臺灣博碩士論文加值系統

先前研究發現炸油飲食在大 / 小鼠均會導致體脂降低伴隨葡萄糖不耐發生。本研究目的在探討炸油導致葡萄糖不耐之機制。

實驗一為比較炸油導致現象是否與共軛亞麻油酸（Conjugated linoleic acid，CLA）引起的Lipodystrophy diabetes類似。將51隻C57BL/6J公鼠分為5組。為觀察CLA之Lipodystrophy diabetes效果設計LF與CLA組，分別餵食含4％新鮮油（LF）與4％新鮮油添加1％ CLA（c9,t11：t10,c12＝1：1）mixture（CLA）飼料；為觀察炸油效果，設計HF、FO及HO三組，分別餵食20％ 新鮮油（HF），10％新鮮油 + 10％炸油（FO）及20％炸油（HO）。炸油來自新鮮黃豆油以205 ± 5 ℃油炸麵片24小時，餵食4週後禁食狀態下犧牲。結果顯示CLA飲食熱量效率降低與白色脂肪組織削減程度更甚於炸油飲食，且兩種飲食均導致肝腫大現象。血脂質方面，CLA飲食與炸油飲食均會使血清三酸甘油酯與游離脂肪酸降低，但CLA飲食會增加血清總脂質與膽固醇含量，相對餵食炸油飲食其血清總脂質與膽固醇仍然降低。此外，可觀察到CLA會造成肝臟三酸甘油酯與膽固醇嚴重堆積，相對於炸油飲食肝臟PPARα下游基因ACO表現增加及肝臟三酸甘油酯降低，乃因促進肝臟之脂肪酸氧化及抑制脂肪酸生合成所致。另以RT-PCR來偵測脂肪細胞分化、脂質生合成及脂肪細胞激素相關基因PPARγ2、LPL、FAS及Leptin。發現餵食小鼠CLA飲食會大幅降低PPARγ2、LPL、FAS與Leptin，明顯抑制脂肪細胞分化與脂質生合成；DNA Ladder顯示CLA飲食導致脂肪組織細胞凋亡。炸油組之PPARγ2、LPL與Leptin僅輕微下降，表示炸油並不像CLA飲食對脂肪細胞分化及脂質生合成有如此大的影響且並無細胞凋亡現象。在胰島素敏感性方面，於試驗第二週進行腹腔注射胰島素測試（ITT），發現2小時內血糖變化之曲線下面積（AUCglu）CLA顯著高於LF組（p＜0.05），顯示CLA導致週邊組織對胰島素產生阻抗現象，而HO組顯著低於HF組（p＜0.05）。葡萄糖耐受性方面，試驗第四週進行口服葡萄糖耐量測試（OGTT），發現2小時內血糖變化之曲線下面積（AUCglu）HO組顯著高於HF組（p＜0.05），顯示HO導致葡萄糖不耐，而CLA與LF組無顯著差異。於飽食狀態下，CLA導致飽食血糖與飽食胰島素顯著上升，而HO導致飽食胰島素顯著下降但對飽食血糖則無影響。故炸油與CLA引起之葡萄糖代謝不正常機制不同，並非是週邊組織胰島素阻抗而可能是胰臟分泌胰島素量不足。

由實驗一觀察到炸油導致血清胰島素降低，為進一步了解胰島素降低原因是否為胰臟β-細胞破壞導致胰島素分泌不足，因此設計實驗二來探討炸油飲食對胰臟胰島素分泌之影響。將32隻C57BL/6J公鼠分為3組，分別餵食含4％新鮮油（LF），20％新鮮油（HF），及20％炸油（HO），餵食24週後飽食狀態下犧牲。飼養期間進行OGTT時同時追蹤血糖、血清胰島素與血清C-胜肽含量，發現HO組血糖高於它組、血清胰島素與血清C-胜肽低於它組，顯示出HO可能導致胰臟β-細胞破壞而使胰島素分泌不足。另外觀察到炸油組肝臟與胰臟維生素E含量均顯著下降，證實炸油組小鼠維生素E缺乏。


