臺灣博碩士論文加值系統

已知胚胎期營養可影響成年後肥胖及代謝症候群的發生，稱為代謝程式化(metabolic programming)。由於餵食炸油動物常見生長遲滯副作用，且加速部分營養損耗，因此本研究擬探討母鼠懷孕期間攝取炸油飲食是否影響胚胎發育及增加成年後對高脂飲食誘發肥胖(diet-induced obesity, DIO)及代謝疾病敏感性。C57BL/6J母鼠於懷孕期分別給予炸油(10% OFO)或新鮮油飲食(10% SO)，模式一給予的炸油飲食不添加維生素E，模式二的炸油飲食額外補充維生素E (a-tocopherol) (250mg / kg diet)且產前(懷孕17d)轉換正常飼料。首先模式一觀察到OFO母鼠有較高比例難產及吃仔情形，原本懷疑與OFO攝取常發生的維生素E缺乏有關，但這些現象於模式二仍無改善；而倖存之子代發現有眼睛發育不全(較小顆且無光澤)、無眼珠或失明的情形(15.8% vs. 0%, OFO vs. SO group)，推測OFO造成維生素A缺乏，而母鼠吃仔原因可能與缺乏維生素A導致畸胎有關。追蹤母鼠懷孕期間血清荷爾蒙變化，顯示OFO母鼠產前estradiol顯著高於對照，同時在E18天有較高血清corticosterone。生產前的OFO 母鼠可觀察到已知的炸油反應：肝腫大、血清TG降低、體脂減少─為PPARa活化特徵。兩組的E18天胚胎不論胚胎數、胚胎體重並無顯著差異。另一方面為了探討子代日後肥胖及代謝疾病敏感性，將存活仔鼠依母親懷孕飲食及各自性別分為OFO-male、OFO-female、SO-male、SO-female四組，哺乳期間所有母鼠皆給予SO diet，斷乳後的仔鼠一律餵食chow diet至七週齡，再給予五週高脂飲食(30% butter)挑戰，誘發肥胖及代謝疾病。模式一結果顯示OFO之子代雄性不易胖，血清與組織TG堆積減少，脂肪組織PPARa下游基因(ACO、PGC-1a、UCP1)表現顯著增加(OFO-male vs. SO-male)，解釋為何不易胖；反之OFO之子代雌性易胖，但TG傾向堆積於脂肪組織，減少流入肌肉中，脂肪組織CPT-1與UCP2表現顯著降低(OFO-female vs. SO-female)，解釋了它們的易胖。模式二結果顯示OFO子代雄性的抗肥胖特質在母親補充維生素E後消失，但在雌性易肥胖特質仍在─合併有易胖、暴食、易高血脂與脂肪肝等情形。以上結果顯示母鼠懷孕期間攝食炸油，的確可程式化子代脂質代謝能力而決定日後肥胖傾向。

