧化的能力，另外還可以降低造成胰島素抗性的風險。然而咖啡因是透過什麼機轉來改善果糖所造成胰島素抗性至今仍不清楚。本論文的目的是研究攝食咖啡因是否能減少腦幹孤立束核過氧化物的產生，加強胰島素訊息傳遞，進而降低果糖所造成高血壓。同時餵食四週果糖及咖啡因這一組和餵食四週果糖組比較起來，可以發現咖啡因可下降果糖所造成高血壓、空腹血糖值、胰島素、HOMA-IR (homeostatic model assessment-insulin resistance)和三酸甘油脂，另外還會增加高密度膽固醇。但和控制組比較，咖啡因就無此功能。咖啡因能改善果糖在腦幹孤立束核所造成一氧化氮下降作用。更進一步從免疫轉漬法(Immunoblotting)及免疫螢光法(immunofluorescence)的結果，可發現咖啡因可降低果糖在腦幹孤立束核所誘發之胰島素接受體受質1(insulin receptor substrate1, IRS1S307)的磷酸化，並回復AktS473及神經性一氧化氮合成酶(neuronal NO synthase；nNOS)的磷酸化。同樣的，咖啡因也可改善果糖在腦幹孤立束核所造成胰島素抗性及胰島素的量。另外咖啡因也可降低腦幹孤立束核過氧化物的產生及receptor of advanced glycation end product 的表現。綜合以上的結果，我們可以發現咖啡因在腦幹孤立束核藉由抑制過氧化物，來加強IRS1-PI3K-Akt-nNOS訊息傳遞，進而降低血壓。

Recent clinical studies found that fructose intake leads to insulin resistance and hypertension. Fructose consumption promotes protein fructosylation and the formation of superoxide. In a previous study, we revealed that inhibition of superoxide production in the nucleus tractus solitarii (NTS) reduces blood pressure (BP). Caffeine displays significant antioxidant ability in protecting membranes against oxidative damage and can lower the risk of insulin resistance. However, the mechanism through which caffeine improves fructose-induced insulin resistance is unclear. The aim of this study was to investigate whether caffeine consumption can abolish superoxide generation to enhance insulin signaling in the NTS, thereby reducing BP in rats with fructose-induced hypertension. Treatment with caffeine for 4 weeks decreased blood pressure, serum fasting glucose, insulin, HOMA-IR, and triglyceride levels and increased the serum dHDL level in fructose-fed rats but not in control rats. Caffeine treatment resulted in recovery of the fructose-induced decrease in nitric oxide (NO) production in the NTS. Immunoblotting and immunofluorescence analyses further showed that caffeine reduced the fructose-induced phosphorylation of insulin receptor substrate 1 (IRS1S307) and reversed AktS473 and neuronal NO synthase (nNOS) phosphorylation. Likewise, caffeine was able to improve insulin sensitivity and decrease the insulin levels in the NTS evoked by fructose. Caffeine intake also reduced the production of superoxide and the expression of receptor of advanced glycation end product in the NTS. These results suggest that caffeine may enhance IRS1-phosphatidylinositol 3-kinase-Akt-nNOS signaling to decrease BP by abolishing superoxide production in the NTS.

論文審定書…………………………………………………………………… i
誌謝…………………………………………………………………………… ii-iii
中文摘要……………………………………………………………………… iv
ABSTRACT……………………………………………………………………v-vi
INDEX …………………………………………………………………………vii-viii
LIST OF FIGURES……………………………………………………………ix-xii
LIST OF TABLE ………………………………………………………………xiii
NONSTANDARD ABBREVIATIONS AND ACRONYMS ……………… xiv
CHAPTER 1
The Molecular Mechanism of frutose on Cardiovascular Regulation in the Nucleus Tractus Solitarii of Rats ………………………………………………………1 Background……………………………………………………………………2-9
Specific Aims …………………………………………………………………10
Materials and methods…………………………………………………………11-16
Results …………………………………………………………………………17-19
Discussion …………………………………………………………………… 20-22
Conclusion …………………………………………………………………… 23
CHAPTER 2
Caffeine intake improves fructose-induced hypertension and insulin resistance by enhancing central insulin signaling…………………………………………… 37
Background ……………………………………………………………………38-39
Specific Aims …………………………………………………………………40
Materials and methods…………………………………………………………41-46
Results ………………………………………………………………47-51
Discussion ……………………………………………………………………52-53
Conclusion………………………………………………………………………54
CHAPTER 3
Future Perspectives………………………………………………………………55-56
REFERENCES …………………………………………………………………57-67
FIGURES AND LEGENDS
Chapter 1 ………………………………………………………………………24-35
Chapter 2 ………………………………………………………………………68-87
TABLES
Chapter 1 …………………………………………………………………………36
Chapter 2 …………………………………………………………………………88
PUBLICATION…………………………………………………………………89

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