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研究生:汪嗣桓
研究生(外文):Wong, Sei-Yung
論文名稱:探討CCR5 和RANTES路徑在高脂飼料誘導肥胖之脂肪組織發炎以及系統性胰島素抗性所扮演的角色
論文名稱(外文):The role of RANTES and CCR5 in the pathogenesis of high-fat diet-induced adipose tissue inflammation and systemic insulin resistance
指導教授:謝博軒
指導教授(外文):Hsieh, Po Hsuan
口試委員:戴元基洪麗滿
口試委員(外文):Day, Yuan JiHung, Li-Man
口試日期:2012-05-28
學位類別:碩士
校院名稱:國防醫學院
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:2012
畢業學年度:100
語文別:中文
論文頁數:74
中文關鍵詞:發炎胰島素抗性肥胖脂肪組織
外文關鍵詞:CCR5CCL5InflammationInsulin Resistance
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肥胖導致的脂肪組織慢性發炎與許多發炎相關化學趨化物質和細胞激素的分泌有關,其中有已廣為研究的MCP-1與其接受器CCR2的系統,而近幾年研究指出另一套系統-RANTES/CCR5亦可能參與了脂肪組織發炎的過程。
本實驗利用CCR5與CCL5基因剔除之小鼠給予正常飼料餵食或者高脂肪飼料餵食誘導其肥胖去探討CCR5與CCL5在肥胖導致的脂肪組織發炎反應與系統性胰島素抗性上之影響。
從研究結果中顯示,在正常飼料餵食下,CCR5 KO 與CCL5 KO小鼠之能量代謝均未與控制組有差異。胰島素抗性的形成上,CCR5 KO小鼠胰島素抗性顯著的下降。反之CCL5 KO小鼠的胰島素抗性較控制組更為嚴重。而在系統性發炎與脂肪組織發炎上,CCR5 KO小鼠發炎相關之調控有降低的現象。而CCL5 KO小鼠則因為肥胖的發展而使得發炎情況較為嚴重。另外在脂肪細胞增生與分化上,CCR5 KO小鼠並未看見與控制組有差異的現象。反之CCL5 KO則因為肥胖的發展使得分化能力下降,並且有異位性脂肪堆積的現象。
而在高脂肪餵食下,在能量代謝上CCR5 KO小鼠有較高的食物體重轉換率,而CCL5則雖然亦較高於控制組,但相較於CCR5 KO小鼠來的低。而在胰島素抗性的形成上,CCR5 KO則表現了較低的胰島素抗性,反之CCL5 KO小鼠則是表現了比控制組更為嚴重的胰島素抗性。另外在脂肪細胞整體之分化與增生上,CCR5 KO有較好的分化與增生情形,反之CCL5 KO小鼠則比控制組差。
根據結果推論,在正常生理狀態下與飲食誘導之肥胖模式下,CCR5與CCL5有協同促進發炎反應之角色,也有分別獨立對於能量代謝、脂肪慢性發炎與脂肪細胞增生分化上不同調控的角色。CCR5在促進脂肪組織發炎與免疫細胞浸潤的角色上較CCL5為顯著,在脂肪組織的增生與分化上則扮演抑制性的角色,進而影響胰島素抗性的產生。CCL5在脂肪組織發炎的反應中是不可或缺的角色,其可能與MCP-1等相關發炎因子共同平衡免疫反應。另一方面CCL5對於脂肪組織脂質的生合成可能有所調控,並且與脂肪的異位性堆積與所導致的系統性胰島素抗性有高度的相關性。

