臺灣博碩士論文加值系統

瘦體素，是分子量約為16 kD的蛋白質，由脂肪組織ob基因所製造並分泌至血液循環中。瘦體素在下視丘透過訊息傳遞，調控攝食行為使食慾降低，減少進食量及促進能量消耗，故被視為一種荷爾蒙。除了ob/ob這種無法正常表現瘦體素的肥胖小鼠外，許多齧齒類肥胖動物模式中，ob基因的mRNA與血清中瘦體素皆有增加的情形，此現象在許多過重及第二型糖尿病病患身上也可觀察到。由於具有功能性的瘦體素接受器Ob-Rb在許多周邊組織如脂肪組織、胰臟蘭氏小島及血管內皮層都有表現，故推測這些組織也是瘦體素的標的器官。近期研究指出瘦體素可影響葡萄糖的利用，推測瘦體素與調控胰島素的分泌及作用有關。許多代謝異常疾病如肥胖及糖尿病，皆與糖類代謝不良相關，更與胰島素阻抗有強烈的關聯性。然而，瘦體素是否參與胰島素阻抗的發生並不清楚。故本實驗的研究方向為(1)在正常大鼠的離體脂肪細胞上，瘦體素是否會影響胰島素所刺激的葡萄糖攝取。(2)高果糖餵飼大白鼠誘發胰島素阻抗中，是否伴隨高瘦體素血症。(3)觀察不同飲食處理下，果糖鼠在不同部位脂肪的瘦體素mRNA表現量是否有差異。本實驗所使用的實驗動物為雄性Sprague-Dawley大白鼠，體重介於250-300克，隨機分為兩組，一組為餵飼正常飼料的控制組；一組為餵飼含60﹪果糖的果糖組，飲食處理共維持12週。大白鼠血壓的測量方式是利用尾部環帶充氣法(tail-cuff method)。血漿胰島素及瘦體素濃度是以放射性免疫法測得。血漿葡萄糖濃度是利用葡萄糖分析儀測得。結果如下述：在正常大白鼠離體脂肪細胞上處理瘦體素會使胰島素所刺激的葡萄糖攝取量受損。餵飼果糖的動物，未禁食狀態血漿瘦體素濃度於第1週時顯著高於控制鼠。未禁食狀態下的血漿胰島素濃度與血壓，分別在第2週及第7週顯著高於控制鼠。而未禁食狀態下血糖也在第8週時，果糖鼠顯著高於控制鼠。第7週時利用口服葡萄糖耐受性試驗發現果糖鼠有胰島素阻抗。由結果顯示，餵飼高果糖飼料可使大白鼠產生一連串具有時間序列的代謝異常現象，包含高瘦體素血症、高胰島素血症、胰島素阻抗及高血壓。果糖鼠副睪脂肪及皮下脂肪的瘦體素mRNA表現量有較高的趨勢。利用迴歸分析發現，瘦體素含量與血壓及胰島素有顯著性的正相關性。由以上結果推論，瘦體素在離體脂肪細胞上造成胰島素阻抗。另外，果糖動物中發現具有高瘦體素血症，懷疑此與胰島素阻抗發生的病理機轉有關。

Leptin, a 16 kD product of the ob gene is predominantly produced in adipose tissue and secreted into the circulation. Leptin acts as a hormonal factor that signals the size of fat depots to the hypothalamic centers and regulates food intake and energy expenditure. Except in the leptin—deficient ob/ob mouse, mRNA levels and serum protein levels are increased in all models of rodent obesity. Similar regulatory phenomena have been observed in overweight people, hypertensive and type II diabetic patients. The functional leptin receptor OB-Rb has been reported to express in many peripheral tissues including fat pads, pancreatic islets and endothelium cells indicated as target locations for leptin action. Recent findings on leptin affecting glucose utilization suggest that leptin might also modulate insulin secretion and action. Many metabolic disorders such as obesity and diabetes are related with malfunctions of glucose metabolism and strongly associated with insulin resistance. However, the involvements of leptin in the pathophysiology of insulin resistance were not clear. The purposes of this study were (1) to examine the acute effect of leptin on insulin-stimulated glucose uptake in adipocytes isolated from normal rats; (2) to measure the plasma concentration of leptin to observe whether hyperleptinemia can be induced on insulin resistant rats caused by fructose diet; (3) to study the mRNA expression of leptin on various fat depots in fructose-fed rats. Twenty male Sprague-Dawley rats initially weighing 250-300 g were divided into two groups, one group fed with standard Purina Chow as control and the other group fed with 60% of fructose diet. The dietary manipulation lasted for 12 weeks. The systolic blood pressure was monitored by tail-cuff method. Plasma levels of insulin and leptin were measured by radioimmunoassay. Plasma glucose concentration was determined by glucose analyzer. In normal rats, leptin impaired the insulin-stimulated glucose uptake in adipocytes. During fructose feeding, non-fasting plasma leptin concentrations were significantly higher in fructose-fed rats than control rats on 1st week. Fructose-fed rats caused a significant increase in non-fasting plasma insulin levels on 2nd week. Thereafter, blood pressure increased after 7th week. Non-fasting plasma glucose and body weight were significantly higher in fructose-fed rats than control rats on 8th week. Insulin resistance was observed on the7th week by oral glucose tolerance test in vivo. These results indicated that fructose diet could cause a sequential of metabolic abnormalities, including hyperleptinemia, hyperinsulinemia, insulin resistance and hypertension. In fructose-fed rats, leptin mRNA expression is higher than control rats. Regression analysis showed that leptin levels were associated with blood pressure and insulin levels. Our data suggest that leptin may impair insulin-stimulated glucose uptake in adipocytes. In addition, hyperleptinemia in fructose-fed rats may be related to the pathophysiology of insulin resistance.

目錄………………………………………………………….i
表次………………………………………………………….ii
圖次………………………………………………………….iii
中文摘要…………………………………………………….v
英文摘要…………………………………………………….vii
壹、緒言…………………………………………………….1
貳、研究動機目的與實驗設計…………………………….10
參、材料與方法…………………………………………….12
肆、結果…………………………………………………….23
伍、討論…………………………………………………….29
圖表與說明………………………………………………….34
陸、參考文獻……………………………………………….57

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