综合上述，以上結果顯示炸油導致之葡萄糖不耐與CLA導致之Lipodystrophy diabetes不同。已知CLA導致小鼠Lipodystrophy diabetes乃因週邊組織胰島素阻抗，高胰島素血症是其特徵。本研究顯示炸油飲食所致葡萄糖不耐並非週邊胰島素阻抗，而是胰臟Islet分泌胰島素不足所致，可能原因是胰臟過氧化壓力增加、發炎反應或維生素E缺乏所致。

We had previously found that dietary oxidized frying oil （OFO）could decrease body fat and induce glucose intolerance in the rats and mice. The aim of this study was to investigate the mechanism of OFO induced glucose intolerance in mice.

Experiment 1 was designed for comparing the OFO effect with the conjugated linoleic acid （CLA） induced lipodystrophy diabetes . 51 C57BL/6J mice were divided into five groups. In order to observe the lipodystrophy diabetes induced by CLA, LF and the CLA group were set, to receive a diet containing 4% （g/g） fresh soybean oil （LF）and LF diet plus 1% CLA mixture（c9,t11：t10,c12＝1：1）, respectively. In order to observe the effect of OFO, HF, FO and the HO group were set, to receive a diet containing 20% fresh soybean oil （HF）, 10％ fresh soybean oil plus 10％ OFO （FO）and 20％ OFO （HO）, respectively. The OFO was prepared by frying wheat dough sheets in soybean oil at 205 ± 5 ℃ for 24 hours. After 4 weeks, mice were killed after an overnight fasting. The results showed the CLA diet could reduce the energy efficiency and the white adipose deposition more prominant than the OFO diet. Both diets（CLA and OFO）could result in liver enlargement. The both diets could also reduce the serum levels of triglyceride and free fatty acids, but the CLA diet caused an increase in the serum levels of total lipid and cholesterol. In contrast, the OFO diet caused a reduction in the serum levels of total lipid and the cholesterol. Moreover, the CLA diet resulted in the accumulation of triglyceride and cholesterol in liver seriously. However, the OFO diet resulted in an up-regulation of PPAR alpha target gene-ACO and the liver triglyceride was significantly reduced by OFO diet, which could be attributed to the increase of fatty acid oxidation and suppression of fatty acid synthesis in the liver. For understanding the two diets effect on adipocyte differentiation, lipogenesis and production of adipocytokines, mRNA levels of peroxisome proliferators-activated receptor gamma 2（PPARγ2）, lipoprotein lipase（LPL）, fatty acid synthase（FAS）and leptin were measured by real time PCR. Results showed the expression of PPAR gamma 2, LPL, FAS and leptin in adipose tissues were greatly reduced by dietary CLA, indicating a serious suppression on the adipocyte differentiation and lipogenesis. Adipocyte apoptosis were demonstrated by DNA ladder in the CLA diet group. The expression of PPAR gamma 2, LPL and leptin were only slightly reduced by OFO diet , indicating that the OFO diet, unlike the CLA diet, didn’t suppress the adipocyte differentiation and the lipogenesis so prominat as CLA diet and the adipocyte apoptosis was not observed in OFO diet group. About the insulin sensitive, an ITT was conducted at wk2, and the AUCglu showed the CLA group had a significant higher level than the LF group（p＜0.05）, demonstrating the peripheral insulin resistance was happened in CLA group, but the AUCglu in the HO group was significantly lower than that in the HF group（p＜0.05）. In addition, an OGTT was conducted at wk4 and the AUCglu showed the HO group had a significantly higher level than the HF group（p＜0.05）, demonstrating the glucose intolerance was happened in the OFO group, but not the CLA group. The CLA group also showed a significantly higher blood sugar and the insulin levels at feeding status, but HO group had a significantly lower blood insulin level than the HF group. Therefore, the mechanism of OFO diet induced glucose metabolism impairment is different from the CLA diet, which is not insulin resistance, but an impairment in insulin secretion from pancreas is involved.