Obesity induced adipose tissue inflammation and systemic insulin resistance is associated with the secretion and functional properties of inflammatory chemokines and cytokines, such as the well-established MCP-1/CCR2 chemokine system. Recent studies showed that the RANTES/CCR5 system could also participate in the complex process of adipose tissue inflammation and insulin resistance.
In this study, CCR5 and CCL5 deficient mice were fed either with normal diet or high fat diet, which are then experimented to study the mechanism of the involvement of CCR5 and CCL5 in adipose tissue inflammation and systemic insulin resistance.
The results show that, under normal diet, CCR5 KO mice and CCL5 KO mice both had no significant differences in energy balance. CCR5 KO mice showed more improved insulin sensitivity, whereas CCL5 KO mice worsen. And for systemic and adipose tissue inflammatory response, CCR5 KO mice showed an attenuated inflammatory response. On the contrary, CCL5 KO mice had a more deleterious condition. And last, CCR5 KO mice showed an overall improved adipogenesis, whereas, CCL KO mice was worsen
The results indicate that, under different diets, CCR5 and CCL5 have collaborative and separate roles in regulating the progress of adipose tissue inflammation and adipose tissue adipocyte differentiation. CCR5 showed dominant influence in promoting adipose tissue inflammation and the infiltration of immune cells, and has a role in down regulating adipocyte proliferation and differentiation, which leads to systemic insulin resistance. On the contrary, CCL5 plays a vital role in the regulation of adipose tissue inflammation, which probably works as a balance between chemokines and cytokines such as MCP-1 in an inflammatory response. On the other hand, CCL5 may play a role in adipose tissue lipogenesis, which may affect ectopic fat accumulation, in which leads to insulin resistance. This study suggests that CCR5/CCL5 pathway could regulate high fat induced adipose tissue inflammation and systemic insulin resistance.

圖目錄 IV
縮寫表 VI
中文摘要 VII
英文摘要 X
第一章、 前言 1
第一節、 肥胖、第二型糖尿病與系統性胰島素抗性 1
第二節、 肥胖與白色脂肪組織 2
第三節、 肥胖與脂肪組織發炎 3
第四節、 MCP-1/CCR2路徑與脂肪組織發炎 5
第五節、 T細胞與脂肪組織發炎 6
第六節、 RANTES/CCR5路徑與脂肪組織發炎 7
第七節、 假說 8
第二章、 實驗目的 9
第三章、 材料與方法 10
第一節、 實驗動物 10
第二節、 儀器設備 11
第三節、 化學製劑 12
第四節、 實驗設計 15
第五節、 實驗方法 17
口服葡萄糖耐受性試驗 17
HOMA-IR之計算 17
脂肪細胞、血管基質細胞之萃取 18
脂肪細胞條件培養液製備 19
血管基質層細胞之流式細胞儀分析-CD3+CD4+, CD3+CD8+, CD11b+細胞群 19
細胞激素測定-TNF-α, IL-6, MCP-1, RANTES, Leptin 19
脂肪組織iNOS、CD206、IL-10、GLUT4、IRS-1和CEBP/α表現量測定 21
免疫組織化學染色 (Immunohistochemistry, CD11b) 23
統計方法 23
第四章、 實驗結果 24
第一節、 各組實驗鼠28週體重變化量、平均進食量以及食物利用效率比 …………………………………………………………………….24
第二節、 各實驗鼠血漿之三酸甘油脂、甘油、總膽固醇以及肝功能指標AST及ALT之生化值測定 25
第三節、 各實驗鼠於12、20、28週之口服葡萄糖耐受性試驗測定 25
第四節、 各實驗鼠之HOMA-IR指標之測定與計算結果 26
第五節、 各實驗鼠內臟脂肪組織GLUT4以及IRS-1基因表現量 27
第六節、 各實驗鼠之內臟脂肪細胞大小、副睪脂肪重量、估計之副睪脂肪細胞數量以及其分化相關之CEBP/α基因表現 27
第七節、 各組實驗鼠血漿TNF-α、IL-6、MCP-1、RANTES與Leptin濃度 28
第八節、 各組實驗鼠內臟脂肪細胞條件培養液中TNF-α、IL-6、MCP-1、RANTES與Leptin濃度 30
第九節、 各實驗鼠內臟脂肪組織所萃取之血管基質層細胞中T4細胞、T8細胞以及巨噬細胞之比例變化測定 31
第十節、 各實驗鼠內臟脂肪組織iNOS、CD206、IL-10之基因表現 32
第五章、 討論 34
第一節、 CCR5與CCL5對於能量調控之影響 36
第二節、 CCR5與CCL5對於系統性發炎之影響 36
第三節、 CCR5與CCL5在正常及肥胖誘發之脂肪組織發炎的影響 38
第四節、 CCR5與CCL5對於脂肪組織之增生與分化之影響 41
第五節、 CCR5與CCL5對系統性胰島素抗性與脂肪異位性堆積之影響 42
第六章、 結論 44
第七章、 參考文獻 46

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