探討 PPARα 促效劑對高脂飲食誘發小鼠代謝失調及情緒障礙之影響

李世欽

doi:10.6342/NTU201703648

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探讨 PPARα 促效剂对高脂饮食诱发小鼠代谢失调及情绪障碍之影响

Effects of PPARα agonists on high-fat diet induced metabolic disorders and emotional disturbance in mice

李世钦 , 硕士　　导师：林甫容　　

繁体中文 DOI： 10.6342/NTU201703648

肥胖； PPARα ； PPARα 促效剂；代谢失调；抗焦虑； obesity ； PPARα ； PPARα agonists ； metabolic syndrome ； anti-anxiety

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摘要 │ 参考文献 (210) │ 国际计量

摘要〈TOP〉

迈入 21 世纪的我们所面临很大的危机就是逐年加剧的肥胖问题，肥胖为许多慢性疾病之危险因子，也是全球重要的公共卫生议题。过氧化物酶体增殖物活化受体α (Peroxisome proliferator-activated receptor alpha, PPARα) 为核受器的一员，可受配体 (ligands) 活化进而调控脂质代谢以达到改善肥胖及代谢症候群的效果。故本实验旨在以 PPARα 转录活性分析平台对中草药及海洋真菌萃取物做功效评估，并进一步筛选活性高之 PPARα 促效剂应用於饮食诱导肥胖之小鼠模式，观察是否有改善代谢症候群、非酒精性脂肪肝及情绪失调的现象。
本实验的第一部分以 PPARα 转录活性分析细胞实验筛选自然界纯物质及粗萃物成为 PPARα 促效剂潜力。结果显示牛樟芝内的三萜类化合物 antcin B、C、H、K 均有具有显着活化 PPARα 之能力，其中以 antcin B、H、K 活化效果最佳，约为正控制组 (1 µM WY14643) 的 120% 左右；此外自然界天然萃物薄姜木、芋叶括楼、台湾鬼督邮及海洋真菌萃取物 (NTOU4295、NTOU4296) 皆具有显着活化 PPARα 之效果，活化倍率约为正控制组的 40-60%；牛樟芝内麦角固醇 EK100 虽不具有活化 PPARα 之能力，但先前研究发现其有抗发炎、降血糖及降血脂之功能，故在第二部分动物实验选择以 antcin K 以及 EK100 辅以正控制组降血脂药物 fenofibrate 进行後续实验，旨於探讨给予 PPARα 促效剂於高脂饮食诱发小鼠代谢失调及情绪障碍之影响。
第二部份动物实验采用 4 周龄大 C57BL/6J 公鼠，以 30% 高脂饲料喂食 8 周诱导肥胖，後续小鼠仍喂食高脂饮食但另以管喂方式给予 20 mg/kg/day BW 之 antcin K以及 EK100 持续 4 周，之後增大剂量为 40 mg/kg/day BW 再持续 4 周，另一组给予 PPARα 促效剂 250 mg/kg/day BW 之 fenofibrate 持续 8 周当正控制组，试验期共 16 周。结果显示，高脂饮食成功诱导小鼠肥胖，给予 fenofibrate 可显着降低小鼠体重、脂肪组织及腓肠肌重量、脂肪细胞大小、血清总胆固醇/三酸甘油酯/游离脂肪酸含量、禁食血糖/胰岛素以及胰岛素阻抗指标 (HOMA-IR index)，并可增加葡萄糖耐受性与胰岛素敏感性、并有较高的个体氧气消耗量及二氧化碳排出量进而增加能量消耗量。可惜的是给予 antcin K 及 EK100 没有明显改善小鼠代谢症候群的现象。有趣的是，以尾部悬吊试验评估小鼠忧郁状况，发现给予 fenofibrate 显着降低小鼠不动之秒数达到降低忧郁行为之表现；此外，十字迷宫行为试验评估抗焦虑状况，发现给予 antcin K 以及 fenofibrate 可显着提升小鼠进入开放臂之次数达到改善焦虑行为之表现。另外，给予 fenofibrate 虽有抗肥胖的效果，但与其余组别相比却有明显肝肿大及较高 ALT 活性的情形，分析肝脏表现型，发现高脂饮食组有明显非酒精性脂肪肝的现象，但给予 fenofibrate 能显着降低肝脏三酸甘油酯含量、减少油滴之堆积，并能活化肝脏 PPARα 下游基因表现，例如参与脂肪酸氧化 (Cpt1a、Acox1)、脂肪酸运送 (Cd36、Fabp1)、脂肪酸合成 (Acaca、Fasn) 及胆固醇运输 (Abca1) 等基因提升肝脏整体能量代谢达到改善非酒精性脂肪肝的效果。
综合以上两部分的实验，给予 PPARα 促效剂 fenofibrate 具有显着改善高脂饮食所诱发小鼠肥胖、代谢失调以及情绪障碍之效果，虽然 antcin K 以及 EK100 并无看到预期改善肥胖之效果，但是 antcin K 在行为试验上有显着抗焦虑之效果，详细机制仍有待更进一步的探讨。

