臺灣博碩士論文加值系統

Calebin-A（CbA）是薑黃中的活性化合物，文獻指出其具有抗發炎、抗腫瘤及抗肥胖等功效，但CbA是否可改善肥胖誘導的胰島素阻抗（insulin resistance；IR）及發炎反應之功效尚未清楚，因此本篇主要目的是探討CbA改善肥胖誘導IR和發炎反應之功效與機制。首先in vitro實驗利用脂多糖誘導RAW264.7巨噬細胞活化後，再處理CbA後發現其可降低nitrite形成、inducible nitric oxide synthase、cyclooxygenase 2蛋白質，以及tumor necrosis factor alpha（TNF-、interleukin （IL-6）和interleukin 1（IL-1）基因表現。動物實驗（in vivo）分為長期及短期；短期餵食模式為先以5週high fat diet（HFD）餵食誘導成肥胖小鼠，再合併CbA 25或100 mg/kg處理5週。長期餵食模式為以10週HFD餵食誘導成肥胖小鼠，再合併CbA 25或100 mg/kg處理10週，探討CbA改善肥胖小鼠發炎反應及IR之功效。短期餵食模式結果顯示，CbA餵食可降低肥胖小鼠體重、肝臟及脂肪組織脂質累積，並可改善肝臟及脂肪組織中TNF-、IL-6、IL-1和active-caspase 1促炎相關因子蛋白質表現；另短期CbA餵食雖無法改善肥胖小鼠葡萄糖耐受性，但可改善肝臟及脂肪組織中磷酸化insulin receptor substrate 1及磷酸化protein kinase B胰島素訊號和葡萄糖轉運蛋白4(2)蛋白質表現，並可降低肝臟中磷酸化forkhead box protein O1（FOXO1）及磷酸化glycogen synthase kinase 3 beta（GSK3）表現。長期餵食結果表明CbA除可改善肥胖小鼠體重、肝臟及脂肪組織的脂質堆積，且可抑制肝臟及脂肪組織促炎相關因子蛋白質表現。此外長期CbA餵食不僅改善肥胖小鼠葡萄糖耐受性，亦改善肥胖小鼠肝臟及脂肪組織中胰島素訊號途徑蛋白質表現，並降低肝臟中磷酸化FOXO1、GSK3和glycogen synthase（GS）蛋白質表現。綜合以上結果表明，CbA不僅能改善LPS誘導RAW264.7巨噬細胞發炎反應，亦可降低HFD誘導肥胖小鼠體重、肝臟及脂肪組織脂質堆積，並藉由降低發炎因子表現及調節胰島素訊號途徑，達到改善肥胖相關發炎反應及IR之功效。

Calebin-A (CbA) is presented in Curcuma longa and showed to has anti-obesity, anti-inflammatory and anticancer activity, however, its effect on modulation of obesity-mediated insulin resistance (IR) and inflammation is unknown. Here, we investigated the therapeutic potential of CbA for treating obesity-induced IR and inflammation as well as examined the possible mechanism by its action. In the in vitro study, the anti-inflammatory effect of CbA was investigated in lipopolysaccharide-induced RAW 264.7 macrophage. The results showed that CbA reduced nitrite production, protein expression of inducible nitric oxide synthase, cyclooxygenase 2 and mRNA level of tumor necrosis factor alpha (TNF-, interleukin IL-6)and interleukin 1IL-1 in LPS-treated RAW264.7 macrophages. The efficacy of long-term and short-term CbA administration on against IR and inflammation was carried out in high fat diet (HFD)-fed obese mice. In short-term CbA treatment , C57BL/6J mice were fed HFD for 5 weeks and treated with CbA 25 or 100 mg/kg and a continued HFD for another 5 weeks; In long-term feeding CbA model, C57BL/6J mice were fed HFD for 10 weeks and then treated with CbA 25 or 100 mg/kg and a continued HFD for another 10 weeks. Short-term CbA treatment showed significantly reduced body weight gain, adipose tissue weight, lipid accumulated in the liver and adipose tissue in obese mice. CbA decreased protein levels of TNF-, IL-6, IL-1 and active-caspase 1 in the liver and adipose tissue from obese mice. Short-term CbA treatment showed no significant effect on improving glucose tolerance in obese mice while it improved insulin signaling including phosphorylation of insulin receptor substrate 1, glucose transporter type 4(2) and phosphorylation of protein kinase B in the liver and adipose tissue. In addition, CbA down-regulated gluconeogenesis maker forkhead box protein O1 and glycogen synthesis marker glycogen synthase kinase 3 beta but not glycogen synthase. Long-term CbA administration reduced weight gain, adipose tissue weight, inflammatory response and showed no obvious toxicity in obese mice. The improved glucose tolerance was found by long-term CbA treatment followed by up-regulating insulin signaling in the liver and adipose tissue. Taken together, these data indicated that CbA improved obesity associated IR and inflammation.

