臺灣博碩士論文加值系統

摘要
Peroxisome proliferator-activated receptor (PPAR)屬固醇類荷爾蒙接受器家族(steroid hormone nuclear receptor superfamily)成員之一，有3種isoforms分別為PPARa、d及g。PPARa主要表現於肝臟，負責調控脂質代謝相關基因轉錄作用。而PPARg則主要表現於脂肪組織，調控脂肪細胞分化及葡萄糖代謝相關基因表現。已知魚油與炸油均可活化大鼠肝臟中PPARa，增加脂肪酸代謝基因表現，並促進b-oxidation，而降低了肝(血)脂質。在我們先前研究也觀察到，炸油如同魚油可抑制高油飲食誘發的腹部脂質堆積及脂肪細胞肥大。但魚油與炸油是否會影響脂肪細胞分化，及炸油對葡萄糖代謝影響仍不清楚。本研究目的為探討魚油與炸油在大鼠抗體脂堆積效應可能原因，及對脂肪細胞分化之影響，並且初步評估炸油對胰島素敏感性之作用。將48隻SD (Sprague-Dawley)公成鼠(約100 g)分為4組，每組12隻，分別給予5 % (g/g)新鮮黃豆油(LF，低油對照組)或20 % (g/g)新鮮黃豆油(HF，高油對照組)、20 %炸油(HO)或20 %魚油(HFO)飼料，炸油來自新鮮黃豆油以205 ± 5 ℃油炸麵片24小時，餵食12週。結果顯示大鼠餵食魚油或炸油會增加肝、腎重(p<0.0001)，降低體重增加量(p<0.0001)、飼料效率(p<0.0001)、腹部脂肪包括副睪脂(epididymal; EP)及腹膜後脂肪(retroperitoneal; RE)脂肪組織堆積(p<0.0001 for EP and RE)、肝中總脂質(p<0.0001)、血中總脂質(p<0.0001)及平均脂肪細胞三酸甘油酯堆積(p<0.0001 for RE)情形；且餵食炸油也使脂肪細胞變小(p=0.05 for EP and RE)。
此外HO組脂肪組織有最高的脂質合成酵素活性，包括glycerol-3-phosphate dehydrogenase (G3PDH)(p<0.01 for RE)與lipoprotein lipase (LPL) (p<0.05 for EP and p=0.05 for RE)，但HO與HFO組的basal lipolysis rate (p<0.05 for EP and RE)均顯著高於HF組。因此，炸油與魚油飲食促進脂肪組織脂解可部分解釋其抗體脂堆積效應。
以北方點墨法偵測脂肪細胞分化指標與脂肪細胞激素基因表現發現，與HF組相較，魚油降低PPARg (p<0.05 for RE)、LPL (p=0.05 for RE)、leptin (p<0.005 for EP and p<0.0001 for RE)及adiponectin (p<0.0005 for RE) mRNA表現；炸油增加PPARg (p=0.05 for EP)、降低leptin (p<0.0001 for RE) mRNA表現。可見魚油似乎抑制脂肪細胞分化，而炸油雖也顯著抑制體脂生成，但並未抑制脂肪細胞分化。
追蹤比較LF、HF及HO三組9週內之禁食全血葡萄糖，及禁食血清胰島素均無差異，但HO組在第9週胰島素與血糖有較高趨勢。在第3週及第9週口服葡萄糖耐受試驗曲線(OGTT)曲線變化及曲線下面積(AUC)顯示，餵食炸油之大鼠葡萄糖耐受有較差情形(AUC, p<0.001 for 3th wk. and p<0.01 for 9th wk.)。
以上結果顯示，以炸油作為高脂飲食油脂來源，會降低高脂飲食誘發之成熟大鼠脂肪細胞肥大，但並不抑制脂肪細胞分化，此抗體脂堆積效應，除可以活化肝臟PPARa解釋外，並與促進脂肪細胞脂解(lipolysis)相關。另外，與新鮮油相較，炸油似乎有可能導致胰島素抗性之趨勢。

Abstract
Peroxisome proliferator-activated receptor (PPAR) is a member of steroid hormone receptor superfamily of ligand-activated transcription factors. To date, three isoforms have been identified, PPARa, d and g, encoded by three separate genes. PPARa is expressed predominantly in lipid metabolizing tissue, such as liver where it plays a role in lipid catabolism. PPARg, on the other hand, is mainly expressed in adipose tissue and has a critical role in adipocyte differentiation and glucose metabolism. We had previously proved that dietary fish oil and oxidized frying oil (OFO) could activate PPARa and increase fatty acid oxidation in liver. Thus, lowering the liver (serum) lipids in rats. The anti-adiposity effect of OFO was also observed as well as fish oil. However, the effect of OFO on adipocyte differentiation, and glucose metabolism had never been explored. The aim of this study was to investigate the morphological change and differentiation status of adipocytes in rats fed with OFO or fish oil. In addition, the insulin sensitivity was also evaluated in rats fed with OFO. 48 SD male rats (about 100 g) were divided into four groups, receiving diet contain 5% (g/g) fresh