雷公藤红素逆转软脂酸导致的肌管细胞胰岛素抵抗与调节TLR4/MD2信号关系研究

Insulin resistance, resulting in metabolic syndrome has become serious health problem, and still lack effective way to prevent and treat. Recently, we found that celastrol, a natural compound from Chinese plant Tripterygium wilfordii, could effectively reverse the insulin resistance induced by palmitate; however, the mechanism behind remain unclear. TLR4/MD2 activation plays important roles in palmitate-inducing insulin resistance. It has reported that celastrol could inhibit TLR4 signaling, and our bioinformatics work also predicate interaction between celastrol and MD2. We, therefore, suggest that celastrol’s improving insulin resistance might be through inhibiting TLR4/MD2. To examine this hypothesis, in this project, we，using insulin resistant myotube cells induced by palmitate, to study whether regulating TLR4/MD2 signaling play its role in celastrol’s amelioration, and the mechanism related to modulating this pathway will also be explored. This research is dedicated to elucidate the related mechanism underlying celastrol’s therapy for palmitate-induing insulin resistance. The results will deepen our understanding of insulin resistance induced by palmitate, and provide useful information in developing novel strategies for insulin resistance management as well.

胰岛素抵抗导致的代谢综合征，已经成为当代严重的健康问题，目前对此尚无有效的防治方法。本项目组最近发现，天然化合物雷公藤红素能有效逆转软脂酸导致的胰岛素抵抗，但机制不清楚。鉴于TLR4/MD2信号活化在软脂酸诱导胰岛素抵抗中起重要作用，且其他研究组研究结果和我们的信息学模拟分析结果都提示，雷公藤红素可能阻断TLR4/MD2活化，因此，我们推测雷公藤红素很可能是通过抑制TLR4/MD2从而改善胰岛素抵抗。本项目中我们拟采用软脂酸诱导的胰岛素抵抗肌管细胞为模型，就雷公藤红素对胰岛素耐受的改善作用，是否与LR4/MD2信号通路有关进行研究，并对相关的分子机制进行了探索。本项目的完成将进一步揭示雷公藤红素逆转软脂酸导致胰岛素抵抗的分子基础，为该化合物用于临床胰岛素抵抗防治提供理论指导，并能加深对软脂酸诱发胰岛素抵抗的认识。

胰岛素抵抗导致的代谢综合征，已经成为当代严重的健康问题，目前对此尚无有效的防治方法。本项目组预实验发现，天然化合物雷公藤红素能有效逆转软脂酸导致的胰岛素抵抗，但机制不清楚。鉴于TLR4/MD2信号活化在软脂酸诱导胰岛素抵抗中起重要作用，且其他研究组研究结果和我们的信息学模拟分析结果都提示，雷公藤红素可能阻断TLR4/MD2活化。.本项目中我们采用软脂酸诱导的胰岛素抵抗肌管细胞为模型，就雷公藤红素对胰岛素耐受的改善作用，是否与LR4/MD2信号通路有关进行研究，并对相关的分子机制进行了探索。.结果发现， 1）雷公藤红素能够有效改善软脂酸导致的胰岛素抵抗；2）雷公藤红素通过调节 TLR4/MD2信号通路抑制NF-κB 活化改善软脂酸导致的肌细胞胰岛素抵抗；3）雷公藤红素有显著的抑制肥胖作用；4）雷公藤红素抑制肥胖的作用与其抗炎作用有关；5）雷公藤红素通过抑制M1型巨噬细胞极化，促进M2型巨噬细胞产生抑制肥胖。.本项目的完成将进一步揭示雷公藤红素逆转软脂酸导致胰岛素抵抗的分子基础，为该化合物用于临床胰岛素抵抗及肥胖的防治提供理论指导，加深对软脂酸诱发胰岛素抵抗的认识，并为深入理解巨噬细胞所介导的炎症在肥胖发生发展过程中的作用提供新的理论依据。