臺灣博碩士論文加值系統

許多研究顯示，飲食限制無論是限制卡路里攝取量或是間斷性禁食在許多物種上皆有正面的幫助，包括可以延長壽命、增加對壓力的抵抗性、改善對胰島素的敏感性以及預防心血管疾病的發生。下視丘是主要掌管食慾的腦區。除此之外，位於下視丘前區的室旁核在調控心血管反應上扮演重要的角色。室旁核可以藉由神經及荷爾蒙的路徑來調控心血管反應。在神經路徑的調控上包括興奮性的麩氨酸以及抑制性的γ-胺基丁酸(GABA)和一氧化氮。過去研究顯示，長期間斷性禁食降低動物的血壓、心跳和交感神經活性以及提高副交感神經活性。然而，長期間斷性禁食究竟是透過什麼機制降低動物的血壓和心跳目前還不是很清楚。因此假設長期間斷性禁食是透過增強下視丘GABA神經系統的活性來影響心血管功能。七週大的雄性大白鼠分成控制組、間斷禁食組(為期二十四週交替禁食的攝食方式)以及恢復攝食組(二十四週間斷禁食後恢復四週正常攝食)。實驗結果顯示1) 間斷禁食組平均攝食量約為控制組的百分之七十；恢復攝食組在恢復正常攝食四週期間的攝食量與控制組沒有差異；2) 各組體重皆隨週齡數增加而漸增，但間斷禁食組及恢復攝食組在間斷禁食期間體重上升的幅度顯著較控制組為低，而恢復攝食組在恢復正常攝食四週期間體重持續上升；3) 間斷性禁食顯著降低動物的血壓及心跳，恢復攝食四週抵銷間斷性禁食的影響； 4) 長期間斷性禁食增加下視丘前區一氧化氮合成酶(nNOS)、麩胺酸脫羧酵素67 (GAD67, GABA合成酶)及gephyrin (具有聚集抑制性離子通道受器功能的蛋白質)的蛋白質表現，而恢復攝食四週抵銷間斷性禁食的影響；5) 免疫組織染色結果顯示長期間斷性禁食主要增加下視丘前區中室旁核的GAD67蛋白質表現；6) 長期間斷性禁食增加下視丘後區nNOS的表現；恢復攝食降低下視丘後區gephyrin的表現量；7) 長期間斷性禁食及恢復攝食皆不改變孤獨核及網狀腹外側核中nNOS、GAD67、GABA甲型接受器及gephyrin的蛋白質表現；8) 至於間斷性禁食是否能改變室旁核中神經樹突的型態則尚未有定論。總結來說，長期間斷性禁食可能透過增強下視丘前區的GABA系統來影響心血管功能。

Dietary restriction, either caloric restriction or intermittent fasting (IF), has been shown to exert many beneficial effects, including increased life span, stress resistance, insulin sensitivity, and the prevention of cardiovascular diseases. Hypothalamus is the brain region controlling appetite and its paraventricular nucleus (PVN) plays an important role in regulating cardiovascular responses via neuronal and hormonal pathways. The synaptic control of the PVN involves excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) and nitric oxide. Animals under IF-condition showed reduced blood pressure (BP), heart rate (HR) and sympathetic tone, and elevated parasympathetic tone. However, the underlying mechanism is still unclear. In the present study, we hypothesized that the cardiovascular effects of IF might involve hypothalamic adaptations. Male Wistar rats (7-wk-old) were divided into three groups: 24-wk IF, 24-wk IF followed by 4-wk ad libitum feeding (IF/AL), and the AL control. Our results showed that 1) IF rats consumed 30% less food and showed less body weight gain than AL controls; the food consumption in IF/AL rats were the same as in the AL controls and their body weight gain increased again during the additional 4 week period under AL diet; 2) IF rats had lower blood pressure and heart rate than controls, whereas IF/AL completely reversed the IF effects on these two parameters; 3) IF increased protein levels of neuronal nitric oxide synthase (nNOS), GAD67 (an enzyme for GABA synthesis) and gephyrin (a clustering protein of inhibitory ion channel receptors) in the anterior hypothalamus, whereas IF/AL blunted IF-upregulated protein levels; 4) immunohistochemical experiments indicated that IF-induced upregulation of GAD67 in the anterior hypothalamus mainly occurred in the PVN; 5) same proteins in the posterior hypothalamus were minimally altered by IF or IF/AL; 6) dietary intervention did not significantly alter the nNOS, GAD67, GABAA receptor, and gephyrin protein levels in either nucleus tractus solitarius or rostral ventrolateral medulla; 7) whether food restriction would alter the dendritic morphology in PVN or not was unclear at present. Taken together, our results suggested that IF upregulated the GABA system in the anterior hypothalamus which might contribute to IF-reduced basal HR and mean BP.

Qualified Certificate........................- 1 -
Abstract in Chinese..........................- 2 -
Abstract in English..........................- 4 -
Acknowlegement...............................- 6 -
Table of Contents............................- 7 -
Abbreviations................................- 8 -
List of Table................................- 9 -
List of Figures.............................- 10 -
Introduction................................- 13 -
Hypothesis and Experimental Design..........- 18 -
Materials...................................- 19 -
Methods.....................................- 27 -
Results.....................................- 33 -
Discussion..................................- 37 -
References..................................- 42 -
Table.......................................- 46 -
Figure......................................- 47 -
Appendix....................................- 71 -

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