基于DAGs/PKCε通路探讨四妙丸改善肥胖型胰岛素抵抗的效应机制

Both ancient records and modern clinical studies have shown that Simiao Pill has the effect on improving obesity-induced insulin resistance, but its pharmacodynamic substances and mechanism of action are still unclear, which limits its clinical application and in-depth development. This project will explore the effect mechanism of Simiao Pill on improving obesity-induced insulin resistance based on the previous discovery that "the extract of Simiao Pill can inhibit the activation of DAGs/PKCε signaling pathway induced by palmitic acid and improve insulin resistance in HFD-induced obesity mice." 1. Based on the key role of small molecule DAGs in obesity-induced insulin resistance, we will construct a screening system targeting DAGs/PKCε pathway for screening the effect component of anti-obesity induced insulin resistance in Simiao Wan; 2. Based on the cell and animal model, we will systematically investigate the efficacy of the active ingredients and explore the potential action pathways; 3 Using multidisciplinary methods and techniques, a deep-level effect mechanism study on the active components of Simiao Pills will be done around the metabolic pathway of DAGs. The research of this project will provide a scientific basis for the clinical application of Simiao Pill, and promote the development of innovative drugs that target the DAGs/PKCε pathway to improve obesity-induced insulin resistance.

古籍记载及现代临床研究均表明四妙丸有改善肥胖型胰岛素抵抗的作用，但其药效物质及作用机制尚不明确，限制了其临床应用与深入开发。课题组前期研究发现四妙丸提取物可抑制棕榈酸诱导DAGs/PKCε信号通路的活化，改善高脂诱导的胰岛素抵抗。在此基础上，本项目将深入探讨四妙丸改善肥胖型胰岛素抵抗的效应机制：①针对小分子DAGs在肥胖诱导胰岛素抵抗中的关键作用，构建靶向DAGs/PKCε通路的筛选体系，发现四妙丸中抗肥胖型胰岛素抵抗的效应成分；②基于细胞和整体动物模型，系统全面考察活性成分的药效，探索潜在作用途径；③围绕DAGs代谢途径，利用多学科方法和技术对四妙丸活性成分进行深层次的效应机制研究，以揭示四妙丸改善肥胖型胰岛素抵抗的科学内涵。本项目的研究将为经典名方四妙丸的临床应用提供科学依据，推动靶向DAGs/PKCε通路改善肥胖型胰岛素抵抗的创新药物研发。

古籍记载及现代临床研究均表明四妙丸有改善肥胖型胰岛素抵抗的作用，但其药效物质及作用机制尚不明确，限制了其临床应用与深入开发。课题组前期研究发现四妙丸提取物可抑制棕榈酸诱导sn-1,2-DAG/PKCε信号通路的活化，改善高脂诱导的胰岛素抵抗。在此基础上，①本项目针对代谢信号分子sn-1,2-DAG在肥胖诱导胰岛素抵抗中的关键作用，构建靶向sn-1,2-DAG/PKCε通路的筛选体系，发现四妙丸中抗肥胖型胰岛素抵抗的强活性成分白术内酯II。②系统地考察了白术内酯II在体内的药代动力学和毒理学（急毒和长毒）后，基于高脂诱导的细胞模型和高脂诱导及自发诱导的整体动物模型，系统全面考察白术内酯II短期和长期给药对肥胖型胰岛素抵抗的改善作用。③围绕sn-1,2-DAG代谢途径，利用ABPP分子垂钓技术，结合分子生物学、结构生物学等多学科方法和技术鉴定白术内酯II的作用靶点为DGKQ。ATII可作用于DGKQ的CRD和PH结构域中的新药物口袋，选择性地别构激活DGKQ，从而抑制sn-1,2-DAG/PKCε信号通路，改善胰岛素敏感性。本项目的研究为经典名方四妙丸的临床应用提供科学依据，推动靶向DGKQ/sn-1,2-DAG/PKCε通路改善肥胖型胰岛素抵抗的创新药物研发。