More recently, epidemiological and experimental evidences suggest that the nutrient state in embryonic period is closely associated with adulthood obesity and metabolic syndrome, giving rise to the concept of “metabolic programming”. Since it has been reported that the oxidized frying oil (OFO) consumption in animals results in growth retardation and nutrients depletion, we hypothesized that OFO consumption of female mice during pregnancy might compromise the fetus development in uterus and increase the suceptibility of their offspring to high fat diet-induced obesity (DIO) and metabolic diseases in laterlife. C57BL/6J female mice were given SO and OFO diets (10% fresh soybean oil and OFO, respectively) throughout the whole gestational period. In model 1, no additional vitE was supplemented in the OFO diet. In model 2, the OFO diet was supplemented with a-tocopherol (250mg / kg diet) and mice in OFO diet were shift to normal diet at E17. At the initiation of model 1, we noticed that the OFO dams had a higher incidence of difficulty in delivery and behavior of eating pups. We suspected these problems might associated with vitE deficiency which frequently occurred in OFO-treated animals. However, in model 2, there was no improvement in these problems after correcting vit E status. Besides, the ratio of pups with congenital malformations was increased in OFO group (15.8 % vs 0%, OFO vs. SO group), implying OFO ingestion during pregnancy might deplete vitA nutrition of dams and pups and the vitA deficiency-mediated teratogenesis was presumed to be the cause of pup-eating behavior. Measurement of hormone levels in serum shows that estradiol in OFO dams was significantly higher than that of control at the late pregnency. Corticosterone levels at E18 was also significantly higher in OFO– than in SO-dams. The pleotropic effects of PPARa activation including hepatomegaly, lowered serum TG, and reduced adiposity were seen in OFO-dams at E18. In fetus at E18, there is no significant difference between two groups in litter size and fetus weight. To further identify the susceptibility to DIO and metabolic diseases in laterlife of offspring, the survival pups were devided into OFO-male, OFO-female, SO-male and SO-female according to the maternal diet during pregnancy and their respective gender. All of them were lactated by dams receiving SO diet. After weaning, they were fed with chow diet until 7 wk of age, subsequently challenged with a high fat diet for 5 weeks. Results of model 1 showed the male offspring came from OFO dams were resistance to DIO, along with a lowered TG level was found in serum and tissues. The mRNA levels of PPARa target genes (including ACO, PGC-1a and UCP1) in the adipose tissue were significantly increased in OFO-male (vs. SO-male), which explained why they resist to obesity. In contrast, the female offspring came from OFO dams were predisposed to DIO. The TG tended to be accumulated in white adipose tissue, rather than flow to muscle. The mRNA levels of CPT-1 and UCP2 were suppressed in adipose tissue of OFO-female (vs. SO-female), which explained their predisposition to obesity. In model 2, the characteristic of resistance to DIO was disappeared in OFO-male after their mother receiving a vitE supplemented OFO diet. However, the predisposition to DIO in OFO-female was sustained-accompanied with obesity, hyperphagia, hyperlipidemia, and fatty liver were seen. We concluded that mothers receiving OFO diet during pregnancy can program the lipid metabolic capacity of offspring, thus determine their suceptibility to DIO in later lifer.

目錄 i
圖目錄 iv
表目錄 vi
縮寫對照表 I
中文摘要 III
Abstract V
第一章 前言 1
第二章 文獻回顧 3
一、代謝程式化(Programming) 3
(一) 流行病學緣起 3
(二) Barker理論 4
(三) 子宮內生長遲緩(Intrauterine growth retardation, IUGR)與代謝程式化之動物模式 6
二、孕期生理 8
(一) 維生素之需求 8
(二) 內分泌 9
三、氧化炸油(Oxidized frying oil, OFO) 12
(一) 炸油之化學組成 12
(二) 炸油對動物生長及肝解毒酵素影響 12
(三) 炸油與維生素E缺乏 14
(四) 炸油與維生素A缺乏 14
(五) 炸油與雌性素合成代謝 15
(六) 炸油與脂質代謝 15
(七) 炸油與葡萄糖代謝 16
第三章 材料與方法 17
一、實驗設計與假說 17
二、動物飼養 19
三、氧化炸油的製備 20
四、油脂品質分析 20
五、試驗飼料配製 22
六、動物犧牲與樣品收集 25
七、口服葡萄糖耐受試驗(Oral glucose tolerance test, OGTT) 26
八、腹腔注射胰島素測試(Insulin tolerance test, ITT) 27
九、血糖分析 29
十、血清胰島素含量測定 30
十一、血清Leptin含量測定 31
十二、血清Estradiol分析 33
十三、血清Corticosterone分析 34
十四、血清脂質分析 36
十五、肝臟脂質分析 40
十六、脂肪組織切片 42
十七、抽取RNA及cDNA的製備 43
十八、Real time polymerase chain reaction(同步定量PCR；qRT-PCR) 49
十九、統計分析 55
第四章 結果與討論 56
第一節 模式一：母鼠懷孕全程給予未額外添加維生素E之OFO diet 56
第二節 模式二：母鼠懷孕全程給予額外添加維生素E之OFO diet並在E17轉換正常飼料 61
第三節 比較模式一與模式二 67
第五章 結論 110
參考文獻 112

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