十字花科蔬菜衍生物indole-3-carbinol對高脂飲食誘導肥胖相關疾病調節及其機制之探討

Effects of indole-3-carbinol on high fat diet-induced obesity related disorders and its mechanisms

張筱珮(Hsiao-Pei Chang)

指導教授 ： 陳玉華

臺北醫學大學/藥學院/藥學系(博士班)/博士(2010年)

https://doi.org/10.6831/TMU.2010.00175

摘要

本研究欲探討十字花科蔬菜衍生物indole-3-carbinol (I3C)對於高脂飲食所誘導肥胖及其相關機制之影響，分為三部分進行。第一部分主要目的為觀察I3C對於高脂飲食誘導肥胖之臨床表徵及脂肪生成相關因子的影響；第二部分則探討I3C對於高脂飲食小鼠之血脂質、脂肪肝及肝臟中脂質相關代謝因子的影響；最後利用小鼠初代脂肪細胞與巨噬細胞RAW 264.7共同培養，模擬體內肥胖細胞發炎狀態，給予I3C是否可改善伴隨肥胖引起相關發炎介質之變化。C57BL/6小鼠隨機分為控制組 (B)、高脂飲食組 (HF)與高脂飲食並給與腹腔注射5 mg I3C/kg (HFI)三組，於給予12週後，結果顯示HF組體重、副睪脂肪皆高於其他兩組。相較於HF組，HFI組降低血清中血糖、三酸甘油酯、瘦體素和胰島素的濃度，增加葡萄糖耐受能力與adiponectin的濃度，以及減少脂肪組織中F4/80的表現。另外，給予I3C可降低脂肪組織中ACC mRNA和增加PPARγ蛋白質的含量。第二部分實驗結果顯示，HF組血清及肝臟中三酸甘油酯濃度顯著增加，而血清及糞便中膽固醇的濃度沒有顯著改變。HFI組在肝臟中的膽固醇含量顯著較控制組上升。HFI組肝臟中三酸甘油酯含量亦較HF組低，且I3C可以顯著降低由高脂飲食所誘導脂質相關代謝基因SREBP-1、ACC及HMGR mRNA與增加PPAR-α mRNA的表現。在脂肪細胞與巨噬細胞共同培養下，給予I3C可抑制iNOS mRNA的表現量，降低NO、MCP-1與IL-6之濃度，以及增加PPARγ mRNA的表現，並可抑制脂肪細胞之分化。綜合以上結果，本研究發現，I3C藉由改善血清中血糖、血脂和脂肪激素的含量，降低脂肪量、調控脂肪組織和肝臟中脂質代謝相關因子以及抑制肥胖細胞之發炎狀態，因而具有抑制肥胖的作用，此結果可支持十字花科蔬菜衍生物I3C於預防或治療肥胖相關疾病之應用。

關鍵字

十字花科蔬菜衍生物 ； 肥胖 ； 發炎反應

並列摘要

The objective of this study was to investigate the effects of indole-3-carbinol (I3C), a compound derivated from cruciferous vegetables, on diet-induced obesity and its associated pathological conditions. The first study was to examine the effects of I3C on obesity and its related factors in high fat diet-induced obese (DIO) mice. Secondly, the effects of I3C on high-fat diet induced hepatic steatosis and on lipid metabolism associated genes were studied. Finally, the model of co-culture of adipocytes and macrophages was conducted to evaluate the anti-obesity activity mechanisms of I3C. For the first two studies, C57BL/6 mice were randomly divided into three groups, and received basal diet, high fat diet (HF), as well as high fat diet + 5 mg I3C/kg intraperitoneally (HFI) 3 times per week for 12 weeks. Results showed that body weight and epididymal adipose tissue weight were greater, and adipocytes were larger in the HF group than in the basal and HFI groups. Compared with the HF group, the HFI group had improved glucose tolerance, a higher serum adiponectin concentration, and lower serum glucose, triglyceride, insulin, and leptin concentrations, as well as less F4/80 expression in epididymal adipose tissue (p<0.001). Furthermore, I3C treatment decreased acetyl CoA carboxylase (ACC) mRNA expression (p<0.05) and increased peroxisome proliferators–activated receptor-γ (PPARγ) protein expression (p<0.05) in epididymal adipose tissue of DIO mice. In the second study, mice fed with high-fat diet had upregulation on serum lipid profiles and on hepatic TG accumulation. I3C reduced high fat diet-induced hepatic steatosis, glucose intolerance, lowered serum glucose, serum and hepatic triglyceride levels, and decreased expressions of sterol response element binding protein-1 (SREBP-1) and ACC mRNA, increased PPARα mRNA expressions in liver comparing to those of HF mice. However, no significant difference was observed in serum and fecal cholesterol levels between HFI and HF groups. As in macrophage and primary adipocyte co-culture study, I3C treatment decreased expression of inducible nitric oxide synthase (iNOS), lowered nitrite and interleukin-6 (IL-6) concentrations in medium, and enhanced mRNA expression of PPAR-γ. I3C also inhibited intracellular lipid accumulation in hypertrophic adipocytes, indicating an inhibition of adipocyte differentiation. In conclusion, I3C possesses anti-obesity activity as observed from decreased adiposity and infiltrated macrophages in epididymal adipose tissue of DIO mice. These reductions were associated with improved glucose tolerance and with modulated expression of adipokines and hepatic lipogenic-associated gene products. Besides, the possible mechanisms for anti-obesity effects of I3C may be involved in inhibition of macrophage-induced inflammatory changes and modulation expression of PPAR-γ and hepatic lipogenic genes.

並列關鍵字

cruciferous vegetable ； obesity ； inflammation

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