Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/52081
標題: Modulatory actions of garcinol and pterostilbene on cell proliferation, adipogenesis and inflammation in 3T3-L1 adipocytes
Garcinol 與 pterostilbene 對 3T3-L1 脂肪細胞增生、脂質生成與發炎反應之調控作用
作者: 林俞君
Lin, Yu-Jyun
關鍵字: Obesity;肥胖;3T3-L1 adipocytes;adipogenesis;macrophages infiltration;inflammation;coculture;conditioned medium;garcinol;pterostilbene;3T3-L1 脂肪細胞;脂肪生成作用;巨噬細胞浸潤;發炎;共培養;conditioned medium;garcinol;pterostilbene
出版社: 食品暨應用生物科技學系所
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摘要: 
肥胖是現代人嚴重的健康問題,已知其為許多疾病之危險因子,如糖尿病、心臟病、高血壓與癌症等。且肥胖會引起全身性的慢性發炎反應,刺激巨噬細胞浸潤於脂肪組織中,經由交互影響釋出大量發炎因子,如 tumor necrosis factor-α (TNF-α)、interleukin-6 (IL-6) 及 monocyte chemoatrractant protein-1 (MCP-1) 等。研究指出,自藤黃科植物分離出的 garcinol 具有抗氧化、抗發炎、抗癌及保護神經細胞等功效;而藍莓中活性成分 pterostilbene 在減少膽固醇、預防動脈粥狀硬化上亦有良好之效果。故本研究乃探討 garcinol 與 pterostilbene 對 3T3-L1 前脂肪細胞週期的影響與分化過程中脂肪生成 (adipogenesis) 及發炎反應之調控作用。
研究結果顯示,garcinol 與 pterostilbene 可促使細胞週期停滯於 G2/M 期,抑制 3T3-L1 前脂肪細胞生長。於脂肪細胞分化期間,garcinol 和 pterostilbene 可有效抑制 triacylglycerol (TG) 的累積及 GPDH 活性。在蛋白質的活性上,garcinol 與 pterostilbene 能顯著抑制脂肪細胞分化轉錄因子 peroxisome proliferator–activated receptor γ (PPARγ) 及 CCAAT/enhancer binding proteinα(C/EBPα) 之蛋白表現(p<0.05)。在成熟的脂肪細胞中,garcinol 亦可顯著減少脂肪細胞中脂質的累積,並抑制 PPARγ、fatty acid synthase (FAS) 及提升 adipose triglyceride lipase (ATGL)、adiponectin 蛋白之表現 (p<0.05)。同時 garcinol 與 pterostilbene 可降低 leptin、FAS、resistin 及提高 adiponectin 之 mRNA 表現 (p<0.05)。
以 TNF-α 誘導 3T3-L1 脂肪細胞發炎後,garcinol 及 pterostilbene 能顯著降低發炎細胞激素 IL-6 之分泌,並抑制發炎指標 COX-2、iNOS、IL-6、IL-1β 與 TNF-α 基因之表現 (p<0.05),且此效應乃因抑制 NF-κB 訊息傳遞路徑的活化而達成。再者,將 3T3-L1 脂肪細胞與 RAW264.7 小鼠巨噬細胞共培養,發現 garcinol 及 pterostilbene 皆可減少巨噬細胞對脂肪細胞的移行作用,且pterostilbene 可減少 IL-6 與 TNF-α 的分泌及基因表現,但 garcinol 無顯著抑制效果。因此進一步分析 pterostilbene 對細胞中發炎指標基因之影響,結果發現其能顯著抑制 COX-2、iNOS、CRP、MCP-1、PAI-1 及提升 adiponectin mRNA 之表現 (p<0.05)。此外,以 3T3-L1 和 RAW264.7 之 conditioned medium 分別培養 RAW264.7 巨噬細胞與 3T3-L1 脂肪細胞,結果顯示 pterostilbene 能有效減少 3T3-L1 脂肪細胞中 IL-6 及 TNF-α與 RAW264.7 巨噬細胞中 IL-6 之分泌,且在發炎指標基因上亦有抑制之效應。綜合上述結果 garcinol 及 pterostilbene 能有效減少分化過程與分化後脂肪細胞的生成與脂質的累積,並透過調控 NF-κB 的活化來抑制由 TNF-α 誘導之發炎作用,且 pterostilbene 在脂肪細胞與巨噬細胞共培養的模式中能作用於兩者而達到抑制發炎反應以減少脂肪組織中巨噬細胞浸潤之功效。因此天然植物成分 garcinol 及 pterostilbene 對改善及預防肥胖所引起的發炎現象應具有良好之潛力。

Obesity is a major obstacle to human health. It may predispose individuals to various diseases, such as type 2 diabetes, cardiovascular disease and cancer. Normally adipocytes can secrete inflammatory mediators, which in turn contribute to the low-level, chronic inflammation via stimulating infiltration of macrophages in adipose tissues. Besides, there are also increased inflammatory mediators such as tumor necrosis factor (TNF)-α、interleukin-6 (IL-6) and monocyte chemoatrractant protein-1 (MCP-1) in obese patients. Polyphenolic compounds have been well-studied for their biological activities. Garcinol isolated from the fruit rind of Garcinia spp. has been shown to have antioxidant, anti-inflammatory and anticancer properties. Pterostilbene isolated from Vaccinium berries can lower plasma cholesterol level and prevent atherosclerosis. However, the anti-obesity ability of these two compounds has not yet been studied. Thus the modulatory actions of garcinol and pterostilbene on cell proliferation, adipogenesis and inflammation in 3T3-L1 adipocytes were