Bis-demethoxycurcumin (BDMC) 抑制脂肪細胞新生作用 及減緩高脂飼料誘導之肥胖

Abstract

肥胖是由於體內脂肪組織過度堆積所致，並與代謝疾病密切相關。脂肪細胞新生作用 (Adipogenesis) 是指前脂肪細胞分化變成脂肪細胞的過程，會使脂肪細胞的數目增加和體積變大，與肥胖的形成有關，因此抑制脂肪細胞新生作用可視為抗肥胖之新策略。類薑黃素 (Curcuminoids) 為薑黃根莖中具有生物活性的成份，其主要包括薑黃素 (Curcumin, Cur)、去甲氧基薑黃素 (Demethoxycurcumin, DMC) 和雙去甲氧基薑黃素 (Bis-demethoxycurcumin, BDMC)。本研究先以3T3-L1前脂肪細胞模式評估類薑黃素對脂肪細胞新生作用之影響，據Oil red O染色結果顯示，在25 μM濃度下，類薑黃素皆能顯著抑制細胞內脂質的累積，且抑制效果BDMC > DMC > Cur，再進而探討BDMC對3T3-L1 前脂肪細胞分化過程之影響及分子作用機轉。研究顯示BDMC能抑制前脂肪細胞分化成脂肪細胞，其主要是作用在分化前期之細胞擴增 (Mitotic clonal expansion, MCE) 階段，使細胞週期延遲或停滯。且發現BDMC是藉由下調Mitogen-activated protein kinases (MAPK) pathways達到抑制MCE的作用。在經BDMC處理後，會降低Cyclin A和Cyclin B之蛋白質表現量，增加p21之蛋白質表現量，使細胞週期停滯於G0/G1期，並降低脂肪細胞分化相關之重要轉錄因子PPARγ和C/EBPα的蛋白質表現，進而抑制脂肪細胞分化之進程，最終達到減少脂質累積之功效。此外，以高脂飼料誘導C57BL/6小鼠肥胖之動物實驗模式，評估BDMC降低體脂肪生成之效用。實驗結果顯示，於高脂飲食中添加0.5 % (w/w) BDMC能顯著減緩體重上升，改善脂肪組織堆積情形，且由切片染色結果可發現餵食BDMC能抑制脂肪細胞體積增大之效果。綜合上述結果顯示，BDMC具有抑制脂肪新生作用之功效，並能改善高脂飼料誘導之肥胖，能減緩體脂肪生成，具有開發成不易形 成體脂肪之保健食品的潛力。

Obesity is caused by excessive accumulation of body fat, which is closely related to complex metabolic diseased. Adipogenesis is a key process in determining the number and size of mature adipocytes in the development of obesity. Curcumin (Cur), has been reported to inhibit on adipocyte differentiation. But other curcuminoids present in turmeric, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) have not been investigated whether they exhibit anti-adipogenic activity. Here, we investigated the effects of curcuminoids on adipogenesis and the molecular mechanisms in adipocyte differentiation. Our Oil Red O staining result revealed that 25 μM curcuminoids effectively suppressed accumulation of lipid in adipocytes. And BDMC may exerts more potent anti-adipogenic function than DMC and Cur. This anti-adipogenic function of BDMC was largely inhibited the early stage of adipogenesis through prevention of mitotic clonal expansion (MCE). We found that BDMC suppressed MCE was accompanied by reducing the mitogen-activated protein kinase (MAPK) signaling pathways activation. In particular, BDMC blocked the cell cycle at G0/G1 phase by regulating the protein expression of cyclin A, cyclin B and p21. Also, BDMC reduced the protein expression level of PPARγ and C/EBPα. Furthermore, we examined the anti-obesity effects of BDMC on obesity animal model. C57BL/6 mice were fed high-fat diet (HFD) and BDMC at same time. The result showed that the HFD supplement with 0.5 % (w/w) BDMC had significantly lower body weight gain and less adipose tissue mass. H & E staining result showed that the mice were fed BDMC could inhibit hypertrophy in adipocyte. In conclusion, BDMC had anti-adipogenic effect in vitro and anti-obesity in vivo. Our results suggested that BDMC has potential to be an anti-obesity functional food.