國立高雄科技大學學位論文審定書 I
博碩士學位論文[延後公開]申請書 II
碩士論文著作權歸屬協議書 III
誌謝 IV
目錄 VI
附表目錄 IX
中文摘要 X
英文摘要 XII
第一章、文獻回顧 1
第一節、肥胖（obesity） 1
一、流行病學研究 1
二、脂肪組織生理功能 3
三、肥胖引起脂肪組織代謝失衡 5
第二節、肥胖引起IR 8
一、胰島素與葡萄糖代謝生理功能 8
二、胰島素與脂質代謝生理功能 12
三、胰島素訊號傳遞 13
四、IR定義 18
五、IR分子機制 19
第三節、脂肪組織慢性發炎反應 23
一、WAT 慢性發炎反應 23
二、肥胖引起WAT中PYD domains-containing protein 3（NLRP3）炎症 24
三、其他促炎因子誘導IR分子機制 26
第四節、肥胖相關疾病（IR與發炎反應）預防及治療 30
一、藥物治療 30
二、天然化合物調節發炎反應及IR 33
第五節、薑黃中活性化合物 37
一、薑黃（Curcuma longa） 37
二、薑黃素（curcumin） 38
三、非類薑黃素（curcumin-free turmeric；CFT）與類薑黃素（curcumin-containing turmeric；CCT） 39
四、Calebin-A生理作用 43
第二章、研究目的 48
第三章、研究架構 50
第四章、實驗材料與方法 52
第一節、儀器與廠牌 52
第二節、藥品與廠牌 54
第三節、實驗方法 55
第五章、結果與討論 75
第一節、CbA改善LPS誘導RAW264.7巨噬細胞發炎現象 75
一、CbA對LPS誘導RAW264.7巨噬細胞之毒性影響 75
二、CbA改善LPS誘導RAW264.7巨噬細胞NO產生 75
三、CbA減少LPS誘導RAW264.7巨噬細胞中iNOS及COX-2蛋白質表現 76
四、CbA降低LPS誘導RAW264.7巨噬細胞促炎性因子分泌 77
第二節、短期CbA餵食改善肥胖小鼠發炎反應及IR之功效 79
一、短期CbA餵食改善肥胖小鼠外觀及體重差異 79
二、短期CbA餵食改善肥胖小鼠臟器重量差異 80
三、血清生化指標 80
四、短期CbA餵食改善肥胖小鼠性腺、腹部、腸膜及BAT組織重量及大小 81
五、短期CbA餵食改善肥胖小鼠肝臟脂質堆積 83
六、短期CbA餵食未改善肥胖小鼠之葡萄糖不耐症 83
七、短期CbA餵食改善肥胖小鼠脂肪組織發炎反應及IR 84
八、短期CbA餵食改善肥胖小鼠肝臟組織發炎反應及IR 87
第三節、長期CbA餵食改善肥胖小鼠發炎反應及IR之功效 90
一、長期CbA餵食改善肥胖小鼠外觀及體重差異 90
二、長期CbA餵食改善肥胖小鼠臟器重量 90
三、血清生化指標 91
四、長期CbA餵食改善肥胖小鼠性腺、腹部、腸膜及BAT重量及大小 92
五、長期CbA餵食改善肥胖小鼠肝臟脂質堆積 93
六、長期CbA餵食改善肥胖小鼠之葡萄糖不耐症 94
七、長期CbA餵食改善肥胖小鼠脂肪組織發炎反應及IR 95
八、長期CbA餵食改善肥胖小鼠肝臟組織發炎反應及IR 97
第六章、結論 99
第七章、結果圖表 101
第八章、參考文獻 122

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