As the hypoinsulinemia was observed in the OFO group, to explore the possibility of destruction of pancreas beta cells and the impairment of insulin secretion, experiment 2 was conducted. 32 C57BL/6J mice were divided into three groups, to receive a diet containing 4% （g/g）fresh soybean oil （LF）, 20％ fresh soybean oil （HF） or OFO （HO）, respectively. After 24 weeks, mice were killed at feeding status. The blood sugar, serum insulin and the C-peptide were measured simultaneously during an OGTT. Results showed the HO group had a significantly higher blood sugar, but the serum insulin and C-peptide were significantly lower than the other two groups, demonstrating HO group did cause pancreas beta cell destroy and result in the insulin secretion insufficiency. The analysis of vitamin E in liver and pancreas demonstrating vitamin E deficiency was observed in the HO group.

In conclusion, our results showed OFO causes the glucose intolerance in mice, which is different from the CLA caused lipodystrophy diabetes. It is well-know that CLA induced lipodystrophy diabetes had characterstic of peripheral insulin resistance, and hyperinsulinemia was observed in CLA-fed mice. This study demonstrated that the glucose intolerance induced by the HO diet is not related with the peripheral insulin resistance, but the pancreas destruction and insulin secretion insufficiency is the main reason. The possibility of pancreas peroxidation, the inflammation, or vitamin E deficiency might be involved.

第一章 前言 1

第二章 文獻回顧 3
一、 氧化炸油 3
（一） 油脂於高溫炸油時之化學變化 4
（二） 油脂之化學性質及其相關之化學反應 4
（三） 影響油脂自氧化反應的因素 8
（四） 油脂品質之鑑定 9
（五） 受熱氧化油脂及其分離物對動物體之影響 10
二、 共軛亞麻油酸 15
（一） 共軛亞麻油酸緣起與種類 15
（二） 共軛亞麻油酸對脂質堆積及胰島素敏感性之影響 17
（三） 共軛亞麻油酸對生物體之影響 19
（四） 影響胰島素阻抗性之脂肪細胞激素 24
（五） 脂質生合成之相關基因 28
三、 胰島素之分泌 33
（一） 胰臟組織生理解剖 33
（二） 胰臟組織之胰島（Islet） 35
（三） 胰島素與C-胜肽 37

第三章 材料與方法 39
第一節 實驗假說與設計 39
第二節 實驗一：比較共軛亞麻油酸（CLA）與炸油飲食對C57BL / 6J小鼠葡萄糖代謝影響 43
一、 氧化炸油的製備 43
二、 試驗飼料配製 44
三、 動物飼養 46
四、 口服葡萄糖耐受試驗（OGTT） 46
（一） 全血葡萄糖含量測定 48
（二） 禁食血清胰島素測定法 48
五、 腹腔注射胰島素測試（ITT） 50
（一） 全血葡萄糖含量測定 51
（二） 飽食血清胰島素測定法 52
六、 動物犧牲與樣品收集 52
七、 血糖分析 53
八、 血清分析 54
（一） 血清酮體測定 54
九、 血清脂質分析 55
（一） 血清總脂質（Total Lipids）含量測定 55
（二） 血清三酸甘油酯（Triacylglycerol, TG）含量測定 56
（三） 血清膽固醇（Cholesterol）含量測定 57
（四） 血清游離脂肪酸（Non-Esterified Fatty Acid）含量測定 58
十、 肝臟脂質分析 60
（一） 肝脂質萃取液製備 60
（二） 肝臟三酸甘油酯（Triacylglycerol, TG）含量測定 61
（三） 肝臟膽固醇（Cholesterol）含量測定 62
十一、 肌肉GLUT4含量分析 63
（一） Isolation total membrane fraction of mice gastrocnemius tissue 63
（二） Lowry’s method蛋白質濃度測定 65
（三） 以西方點墨法分析肌肉之GLUT4蛋白質表現量 66
十二、 以RT-PCR分析副睪脂（EP）中RNA含量 77
（一） 總RNA之抽取 77
（二） RNA電泳 79
（三） RNA轉成cDNA（Reverse transcription reaction） 81
（四） Real time polymerase chain reaction（RP-PCR） 83
十三、 副睪脂（EP）之細胞凋亡分析 87
（一） 脂肪組織DNA之抽取 87
（二） DNA電泳 90
十四、 副睪脂（EP）中細胞激素含量測定 93
（一） 脂肪組織蛋白質之抽取 93
（二） Lowry’s method蛋白質濃度測定 95
十五、 以RT-PCR分析肝臟組織中RNA含量 95
十六、 統計分析 95