investigated. First, the effects of garcinol and pterostilbene on cell proliferation and adipogenesis in 3T3-L1 preadipocytes were investigated. The flow cytometry assay indicated that the treatment of 3T3-L1 preadipocytes with garcinol and pterostilbene caused cell cycle arrested at G2/M phase. During adipocytes differentiation, both garcinol and pterostilbene had inhibitory effect on fat droplet formation and triglyceride accumulation. For glycerol-3-phosphate dehydrogenase (GPDH) activity, the data indicated that garcinol and pterostilbene could inhibit the GPDH activity by 97.8 and 61.5%, respectively, as compared to the control. Both garcinol and pterostilbene significantly (p<0.05) attenuated the protein expressions of adipogenic transcriptional factors peroxisome proliferator-activated receptor (PPAR)γ and CCAAT/ enhancer-binding proteins (C/EBP)α in maturing 3T3-L1 preadipocytes. Moreover, the lipid accumulation in the mature adipocytes was reduced by garcinol. Garcinol also modulated the obesity markers in vitro, such as PPARγ, C/EBPα, FAS, ATGL and adiponectin at protein level (p<0.05). In addition, garcinol and pterostilbene had anti-adipogenesis effects on gene expression of leptin, resistin, adiponectin and FAS. These results suggest that garcinol and pterostilbene have anti-adipogenic effect on preadipocytes and adipocytes.
We further examined whether these two compounds could decrease the production of inflammatory mediators by the interaction between 3T3-L1 adipocytes and RAW264.7 macrophages. The results showed that garcinol and pterostilbene could inhibit the TNF-α-induced NF-κB activation by suppressing phosphorylation of IκB and p65. The inflammatory genes such as COX-2, iNOS, IL-6 and IL-1β were also down-regulated by these two compounds (p<0.05). The protein expression of COX-2 and secretion of IL-6 were also inhibited by treatment with garcinol or pterostilbene in adipocytes. Furthermore, the results indicated that garcinol and pterostilbene could reduce migration of macrophages to adipocytes in transwell coculture system. However, only pterostilbene suppressed (p<0.05) the release of cytokines (IL-6 and TNF-α) and mRNA expression of several inflammatory genes (COX-2, iNOS, IL-6, TNF-α, CRP, MCP-1 and PAI-1) in contact coculture system. In addition, the effect of pterostilbene on inflammatory responses toward adipocytes and macrophages was also evaluated by in vitro model of conditioned medium experiment. The results indicated that both adipocytes and macrophages were targets for the suppressive effect of pterostilbene. In conclusion, garcinol and pterostilbene could reduce the lipid accumulation in 3T3-L1 adipocytes and inhibit TNF-α-induced inflammation via blocking NF-κB activation and reduce macrophage infiltration. Pterostilbene also could regulate the interaction between adipocytes and macrophages to suppress the level of inflammatory mediators. Our findings suggest that garcinol and pterostilbene may provide novel and useful application to reduce adipogenesis and inhibit the chronic inflammatory properties in adipocytes. These results may be potential for the treatment of obesity-related pathologies.
URI: http://hdl.handle.net/11455/52081
Appears in Collections:食品暨應用生物科技學系

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