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系統識別號 U0026-1307201614590100
論文名稱(中文) 探討介白素二十與瘦素在肥胖中的關係
論文名稱(英文) Study of IL-20 and leptin in obesity
校院名稱 成功大學
系所名稱(中) 生物化學暨分子生物學研究所
系所名稱(英) Department of Biochemistry and Molecular Biology
學年度 104
學期 2
出版年 105
研究生(中文) 張宜潔
研究生(英文) Yi-Chieh Chang
學號 S16034071
學位類別 碩士
語文別 中文
論文頁數 69頁
口試委員 指導教授-張明熙
口試委員-陳昌熙
口試委員-黃柏憲
中文關鍵字 瘦素  脂肪細胞  介白素二十  肥胖 
英文關鍵字 Leptin  adipocyte  IL-20  obesity 
學科別分類
中文摘要 根據世界衛生組織統計,肥胖已經成為全球流行性疾病,肥胖又與心臟病與糖尿病的發生有關,因此肥胖可能是一個健康出現危機的表徵,而基因遺傳或飲食代謝失調都可能是造成肥胖的因素。人體攝食量和能量消耗兩者間失去平衡後促使肥胖發生,由脂肪細胞分泌的瘦素(Leptin)扮演調控能量平衡的角色。Leptin可以降低人體攝食量與提升能量的消耗而維持我們正常的體重;文獻提出,相較於體重輕的人,肥胖的人血液中雖然有更多leptin,卻因為瘦素抗阻(Leptin resistance)的出現而無法調節能量平衡。其中,在肥胖婦女血液中可偵測到高含量的介白素二十(Interleukin-20, IL-20)。實驗室過去研究已知IL-20參與在類風濕性關節炎,動脈粥狀硬化與骨質疏鬆等疾病上。因此,我想探討在肥胖中介白素二十和瘦素之間是否有相關連性。首先,從組織免疫染色得知高脂肪飲食肥胖小鼠的脂肪中有IL-20表現,而且發現比起餵食一般飼料(Chow diet)的小鼠,高脂肪飼料(High-fat diet)小鼠的血清中IL-20含量更高。介白素二十單株抗體(7E)可以降低高脂肪飲食所引發的肥胖小鼠血清中IL-20的含量,進一步從細胞實驗中發現IL-20可促進脂肪細胞產生leptin。IL-20透過ERK1/2訊息傳遞路徑增加脂肪細胞leptin 的產生。在缺氧的環境下發現不僅會誘發脂肪細胞分泌IL-20,7E也降低脂肪細胞Leptin的產生。進一步從臨床上肥胖的人體血清中分析得知,IL-20和leptin的表現量具有正相關。另外,IL-20促進脂肪細胞油滴生成並增加調控脂肪分化的轉錄因子的基因表現量。綜合以上的實驗結果,我們找出在缺氧的環境下脂肪細胞是產生IL-20的來源,IL-20增加脂肪細胞leptin的表現量以及促使脂肪細胞油滴生成,因此,IL-20在肥胖疾病中可能扮演著重要的角色。
英文摘要 Obesity results from an imbalance between energy expenditure and food intake and it has become an epidemic disease worldwide. Obese individuals have highr risk for heart disease and diabetes. Leptin plays a critical role in regulating the energy balance. Compared to lean people, obese people have higher serum leptin that is accompanied with leptin resistance. In addition, higher serum IL-20 is indicated in obese woman. Our previous studies showed that IL-20 was involved in various inflammatory diseases, such as rheumatoid arthritis, atherosclerosis and osteoporosis. Hence, we aim to investigate whether there is correlation between IL-20 and leptin in obesity. IL-20 expression in adipose tissue was detected using immunohistochemical staining in High-fat-diet(HFD)-induced obese mice. Serum IL-20 and leptin were higher in HFD-induced obese mice than those of chow-diet mice. Anti-IL-20 mAb (7E) decreased leptin production in HFD-induced obese mice. In vitro, IL-20 upregulated leptin mRNA and protein expression in adipocyte. IL-20 increased phosphorylation of ERK1/2 and may play a role in upregulating transcription of leptin. Hypoxia induced IL-20 secretion in adipocyte and 7E reduced leptin production. Moreover, serum IL-20 and leptin have positive correlation in patients with obesity. IL-20 promoted adipocyte differentiation and increased expression of transcription factors for adipocyte differentiation. Taken together, our data demonstrated that adipocyte was the cellular source of IL-20 under hypoxia and IL-20 enhanced leptin expression and adipocyte differentiation. Therefore, IL-20 may play an important role in the pathogenesis of obesity.