第三節 實驗二：研究炸油飲食引起C57BL / 6J小鼠葡萄糖不耐之機制 96
一、 氧化炸油的製備 96
二、 試驗飼料配製 96
三、 動物飼養 98
四、 口服葡萄糖耐受試驗（OGTT） 98
（一） 全血葡萄糖含量測定 99
（二） 血清胰島素含量測定 99
（三） 血清C-胜肽含量測定 101
五、 動物犧牲與樣品收集 103
六、 胰臟組織 104
（一） 胰臟組織中β-細胞（Insulin）之免疫染色 104
（二） 胰臟組織之bicyclo PGE2含量測定 112
（三） 胰臟組織之TNF-α含量測定 114
七、 血清bicyclo PGE2含量測定分析 115
八、 飽食狀態下之全血葡萄糖與血清胰島素含量分析 115
（一） 全血葡萄糖含量測定 115
（二） 飽食血清胰島素測定法 116
九、 以RT-PCR分析副睪脂（EP）中RNA含量 116
十、 以RT-PCR分析肝臟組織中RNA含量 116
十一、 統計分析 116





第四章 結果 117
第一節 實驗一：比較共軛亞麻油酸（CLA）與炸油飲食對C57BL / 6J小鼠葡萄糖代謝影響 117
一、 共軛亞麻油酸與炸油對攝食及飼料效率影響 117
二、 共軛亞麻油酸與炸油對生長影響 118
三、 共軛亞麻油酸與炸油對組織之絕對及相對重量影響 118
四、 共軛亞麻油酸與炸油對血脂質含量影響 120
五、 共軛亞麻油酸與炸油對肝脂質含量影響 121
六、 共軛亞麻油酸與炸油於口服葡萄糖耐受試驗對血糖變化之影響 121
七、 共軛亞麻油酸與炸油於腹腔注射胰島素測試對血糖變化之影響 123
八、 共軛亞麻油酸與炸油對禁食血糖及胰島素與飽食血糖及胰島素之影響 124
九、 共軛亞麻油酸與炸油對血清酮體之影響 125
十、 共軛亞麻油酸與炸油對肌肉組織GLUT4蛋白質之影響 126
十一、 共軛亞麻油酸與炸油對脂肪組織mRNA之影響 126
十二、 共軛亞麻油酸與炸油對脂肪組織細胞凋亡之影響 127
十三、 共軛亞麻油酸與炸油對肝臟組織mRNA之影響 127





第二節 實驗二：研究炸油飲食引起C57BL / 6J小鼠葡萄糖不耐之機制 149
一、 長期給食炸油飲食對攝食及飼料效率影響 149
二、 長期給食炸油飲食對生長影響 150
三、 長期給食炸油飲食對組織之絕對及相對重量影響 150
四、 長期給食炸油飲食於飽食狀態下對血糖及血清胰島素之影響 152
五、 長期給食炸油飲食於禁食狀態下對血糖及血清胰島素之影響 152
六、 長期給食炸油飲食於口服葡萄糖耐受試驗（OGTT）對血糖、血清胰島素及血清C-胜肽之影響 153
七、 長期給食炸油飲食對胰臟組織切片與β-細胞免疫染色之影響 155
八、 長期給食炸油飲食對胰臟組織中TNF-α之影響 155
九、 長期給食炸油飲食對胰臟組織與血清bicyclo PGE2之影響 156
十、 長期給食炸油飲食對脂肪組織mRNA之影響 156
十一、 長期給食炸油飲食對肝臟組織mRNA之影響 157

第五章 討論 188
第六章 結論 205
第七章 參考文獻 207

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