Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/23168
標題: 高度表現第四型介白素於胰島素訊息傳遞與改變代謝作用之研究
Overexpression of Interleukin-4 Improves Insulin Signaling and Alters Metabolism
作者: 何國鼎
Ho, Kuo-Ting
關鍵字: interleukin-4;第四型介白素;insulin;macrophage activation;lipid metabolism;type 2 DM;胰島素;巨噬細胞的活化;脂肪代謝;第二型糖尿病
出版社: 生命科學系所
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摘要: 
越來越多的文獻證實了造成肥胖以及第二型糖尿病的主要危險因子來自於身體長期暴露在與發炎反應相關之細胞激素的環境。本論文的研究將焦點放在第四型介白素(interleukin-4; IL-4)這個主要由Th2細胞分泌的細胞激素,來探討IL-4對於代謝作用以及第二型糖尿病之病程中所扮演的角色。我們分別於小鼠腹腔注射帶有IL-4基因的腺病毒或是給予重組IL-4蛋白以模擬暫時性以及長時間高度表現IL-4的狀態。接著利用葡萄糖耐受性試驗、胰島素敏感度試驗、觀察胰島素訊息傳遞中的Akt及GSK3β兩個重要的下游分子磷酸化狀態、測量血液中一些生化數值以及免疫組織染色法等多項方法來檢測IL-4對於小鼠的葡萄糖以及脂肪代謝的影響。研究結果顯示,高度表現IL-4的小鼠能透過改變Akt以及GSK3β磷酸化的量來改善葡萄糖的耐受能力以及胰島素的敏感度。IL-4同樣藉由調節血液中脂肪細胞的細胞激素及游離脂肪酸的濃度影響小鼠的脂肪代謝作用。此外,研究亦發現小鼠的體重在給予IL-4處理之後明顯地相較於未給予IL-4處理之小鼠來得輕;小鼠附睪脂肪組織塊的大小及重量在經過IL-4的處理之後也顯著地變少;而小鼠的附睪脂肪組織切片中也發現在給予IL-4處理之後,脂肪組織細胞的切面面積顯著變小。這些研究結果都顯示出IL-4可能在抑制脂肪組織中的脂肪堆積作用中扮演一定的角色。接著在給予IL-4的小鼠中也觀察到其肝臟及脂肪組織中有較多的巨噬細胞浸潤;而受到IL-4的刺激影響,試驗發現在脂肪組織中所浸潤的巨噬細胞是屬於M2表現型的巨噬細胞。因此,在本研究中首次發現,IL-4給予小鼠後也許展現了雙向的影響:IL-4在胰島素訊息傳遞扮演了正向的角色以促進葡萄糖的利用,並且趨化M2表現型巨噬細胞,抑或是將脂肪組織中的巨噬細胞轉變成M2表現型的巨噬細胞;倒是反觀長期IL-4處理的小鼠之肝臟,脂肪細胞浸潤現象更加顯著,這意味著IL-4也許參與了代謝性疾病的病程促使肝臟脂肪化的程度加劇,最終成為一個影響因子。本試驗結果首度揭開了IL-4在代謝作用中所扮演的角色,並且也提供了關於細胞激素、免疫反應、胰島素敏感度以及代謝作用相互關係的一個新觀點。

Abundant evidence has demonstrated that long-term cytokine-mediated inflammation is a risk factor for obesity and type 2 diabetes mellitus (T2DM). In this study, we focused on investigating the putative involvement of Th2-derived cytokine, interleukin-4 (IL-4), in metabolism and T2DM pathogenesis. Mice were intraperitoneal (i.p.) injected with either adenovirus containing IL-4 encoding gene (AdIL-4) or recombinant IL-4 for mimicking the status of transient and long-term IL-4 overexpression, respectively. Glucose tolerance test, insulin tolerance test, phosphorylation of key enzymes (Akt and GSK3β) in insulin signaling, biochemical parameters and immunohistochemistry were conducted to examine the effects of IL-4 on glucose and lipid metabolism. Our results revealed that IL-4 overexpression improves insulin sensitivity and glucose tolerance through significantly up-regulating Akt phosphorylation and attenuating GSK-3β activities. IL-4 is also involved in lipid metabolism by regulating serum levels of adipokines and free fatty acids. Body weights of mice with IL-4 treatment were significantly lower than their counterparts without IL-4 injection. We also found that epididymal fat pad mass was significantly decreased in IL-4 treated mice, in addition, the cross-sectional areas of epididymal adipocytes were significantly smaller in IL-4 administered mice, suggesting that IL-4 may inhibit lipid accumulation in fat tissues. Enhanced macrophage infiltration is observed in liver and adipose tissues, particularly, accumulation of M2 macrophage is triggered by IL-4 in epididymal fat. Our study, for the first time, demonstrates that IL-4 might have bi-directional effects: IL-4 may play a positive role to promote glucose utilization under normal physiological condition and trigger ATM switch into M2 phenotype or recruit M2 ATM accumulation. Whereas, the long-term elevated IL-4 might promote hepatic adiposity, which might eventually become a susceptible factor to metabolic disorders. Our data uncovered the novel roles of IL-4 in metabolism, and provide new insights in the interaction between cytokines/immune responses, insulin sensitivity and metabolism.
URI: http://hdl.handle.net/11455/23168
其他識別: U0005-3008201008565600
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