并列摘要〈TOP〉

Prevalence of obesity is rapidly increasing, and has led to increased morbidity and mortality of various chronic diseases. Obesity has become one of most serious public health challenges of the 21st century. Peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. Activation of PPARα has been shown to ameliorate obesity and metabolic syndrome through regulation of lipid metabolism. The aim of this study is to identify the natural PPARα agonists from Chinese herbs and marine fungus extracts using in vitro PPARα transactivation system. We further investigate the effects of selected PPAR agonists on metabolic abnormalities, non-alcoholic fatty liver disease (NAFLD) and emotional disturbance in diet-induced obesity mouse model.
In the first part of the study, the PPARα transactivation assay was used to identify the potential PPARα agonists from natural pure compounds and crude extracts. We showed that antcin B, C, H, K, triterpenoid compounds from Antrodia cinnamomea, significantly activated PPARα activity (120% vs. 1 μM Wy14643, 100%). In addition, the natural crude extracts from Vitex quinata (Lour.) F. N. Williams, Trichosanthes homophylla, Ainsliaea reflexa Merr, as well as few marine fungus extracts (NTOU4295, NTOU4296) increased PPARα activity (40-60% vs. 1 μM Wy14643, 100%). In contrast to antcins, EK100, an ergosterol from Antrodia cinnamomea, has limited effects on PPARα activation. Given that EK100 has been shown to exhibit anti-inflammatory, anti-diabetic and anti-hyperlipidemic effects, antcin K, EK100 and fenofibrate (hypolipidemic drugs as positive control) were tested in high-fat diet induced obese mouse model.
4-week-old C57BL/6J mice were fed with 30% high-fat diet to induce obesity for 8 weeks. The mice were treated with antcin K (20 mg/kg/day BW) for 4 weeks and then (40 mg/kg/day BW) for another 4 weeks, EK100 (20 mg/kg/day BW) for 4 weeks and then (40 mg/kg/day BW) for another 4 weeks, fenofibrate (250 mg/kg/day BW) for 8 weeks, or vehicle for 8 weeks afterward. We showed that high-fat diet has successfully induced mice obesity. Treatment of fenofibrate significantly reduced body weight, fat mass, gastrocnemius weight, adipocytes size, serum cholesterol / triglyceride / NEFA and fasting glucose / insulin / HOMR-IR index. In addition, treatment of fenofibrate in mice significantly improved glucose tolerance, insulin sensitivity, increased oxygen consumption and carbon dioxide production. Unexpectedly, antcin K and EK100 have limited effects on prevention of obesity. Interestingly, to further investigate antidepressant activity of PPARα agonists, tail suspension test was performed. We found that treatment of fenofibrate significantly reduced the immobility time compared to high-fat group, indicating less depression-like behavior. Furthermore, we also investigate antianxiety-like activity of PPARα agonists using elevated plus maze. We found that mice treatment with antcin K and fenofibrate significantly increased the time spent in open arms, suggesting less anxiety-like behavior. Although treatment of fenofibrate prevented obesity, the mice exhibited hepatomegaly and increased ALT activity. Besides, hepatic lipid accumulation was significantly decreased in fenofibrate-treated group, suggesting a significant effect on treatment of NAFLD. Exploring the mechanism, the expression of hepatic PPARα target genes, such as fatty acid oxidation (Cpt1a, Acox1), fatty acid transport (Cd36, Fabp1), fatty acid synthesis (Acaca, Fasn) and cholesterol transport (Abca1) was markedly elevated to increased energy metabolism rates in the liver and ameliorated the non-alcoholic fatty liver disease.
Taken together, treatment of PPARα agonist fenofibrate prevented obesity, metabolic disorders, emotional disturbance in high-fat diet fed C57BL/6J male mice. Although antcin K and EK100 treatment has limited effects in this study, the potential anti-anxiety function of antcin K remains to be further investigated.

参考文献 ( 210 ) 〈TOP〉

(2005). [A worldwide consensus definition for the metabolic syndrome]. Rev Panam Salud Publica 18, 451-454.
连结：
Abdelmegeed, M.A., Yoo, S.H., Henderson, L.E., Gonzalez, F.J., Woodcroft, K.J., and Song, B.J. (2011). PPARalpha expression protects male mice from high fat-induced nonalcoholic fatty liver. The Journal of nutrition 141, 603-610.
连结：
Abildgaard, A., Solskov, L., Volke, V., Harvey, B.H., Lund, S., and Wegener, G. (2011). A high-fat diet exacerbates depressive-like behavior in the Flinders Sensitive Line (FSL) rat, a genetic model of depression. Psychoneuroendocrinology 36, 623-633.
连结：
Alberti, K.G., Eckel, R.H., Grundy, S.M., Zimmet, P.Z., Cleeman, J.I., Donato, K.A., Fruchart, J.C., James, W.P., Loria, C.M., Smith, S.C., Jr., et al. (2009). Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120, 1640-1645.
连结：
Angulo, P., and Lindor, K.D. (2002). Non-alcoholic fatty liver disease. Journal of gastroenterology and hepatology 17 Suppl, S186-190.
连结：

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DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。如想对DOI的使用与概念有进一步了解，请参考（）。