白皮杉醇抑制小鼠肥胖的功效及相關分子機制的探討

Abstract

肥胖已是全球性的健康問題，過多的脂肪堆積會導致許多疾病的發生，包括心血管疾病、非酒精性脂肪肝、癌症、第二型糖尿病、中風、骨關節炎等，如何預防肥胖或是減重已成為近年來科學家研究的重要議題之一。白皮杉醇 (Piceatannol) 是白藜蘆醇 (Resveratrol) 的類似物，已有多篇研究指出其生理功效，包含抗癌、抗發炎及降低血糖等。在細胞實驗中，白皮杉醇能有效減少3T3-L1細胞中的脂肪堆積，並抑制細胞擴增期 (Mitotic clonal expansion, MCE)，但目前白皮杉醇在動物體內的抗肥胖效果還未被討論及研究，因此本實驗目的為評估白皮杉醇在動物模式中抗肥胖、脂肪肝及其調節機制之探討。本實驗中，將40隻五週齡雄性C57BL/6小鼠分成5組，分別是正常飲食 (n=8)、高脂飲食 (45% energy from fat, n=8)、高脂飲食混入0.1% Resveratrol (n=8)、高脂飲食混入0.1% Piceatannol (n=8) 和高脂飲食混入0.25% Piceatannol (n=8)，自由攝食飼養18周後犧牲。結果顯示0.1% 和0.25% piceatannol組能顯著的降低小鼠的體重並呈現劑量效應，且不影響攝食量。血液中總膽固醇、血糖及LDL/HDL ratio也有顯著性的降低。在脂肪組織方面，0.1% 和0.25% Piceatannol組能顯著降低性腺脂肪和腹膜後脂肪重量，性腺脂肪切片顯示其脂肪細胞大小也有顯著性的下降。飼料添加Piceatannol組和高脂飲食組相比能顯著降低肝臟和脾臟重量，由肝臟切片也可看出脂肪空泡的數量和大小減少。Piceatannol透過增加pAMPK的表現量降低脂肪細胞分化轉錄因子C/EBPα和PPARγ，並影響pACC和FAS的表現量，減少脂肪酸的形成，進而減少三酸甘油酯的合成。綜合上述結果，Piceatannol在小鼠模式中能改善高脂飼料誘導之肥胖，減少體脂肪及脂肪肝，具有開發成不易形成體脂肪之保健食品的潛力。

Obesity is a global health concern. Excess storage of lipids in adipose tissue is associated with cardiovascular disease, fatty liver, cancer, type 2 diabetes, stroke and osteoarthritis. Piceatannol, an analogue of resveratrol, was found to have anti-cancer, anti-inflammatory and hypoglycemic effects. Previous studies indicated that piceatannol significantly reduced lipid accumulation and inhibited mitotic clonal expansion phase in 3T3-L1 cell model. In this study we investigated the anti-obesity effect of piceatannol in vivo. Five-week-old Mice were fed ad libitum with normal diet (n=8), high-fat diet (45% energy from fat, n=8), high-fat diet with 0.1% resveratrol (n=8), high-fat diet with 0.1% piceatannol (n=8) and high-fat diet with 0.25% piceatannol (n=8) for 18 weeks. The results showed that 0.1% piceatannol and 0.25% piceatannol significantly reduced mice body weight in a dose-dependent manner without affecting their food intake. Serum total cholesterol levels, LDL/HDL ratio, and blood glucose were significantly lowered for both piceatannol-treated groups. As for adipose tissue, piceatannol significantly decreased the weight of perigonadal and retroperitoneal fat. The perigonadal adipose tissue histology showed a significant cell size reduction in piceatannol-treated groups. The weight of liver and spleen were significantly reduced compared with high-fat diet group. From hepatic histology, a decrease in lipid accumulation in both size and number were observed. Piceatannol showed a higher pAMPK expression and decreased expression of adipogenic transcriptional factors, C/EBPα and PPARγ. It also altered the expression of pACC and FAS, hence reduced the synthesis of fatty acid and triglyceride. Collectively, these results suggested that piceatannol could ameliorate high-fat-diet induced obesity, reduce adipose tissue weight and hepatic steatosis. It has potential to be further developed into functional food or medicine.