臺灣博碩士論文加值系統

隨著飲食和生活型態的改變，全世界肥胖人口逐年攀升，已經成為日益嚴重的健康問題，肥胖會增加罹患許多慢性疾病的風險，例如：第二型糖尿病、非酒精性脂肪肝、心血管疾病及癌症等，如何預防及延緩肥胖成為近年來研究的重要議題之一。紅豆 (Vigna angularis) 富含多酚類、皂苷及膳食纖維，在先前的研究中發現紅豆萃取物具有保護心血管、抗高血壓及改善胰島素阻抗等功效。因此本研究使用國產老鷹紅豆高雄 9 號，利用四種不同方法萃取，並以 3T3-L1 前脂肪細胞模式評估其對脂肪細胞新生作用的影響。結果顯示，熱水萃取之紅豆萃取物 (HWE) 最能有效抑制脂肪細胞內油滴堆積，故選擇 HWE 進行動物實驗。動物模式以 50% 高脂飲食誘導 C57BL/6 小鼠肥胖，同時給予不同比例的 HWE，評估 HWE 是否具有減緩肥胖之功效，並額外加入一組同時餵食正常飲食及高劑量 HWE 之組別 (NDHWE)。飼養 13 週後犧牲，結果顯示，餵食 1% 及 5% HWE 的組別與 high-fat diet (HFD) 組相比，小鼠之體重、白色脂肪組織重量及體脂率在不影響其攝食量的情況下，皆顯著下降並呈現劑量效應。血液中總膽固醇及三酸甘油酯也顯著的降低，其中 NDHWE 組三酸甘油酯含量更是顯著低於 ND 組，表示 HWE 可能具有降血脂之潛力。由肝臟切片則可觀察到餵食 HWE 的組別，其肝臟內脂肪空泡的數量和大小明顯減少，顯示 HWE 可以減緩高脂飲食造成之小鼠肝臟脂肪堆積。在先前的研究中已證實在 3T3-L1 細胞模式中活化 Wnt/β-catenin 路徑可以抑制脂肪細胞新生，HWE 可以透過增加 Wnt/β-catenin 路徑中 Wnt10b、Dvl2、β-catenin 及 cyclin D1 蛋白質表現量，同時降低 destruction complex 成員 Axin1 表現量，活化 Wnt/β-catenin 路徑，進而減少脂肪細胞新生必須之轉錄因子 PPARγ 及 C/EBPα 表現量，以抑制脂肪細胞新生。餵食高脂飲食後會提高 Firmicutes/Bacteroidetes 之比例 (F/B ratio)，導致腸道菌相失衡，同時給予 HWE 則可降低 F/B ratio，提升菌種多樣性，另外也發現 HWE 可以提升腸道內益生菌 Lactobacillus 及 Akkermansia 比例，降低 Blautia 及 Ruminococcus 比例，使小鼠腸道菌相組成恢復至與 ND 組相似，推測 HWE 可以透過調節小鼠腸道菌相而減緩肥胖。綜合上述結果，HWE 具有抑制脂肪細胞內脂質累積之能力，並透過活化 Wnt/β-catenin 路徑及改善腸道菌相減緩高脂飲食誘導之肥胖，達到降低體脂、血脂及改善脂肪肝之功效。顯示未來 HWE 具有相當潛力被開發成不易形成體脂肪之保健食品，提升國產紅豆經濟價值。

Due to rapid changes in our diet and lifestyle, obesity population is rising year by year worldwide and become a serious health problem. Obesity is associated with numerous chronic diseases such as type 2 diabetes, nonalcoholic fatty liver, cardiovascular disease and cancer. Adzuki bean (Vigna angularis), one of Taiwan''s important economic crops, are known to include many polyphenols, saponins and dietary fiber. The extracts of adzuki bean were found to have cardiovascular protection, anti-hypertenison and insulin resistance improvement effect. In this study we used four different solvent to extract adzuki bean. Further, we investigated the anti-adipogenic effect of different adzuki bean extracts in 3T3-L1 cell model. The results showed that hot water extract (HWE) group had the most significant anti-adipogenic effect, it could inhibit lipid accumulation in adipocyte. Therefore, we choosed HWE for further animal experiments. Five-week-old C57BL/6 male mice were fed with normal diet (ND), high-fat diet (50% energy from fat, HFD), HFD with 1% or 5% HWE (LHWE, HHWE) and ND with 5% HWE (NDHWE) for 13 weeks. Compared with HFD group, body weight, white adipose tissue weight and body fat ratio were significantly reduced in both HWE-treated groups in dose-dependent manner without affecting their food intake. Serum total cholesterol and triglyceride levels were significantly lower in both HWE-treated groups compared with HFD group. NDHWE group also had lower triglyceride content compared with ND group, it suggested that HWE may has potential hypolipidemic effect. The number and size of fat vacuoles in liver lesions were significantly reduced, indicating that HWE could ameliorate steatosis in HFD-induced mice. In previous studies, it has been demonstrated that activating Wnt/β-catenin pathway can inhibit adipogenesis in 3T3-L1 cell model. The results showed that HWE-treated groups inhibited adipogenesis via increasing Wnt10b, Dvl2, β-catenin and cyclin D1 protein levels and decreasing protein levels of Axin1 (destruction complex member), activated Wnt/β-catenin pathway and reduced adipogenesis associated transcription factors PPARγ and C/EBPα expression. Moreover, our studies firmed that mice fed with HFD increasd Firmicutes/Bacteroidetes ratio (F/B ratio) and caused gut microbiota imbalance. Supplementation of HWE altered the composition of the gut microbiota by decreasing F/B ratio, improving bacterial diversity, increasing intestinal probiotics Lactobacillus and Akkermansia and decreasing Blautia and Ruminococcus compared with HFD-treated group, suggesting that HWE could improve obesity through modulating gut microbiota. Taken together, these results suggested that HWE could inhibited lipid accumulation in 3T3-L1 cells and ameliorated high-fat-diet induced obesity by activating Wnt/β-catenin pathway and regulating gut microbiota. HWE may has potential to be developed into functional food to improve metabolic disorders and enhance the economic value of domestic adzuki bean in Taiwan.

