糖尿病及高脂飲食皆會加速的肌肉流失，魚油在人體實驗中已被證實可以增加肌肉蛋白質合成，但動物實驗研究較少探討魚油對糖尿病引起的肌少症之影響，因此作用機制仍不明確，故本實驗探討在糖尿病及高脂飲食下給予魚油對肌肉流失之影響。先前本研究室於高脂飲食中添加 5% 魚油，飼養16週後發現肌肉中的AKT、mTOR、AMPK及PGC-1α蛋白質表現量顯著增加，進而改善高脂飲食所導致的粒線體功能異常及蛋白質合成減緩；另外魚油也可以使PPARγ、TNF-α及NF-κB表現量顯著下降，減少肌肉中的脂肪堆積並抑制發炎反應，改善高脂飲食所導致的肌肉流失。本研究以6週齡雄性Wistar大鼠為實驗動物，共分為三組：(1) 正常飲食組 (Normal control diet, NC) (2) 糖尿病組 (Diabetes + high fat diet, DM) (3) 魚油組 (Diabetes + high fat diet + 5% fish oil, DF)。實驗共進行18週。結果顯示，魚油可以降低血液中的TC及肝臟中TG，肝臟切片顯示NC組及DF組肝臟脂肪油滴相較於DM組顯著減少。魚油透過活化肌肉p-AMPKα/AMPKα、LPL使肌肉中的三酸甘油酯分解成游離脂肪酸，減少肌肉脂肪的堆積。魚油也可以透過增加肌肉p-AKT/AKT、p-mTOR/mTOR途徑，使p-p70s6k1/p70s6k1蛋白質表現增加，增加肌肉中的蛋白質合成，並使Sirt1、PGC-1α蛋白質表現增加，增加粒線體的生合成。同時魚油會降低血液中的AGEs，並增加肌肉中的RAGE、GLUT4表現。此外，魚油透過增加肌肉中p-mTOR/mTOR，使ATG5、LC3及p62表現減少，減緩糖尿病引起的自噬作用速率增加。抑制促發炎因子TNF-α、p-p38MAPK/p38MAPK，抑制FoxO1a進入細胞中轉錄成Atrogin-1及MuRF1。綜合上述結果，推測魚油有助於改善糖尿病在高脂飲食下所導致的肌少症。

Both diabetes and high fat diet will accelerate the loss of muscle weight. Fish oil has been confirmed to increase protein synthesis in human study, but it is lack of animal study between diabetes and sarcopenia so the mechanism is still unknown. In this experiment, we study the effect of fish oil enriched in omega-3 fatty acids on sarcopenia in diabetic rats induced by streptozotocin. In present study, we found that after 16 weeks, 5% fish oil with high fat diet could significantly increase AKT, mTOR, AMPK, and PGC-1α protein level expressions in muscle to improve mitochondrial dysfunction and increase protein synthesis which are caused by high fat diet. Moreover, fish oil could significantly decrease PPARγ, TNF-α, and NF-κB protein expressions to reduce the accumulation of fatty acid and anti-inflammation, in order to improve muscle wasting which was result from high fat diet. This study used male Wistar rats (six-weeks-old). Rats were randomly divided into three groups. Normal control diet (NC), Diabetes with high fat diet (DM), and Diabetes with high fat diet and 5% fish oil (HF+FO). After 18 weeks feeding, the results showed fish oil could decrease total cholesterol in plasma and triglyceride in liver. H&E stain showed that free fatty acid in liver were significantly decrease in NC and DF groups. Fish oil could promote adipolysis in muscle by activating p-AMPKα/AMPKα and LPL. Besides, fish oil could increase protein synthesis in muscle by activating AKT/mTOR pathway and p-p70s6k1/ p70s6k1 protein expressions and increase mitochondria synthesis by activating Sirt1 and PGC-1α. Fish oil could decrease AGEs in plasma, increase RAGE and GLUT4 expression. Moreover, fish oil could reduce the rate of autophagy which was cause by diabetes by activating p-mTOR/mTOR and decreasing ATG5, LC3 and p62 expressions. Fish oil also could inhibit proinflammatory cytokine TNF-α and p-p38MAPK/p38MAPK, also inhibit transcription of FoxO1a and NF-κB to Atrogin-1 and MuRF1. In conclusions, our results demonstrated fish oil could improve sarcopenia in diabetes with HFD.

第壹章 前言 1
第貳章 文獻回顧 2
第一節 肌少症 2
第二節 糖尿病 3
第三節 魚油 4
第四節 肌肉的合成與降解 5
第五節 鏈佐菌素 (Streptozotocin, STZ) 誘導糖尿病 7
第六節 粒線體 7
第七節 發炎介質 8
第八節 肌肉代謝基因蛋白 8
第九節 脂質代謝基因蛋白 11
第十節 醣類代謝基因蛋白 12
第參章 實驗設計 14
第一節 實驗動機 14
第二節 實驗流程 14
第三節 分析項目 16
第肆章 實驗材料 17
第一節 實驗動物 17
第二節 實驗飼料 17
第三節 實驗藥品 17
第四節 膳食魚油 17
第五節 實驗儀器 18
第伍章 實驗方法 20
第一節 實驗分組 20
第二節 動物飼養 20
第三節 樣品收集 20
第四節 飼料配方 21
第五節 樣品分析 22
第陸章 結果 29
第一節 誘導後空腹血糖之結果 29
第二節 實驗期間大鼠口服葡萄糖耐受性試驗之結果 29
第三節 實驗期間大鼠體重、攝食量、飲水量及排尿量 29
第四節 犧牲後大鼠組織臟器重量 29
第五節 犧牲後大鼠血漿生化指標 30
第六節 犧牲後大鼠肝臟生化指標 30
第七節 犧牲後大鼠肌肉生化指標 31
第八節 犧牲後大鼠肌肉及肝臟蛋白表現 31
第柒章 討論 34
第一節 魚油對糖尿病大鼠體重、攝食量及組織臟器之影響 34
第二節 魚油對糖尿病大鼠糖類代謝之影響 35
第三節 魚油對糖尿病大鼠脂質代謝之影響 36
第四節 魚油對糖尿病大鼠肝功能及發炎因子之影響 36
第五節 魚油對糖尿病大鼠肌肉蛋白質合成之影響 37
第六節 魚油對糖尿病大鼠肌肉蛋白質分解之影響 37
第捌章 結論 40
參考文獻 42

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