花色苷抑制JNK活化与改善胰岛素抵抗的关系研究

项目名称： 花色苷抑制JNK活化与改善胰岛素抵抗的关系研究

项目编号： No.30800913

项目类型： 青年科学基金项目

立项/批准年度： 2009

项目学科： 无线电电子学、电信技术

项目作者： 郭红辉

作者单位： 韶关学院

项目金额： 21万元

中文摘要： 胰岛素抵抗（IR）是肥胖、2型糖尿病和非酒精性脂肪肝等疾病的共同发病基础，目前缺乏有效防治措施。抑制 c-Jun 氨基端激酶（JNK）的过度活化被认为是防治IR相关疾病新的作用靶点。我们利用分化成熟的3T3-L1脂肪细胞，筛选出矢车菊素-3-葡萄糖苷（Cy-3-G）和矮牵牛素-3-葡萄糖苷两种能够显著提高脂肪细胞胰岛素敏感性的花色苷类型；发现花色苷可以通过降低氧化应激状态下脂肪细胞内的JNK活化程度而非直接抑制该激酶的活性来阻止胰岛素受体底物1的丝氨酸磷酸化，改善胞内胰岛素信号转导。利用高脂喂养肥胖小鼠和db/db糖尿病小鼠，以Cy-3-G单体作为受试物，证实了花色苷在体内对IR的改善作用；发现花色苷可以通过降低脂肪组织和肝脏的炎症因子表达，抑制IR状态下JNK的过度活化，促进饱腹时蛋白激酶B对核转录因子FoxO1的磷酸化及从胞核至胞浆的易位，从而减少肝脏脂肪积聚和糖输出，提高外周组织对胰岛素的敏感性。以上研究结果说明，花色苷类植物化学物可以通过JNK-FoxO1信号通路发挥改善IR的作用。该研究进一步丰富了膳食花色苷防治IR相关疾病的理论基础。

中文关键词： 花色苷；胰岛素抵抗；c-Jun 氨基端激酶

英文摘要： Insulin resistance (IR) is the common pathological basis for obesity, type 2 diabetes, and non-alcoholic fatty liver diseases; however, there is a lack of effective medical treatments. Targeting inhibition of c-Jun NH2-terminal kinase (JNK) activation may have a therapeutic role in IR-related diseases. By using the differentiated 3T3-L1 adipocytes as cell models, we identified two anthocyanins mediating potent insulin-sensitizing effects, namely cyanidin-3-gluside (Cy-3-G) and petunidin-3-glucoside. Furthermore, we demonstrated that anthocyanin Cy-3-G affords a significant protection against oxidative stress-induced insulin resistance in 3T3-L1 adipocytes by blocking JNK-mediated Ser307 phosphorylation of insulin receptor substrate 1. By using high-fat diet fed obese mice and db/db diabetic mice as animal models, we confirmed the anti-insulin resistance effects of anthocyanin Cy-3-G in vivo. We also found that dietary Cy-3-G reduced the expression levels of inflammatory factors in the liver and adipose tissues, which was parallel with its inhibition of JNK activation and the subsequent decrease of FoxO1 transcriptional activity. Therefore, we conclude that the beneficial effects of anthocyanin against insulin resistance, hepatic glucose production and lipid accumulation are associated with its inhibition on the JNK/FoxO1 pathway. This study further enriched the theoretical basis of dietary anthocyanin for controlling IR-related diseases.

英文关键词： anthocyanin; insulin resistance; c-Jun NH2-terminal kinase