代謝症候群動物模式之評估探討

Abstract

代謝症候群(MS)為血糖調節異常、高血脂、腹部肥胖及高血壓等危險因子中至少三項同時存在即可稱之。若未適當控制容易導致發展成為心血管疾病和第二型糖尿病等慢性病。本實驗室過去研究發現，山苦瓜(Momordica charantia L.) 具有改善代謝症候群之潛力，因此以其測試三種抗代謝症候群功能性評估動物模式之有效性。本研究旨在建立『抗代謝症候群』健康食品之功效評估方法。 比較高脂及高果糖飼料餵食12週所誘發代謝症候群之指標，觀察到高油脂飲食可誘發大鼠肥胖、腹部脂肪堆積、血糖調節異常、高胰島素血症、口服葡萄糖不耐、高血脂與高血壓，而高果糖飲食可誘發大鼠高血脂、高胰島素血症與高血壓，效果不若高油脂飲食引起MS那麼全面性。使用Teklad mixture和AIN-93G mixture的高果糖飼料，發現給予AIN-93G mixture配製的高果糖飼料，其無法誘發高血壓及肝脂堆積部份。檢測肝臟中基因表現，發現高果糖飼料顯著增加肝臟中脂肪合成作用基因之表現，但高脂飼料則無。高脂及高果糖飼料餵食後，造成腎周圍白色脂肪組織中的LPL和Agt基因表現下降。 給予高脂飲食誘發3週後，將山苦瓜凍乾粉末補充於高脂飲食餵食大鼠11週後觀察到降血脂和改善肝脂堆積效果。山苦瓜凍乾粉末補充於高果糖飼料餵食8週後，可觀察到顯著改善口服葡萄糖耐受性及抑制血壓升高。山苦瓜補充實驗中，高果糖飼料之誘導效果沒有第二章實驗明顯，可能與餵食時間長短、個體差異及每組動物隻數等有關。Rosiglitazone除了可以改善兩種飲食模式中所造成的高血脂、高胰島素血症、血糖調節異常和肝脂堆積外，亦可降低血壓。 Wy14643則可以降低體重、體脂堆積和肝脂堆積，但是增高血壓。文獻指出PPARs有降血壓功用，但在此次研究中則發現Wy14643無此效用。 比較 Chow diet、含蔗糖及不含蔗糖之AIN76 purified diet 餵食C57BL/6J 小鼠13週後之結果，含蔗糖之AIN-76飼料造成較高之體重增加、腹部脂肪堆積與血脂質增加等現象較為顯著，且胰島素濃度較高，故飲食中含蔗糖對於高血糖之影響比C57BL/6J小鼠遺傳背景所導致的影響來的明顯。 綜上所述，長期餵食大鼠12週以上高脂飲食，可全面發展出代謝症候群各指標症狀，本研究使用之山苦瓜樣品處理在短期間可以改善胰島素抗性，但長期則無。建議應用此模式時，餵食樣品期間縮短為4週。高果糖飲食模式需使用Teklad配方之礦物質及維生素混合物，餵食8週，山苦瓜樣品添加可觀察到血糖調節及血壓之改善。C57BL/6J小鼠模式則使用含50%蔗糖之AIN76飲食對於血糖影響更為明顯。

Metabolic Syndrome (MS) is characterized by clustering of risk factors including: central obesity, hyperglycemia, dyslipidemia, insulin resistance and hypertension. MS is associated with a very high risk of developing cardiovascular disease and/or type 2 diabetes. This study aims at developing animal models for examining the anti-MS effect of functional food. Three rodent models were validated: 1) High fat diet-induced MS: Adult male Wistar male rats were fed a 30% fat diet in which 29% of fat source was butter for 14 weeks; 2) High fructose diet-induced MS: Adult male Wistar rats were fed a 60% fructose diet for 8 weeks; 3) 8.5 weeks old C57BL/6J mice were fed a AIN-76 purified diet. The last model was found to be hyperglycemic as their age and body weight increase. Since wild bitter gourd (Momordica charantia L.) has been found to improve MS, this sample is used to further validate the feasibility of these two models. Full spectrum of MS was observed in high fat fed rats, including: higher abdominal fat accumulation, hyperinsulinemia, impaired glucose tolerance, hyperlipidemia and hypertension at 12 weeks. High fructose diet with Teklad mixture resulted in hyperlipidemia, hyperinsulinemia and hypertension. High fructose diet with AIN-93G mixture resulted in hyperlipidemia and hyperinsulinemia but no hypertension. The high fat diet-feeding and high fructose diet-feeding led to reduced lipoprotein lipase and angiotensinogen mRNA expression in retroperitoneal white adipose tissue. Improvement of some MS risk factors could be observed in the high fat diet and high fructose diet induced MS model with the supplementation of 0.5%, 1% and 5% wild bitter gourd powder (group 0.5BGP, 1BGP and 5BGP), but much less apparent in the long-term feeding of the high fat diet model. Compared to C57BL/6J mice fed chow diet, the AIN-76 purified diet fed mice showed increased body fat, hyperglycemia and hyperlipidemia. AIN-76 purified diet with 50% sucrose could induce more MS risk factors. In conclusion, these three models could be used to evaluate the anti-MS functional food. It is recommended that the total feeding period for the high fat diet-induced MS model is limited to around 4 weeks. The high fructose diet-induced MS model Teklad mixture is preferred and feeding period for 8 weeks is recommended. C57BL/6J mice fed AIN-76 diet with 50% sucrose could lead to higher blood sugar.