soybean oil (LF), 20% fresh soybean oil (HF), OFO (HO) or fish oil (HFO), respectively. The OFO was prepared by frying wheat dough sheets in soybean oil at 205 ± 5 ℃ for 24 h. After 12 weeks feeding, rats in HO and HFO groups showed a significantly increased in liver and kidney weight (p<0.0001), and a significantly decreased in body weight gain (p<0.0001), feeding efficiency (p<0.0001), abdominal fat weight including epididymal (EP) and retroperitoneal (RE) (p<0.0001), serum and liver lipids (p<0.0001). The TG (triglyceride) content of adipocytes isolated from EP and RE was also significantly lower than those of rats fed with fresh soybean oil (p<0.0001 for RE). The volume of adipocytes isolated from EP and RE was also significantly lower in OFO than those of rats fed with fresh soybean oil (p=0.05 for EP and RE).
Though the activities of enzymes participated in lipogenesis of adipose tissue including glycerol-3-phosphate dehydrogenase (p<0.01 for RE) and lipoprotein lipase (p<0.05 for EP and p=0.05 for RE) were significantly increased in rats fed with OFO, the basal lipolysis rate (p<0.05 for EP and RE) in adipose tissue of HO and HFO group was significantly higher than HF group. The enhanced lipolysis rate in adipose tissue of rats fed with fish oil and OFO partly explained the anti-adiposity effect observed in those rats.
The gene expression of adipocyte differentiation markers and adipocytokines was analyzed by Northern blot. Compared with HF group, PPARg (p<0.05 for RE), LPL (p=0.05 for RE), leptin (p<0.005 for EP and p<0.0001 for RE) and adiponectin (p<0.0005 for RE) mRNA in adipose tissue was significantly reduced in HFO group. On the other hand, PPARg mRNA was significantly increased (p=0.05 for EP) but leptin mRNA was significantly decreased (p<0.0001 for RE) in adipose of HO group. Thus, the adipocyte differentiation seems to be slightly inhibited by fish oil, but not by OFO, though the adiposity was significantly reduced in OFO-fed rats.
The fasting blood glucose and serum insulin were followed for 9 wk in LF, HF and HO groups of rats. There was no significant difference among three groups, but the insulin and blood glucose tended to be higher in HO group of rats at the 9th wk. Rats fed with OFO also showed a significantly higher area under curve (AUC) in oral glucose tolerance test (OGTT) performed at the 3th and 9th wk (p<0.001 and p<0.01 for the 3th and 9th wk respectively).
In conclusion, these results showed OFO inhibit the hypertrophy of adipocytes induced by high-fat diet, but didn’t restrain the differentiation of adipocytes. The anti-adiposity effect in rats fed with fish oil and OFO-rich diet could be attributed to PPARa activation in liver and increased lipolysis rate in adipose tissue. Compared with fresh soybean oil, OFO may result in insulin resistance.