謝誌 I
中文摘要 III
Abstract V
目錄 VII
附圖目錄 XI
附表目錄 XII
圖目錄 XIII
表目錄 XV
縮寫表 XVI
第一章、緒論 1
第二章、文獻回顧 2
第一節、肥胖 (Obesity) 2
(一) 簡介 2
(二) 肥胖之定義 2
(三) 肥胖之成因 4
(四) 肥胖與疾病之關係 5
(五) 肥胖之預防及治療 6
第二節、脂肪組織 (Adipose tissue) 8
(一) 簡介 8
(二) 脂肪組織之功能 9
第三節、脂肪細胞新生作用 (Adipogenesis) 11
(一) 簡介 11
(二) 脂肪細胞新生過程中參與之轉錄因子 12
第四節、調控脂肪細胞新生期間之分子訊息傳遞路徑 14
(一) 簡介 14
(二) Wnt/β-catenin訊號傳遞路徑 (Wnt/β-catenin signaling pathway) 16
第五節、腸道菌與肥胖 19
第六節、紅豆 (Vigna angularis) 22
(一) 簡介 22
(二) 老鷹紅豆 23
(三) 紅豆之活性成分 24
(四) 紅豆之已知功效 24
第三章、實驗目的與架構 26
第一節、研究目的 26
第二節、實驗架構 26
第四章、材料與方法 28
第一節、實驗材料 28
(一) 儀器設備 28
(二) 藥品試劑 29
第二節、樣品萃取方法 32
(一) 樣品來源 32
(二) 樣品萃取及製備 32
第三節、樣品分析方法 35
(一) 總醣含量測定 (Phenol-sulfuric acid assay) 35
(二) 總酚含量測定 (Folin-Ciocalteu assay) 35
第四節、細胞實驗 (in vitro) 方法 37
(一) 樣品配製 (Sample preparation) 37
(二) 細胞培養 (Cell culture) 37
(三) 細胞分化 (Adipocyte differentiation) 39
(四) 油紅染色 (Oil red O stain) 40
(五) 細胞增生率試驗 (MTT assay) 41
(六) 細胞存活率試驗 (Trypan blue assay) 42
第五節、動物實驗 (in vivo) 方法 44
(一) 動物品系與飼養環境 44
(二) 飼料配製 45
(三) 動物犧牲 46
(四) 組織切片染色 47
(五) 肝臟三酸甘油酯萃取及定量 50
(六) 組織均質及蛋白質萃取 52
(七) 蛋白質定量 53
(八) 西方墨點法 (Western blot) 54
(九) 次世代定序 (Next generation sequencing) 58
第六節、統計分析 60
第五章、結果與討論 61
第一節、樣品萃取 61
(一) 不同萃取方法之紅豆萃取物萃取率 61
(二) 不同萃取方法之紅豆萃取物初步成分分析 61
第二節、細胞實驗 (in vitro) 63
(一) 3T3-L1 前脂肪細胞分化期間之型態觀察 63
(二) 不同萃取方法之紅豆萃取物對 3T3-L1 前脂肪細胞增生率之影響 63
(三) 不同萃取方法之紅豆萃取物對 3T3-L1 前脂肪細胞存活率之影響 64
(四) 不同萃取方法之紅豆萃取物抑制 3T3-L1 前脂肪細胞內脂質堆積之情形 65
(五) 動物實驗樣品選擇 66
第三節、動物實驗 (in vivo) 67
(一) HWE 對高脂飲食 C57BL/6 小鼠體重之影響 67
(二) HWE 對高脂飲食 C57BL/6 小鼠攝食量之影響 68
(三) HWE 對高脂飲食 C57BL/6 小鼠脂肪重量之影響 69
(四) HWE 對高脂飲食 C57BL/6 小鼠脂肪細胞大小之影響 70
(五) HWE 對高脂飲食 C57BL/6 小鼠臟器重量之影響 71
(六) HWE 對高脂飲食 C57BL/6 小鼠肝臟脂肪之影響 72
(七) HWE 對高脂飲食 C57BL/6 小鼠血清生化數值之影響 73
(八) HWE 對高脂飲食 C57BL/6 小鼠脂肪細胞新生相關轉錄因子之影響 74
(九) HWE 對高脂飲食 C57BL/6 小鼠 Wnt/β-catenin 路徑中相關蛋白之影響 75
(十) HWE 對高脂飲食 C57BL/6 小鼠腸道菌相之影響 76
第六章、結論 79
第七章、圖表 80
第八章、參考文獻 104
第九章、附錄 116

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