論文目次 中文摘要…………………………………………………………………………..…….I
英文延伸摘要…………………………………………………………………………..II
致謝…………………..…………………………………………………………………VI
目錄…………………..…………………………………………………………………VII
圖目錄………...…………………………………………….………………….…….XI
表目錄……………………………………………..…………………………..…….XIII
附錄目錄…………………………………………………………………..….……. XIV
縮寫檢索表………………………………………………………………….………. XV
第一章 緒論……………………………………………………………….……….....1
1-1 肥胖 (Obesity)…………………………………………………………………1
1-2肥胖相關疾病(Obesity related diseases)…………….………………………….1
1-3白色脂肪細胞(White adipocyte)………………………………………………….1
1-4 瘦素(Leptin)…………………………………….………………………………….2
1-5 瘦素的調控(Regulation of leptin)…………….………………………………….3
1-6 瘦素抗阻(Leptin resistance)…………….……………………….……………..4
1-7慢性發炎與肥胖(Low-grade chronic inflammation and Obesity)…………………5
1-8缺氧與肥胖(Hypoxia and obesity)……….……………………………….……...6
1-9介白素二十(Interleukin-20, IL-20)…….………………………………….……...6
1-10介白素二十的生物功能(Biological function of IL-20)………………………..7
1-11介白素二十單株抗體(Anti-IL-20 monoclonal antibody, 7E)………………..7
第二章 研究目的與動機…………………………………………………..…….……8
第三章 材料與方法………………………………………………………..….……..9
3-1實驗材料……………………………...……..............…...…….……………..……9
3-1-1細胞株來源與背景……………………………………….…………….…….....9
3-1-2 實驗動物…..……..……..……..………………………………..….....….….….9
3-1-3 蛋白質以及單株抗體來源…..……..……..……..……………..……..…….….9
3-1-4 實驗培養基與緩衝液…...........…..……..….....……….….9
3-1-5實驗溶劑…...........…..……..…...….………………..……………………..….11
3-2實驗方法…………………………………………………………………….……14
3-2-1 SGBS脂肪分化(Adipocyte differentiation)………………………………….14
3-2-2 免疫細胞化學染色(Immunocytochemical staining)………………………14
3-2-3 RNA萃取(RNA extraction)…………………………………………………14
3-2-4 反轉錄酶-聚合酶鏈鎖反應(Reverse transcription polymerase chain reaction, RT-PCR)……………………………………………………………………………….15
3-2-5 聚合酶鏈鎖反應(Polymerase chain reaction, PCR)………...........................15
3-2-6 同步定量聚合酶鏈鎖反應(Real time PCR)………………………………...16
3-2-7 酵素結合免疫吸附分析(Enzyme-Linked Immunosorbent Assay)…….……17
3-2-8 細胞內訊息傳遞分析(Cellular signal transduction)………………………….17
3-2-9 西方點墨法(Western blotting) ………………………………………………18
3-2-10 油紅染色(Oil red O staining)...................……18
3-2-11 油紅染色定量(Quantification of Oil red staining)………………………….19
3-2-12 細胞免疫螢光染色(Immunofluorescence staining)………………………….19
3-2-13 單株抗體純化(Antibody purification)……………………………………….19
3-2-14 蛋白質純化(Protein purification)……………………………………..…..20
3-2-15 動物實驗(Animal model)……………………………….……………………20
3-2-16 星狀神經膠細胞的初代培養(Primary culture of mouse astrocyte)…………21
3-2-17 臨床上病人血清檢體(Pateints’ serum) ……………….…………………..…21
第四章 結果…………………………………..………………………..………..……..23
4-1. 成熟SGBS人類白色脂肪細胞具有內生性leptin基因……….……………...23
4-2. SGBS人類白色脂肪細胞具有IL-20接受器IL-20R1、IL-20R2與IL-22R1.23
4-3. IL-20促進SGBS人類白色脂肪細胞leptin基因表現………..……….……...23
4-4. IL-20促進SGBS人類白色脂肪細胞leptin蛋白分泌………..……….....24
4-5. 高脂肪餵食的小鼠血液中有更高濃度IL-20………………..……….………..24
4-6. 7E降低高脂肪餵食的小鼠血液中的leptin濃度…………….………………..24
4-7. 7E降低高脂肪餵食的小鼠脂肪組織中的IL-20的表現….…………………..25
4-8. 在Normoxia培養下,SGBS人類白色脂肪細胞具有內生性IL-20的基因,但沒
有偵測到IL-20蛋白的分泌..………….…………………………….25
4-9. 在缺氧細胞培養箱環境(1% O2)條件下,誘發成熟SGBS人類白色脂肪細胞分泌IL-20蛋白..................................……………..…..25
4-10. 在缺氧細胞培養箱環境(Hypoxia)或Normoxia培養下,Raw264.7巨噬細胞不會分泌IL-20蛋白..................................….26
4-11. 在Hypoxia培養下,7E降低成熟SGBS人類白色脂肪細胞leptin的產量…26
4-12. 臨床的肥胖人類血清檢體中,IL-20和leptin的濃度具有正相關……….......27
4-13. IL-20誘導成熟SGBS人類白色脂肪細胞內訊息傳遞分子的磷酸化………27
4-14. IL-20透過ERK1/2的訊息傳遞而促進成熟SGBS細胞leptin蛋白的表現……………28
4-15. IL-20促進SGBS人類白色脂肪細胞油滴的生成……..………………..……..28
4-16. IL-20促進SGBS脂肪細胞分化轉錄因子的基因與蛋白表現.........29
第五章 討論………………………………………..30
參考文獻…………………………………………………34
實驗結果圖表……………………………………………43
表格……………………………………………………………63
附錄……………………………………………………………64
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