目錄
摘要…………………………………………………………………………..I
Abstract …………………………………………………………………...III
第一章 前言………………………………………………………………...1
第二章 文獻回顧…………………………………………………………...2
一、 過氧化體與PPAR……………………………………………….2
(一) 過氧化體…………………………………………………2
(二) 過氧化體中之b-oxidation……………………………….2
(三) 過氧化體增殖劑…………………………………………3
(四) PPAR……………………………………………………..3
(五) PPAR標的基因與PPRE………………………………..5
(六) PPAR的活化劑(activators)與結合子(ligands)………..6
二、 脂肪細胞分化…………………………………………………….7
(一) 調控脂肪細胞分化之重要因子- PPARg..........................9
(二) 脂肪細胞分化與胰島素阻抗性………………………..11
三、 脂肪細胞分泌之脂肪細胞激素對胰島素阻抗性之影響……..12
(一) TNF- a..............................................................................12
(二) Leptin……………………………………………………14
(三) Adiponectin……………………………………………..15
(四) Resistin………………………………………………….16
四、 魚油影響脂肪細胞分化及胰島素敏感性……………………..18
五、 共軛亞麻油酸對脂質堆積及胰島素敏感性之影響…………..20
六、 炸油對於PPAR活性及脂質代謝之影響……………………21
第三章 材料與方法……………………………………………………….24
實驗設計……………………………………………….…………….24
一、氧化炸油的製備…………………………………………………25
二、油脂品質分析……………………………………………………25
(一) 酸價 (Acid Value, AV).………………………….…….25
(二) 共軛雙烯測定………………………………………26三、試驗飼料之配製…………………………………………………26
四、動物飼養…………………...…………………………………….28
五、動物犧牲與樣品收集…………...……………………………….29
六、G3PDH (glycerol-3-phosphate dehydrogenase)
酵素活性測定…………………………………………………..29
七、脂解速率測定…………………………………………………...33
八、LPL (lipoprotein lipase)酵素活性測定………………………..34
九、以北方墨點法(Northern blot)分析PPARg、LPL、ADD1/SREBP、adipisin、resistin、leptin及adiponectin
mRNA表現量………………………………………………..38
(一) 總RNA之抽取…………………………………………38
(二) RNA電泳………………………………………………..39
(三) RNA轉印法……………………………………………..42
(四) 探針標幟………………………………………………..42
(五) 雜交反應………………………………………………..43
十、血清脂質及甘油分析…………………………………………..44
(一) 血清總脂質含量測定…………………………………..44
(二) 血清三酸甘油酯含量測定……………………………..44
(三) 血清膽固醇含量測定…………………………………..45
(四) 血清游離脂肪酸含量測定……………………………..46
(五) 血清甘油含量測定……………………………………..47
十一、 肝臟脂質分析………………………………………………48
(一) 肝脂質萃取液製備……………………………………..48
(二) 肝臟總脂質含量測定…………………………………..49
(三) 肝臟三酸甘油酯含量測定……………………………..49
(四) 肝臟膽固醇含量測定…………………………………..49
(五) 肝臟游離脂肪酸含量測定……………………………..49
十二、脂肪組織三酸甘油酯含量測定………………………………49
(一) 脂肪組織脂質萃取液製備…….……………………….50
(二) 脂肪組織三酸甘油酯含量測定………………………..50
十三、脂肪組織DNA測定………………………………………....50
十四、脂肪組織包埋切片…………………………………………...52
十五、口服葡萄糖耐受測試…………………………………………54
十六、全血葡萄糖含量測定…………………………………………55
十七、禁食血清胰島素測定法………………………………………55
十八、統計分析………………………………………………………56
第四章 結果……………………………………………………………….57
第五章 討論……………………………………………………………..101
第六章 結論……………………………………………………………..116
第七章 參考文獻……………………….……………………………….118
附錄………………………………………………………………………132

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