新兴证据显示，高果糖和高脂肪饮食（HFHF）引发的肥胖和脂肪肝病已成为全球最常见的代谢紊乱之一。因此，迫切需要对靶向肥胖和脂肪肝疾病的化合物进行创新性研究。我们进行了高通量自然化合物筛选，以筛选出重要的化合物。构建了大鼠HFHF模型，进一步探索了氧化苦参碱在HFHF引发的肥胖中的调控功能。我们发现，氧化苦参碱，一种从苦参中提取的天然化合物，在高脂肪饮食引发的脂肪肝病中显示出潜在的作用能力。我们发现氧化苦参碱通过大鼠HFHF模型明显抑制了HFHF引发的肥胖。此外，我们通过针对H3K27ac组蛋白修饰的抗体进行的ChIP-seq分析发现，氧化苦参碱改变了皮下脂肪组织的启动子景观。Motif富集分析显示，在氧化苦参碱处理后，Smad位点在启动子中富集显著增加。进一步的染色质免疫共沉淀-定量PCR（ChIP-qPCR）分析和荧光素酶报告基因实验表明，氧化苦参碱改变了Smad3在B细胞淋巴瘤2（Bcl2）启动子区域的结合和Bcl2的启动子活性。综上，我们的研究强调氧化苦参碱通过抑制母显性灭脑白癜单胞菌3（Smad3）在与肥胖相关的启动子上的结合，可以抑制高果糖和高脂肪饮食引发的肥胖。版权所有©2023年Ren、Liu、Huang、Zhang、Fei、Yu、Hu、Zhen和Chen。

Emerging evidence demonstrates that the high-fructose and high-fat diet (HFHF) induced obesity and fatty liver disease has become one of the most common metabolic disorders worldwide. Therefore, innovative investigations on compounds targeting obesity and fatty liver diseases are urgently needed.The high-throughput natural compounds screen was performed to screen the important compounds. A rat HFHF model was constructed, the regulatory function of Oxymatrine in HFHF-induced obesity was further explored.We identified Oxymatrine, a natural compound extracted from Sophora flavescens, showed a potential compacity in high-fat diet-induced fatty liver disease. We found that oxymatrine significantly inhibited HFHF-induced obesity using a rat HFHF model. Additionally, we found that oxymatrine altered the enhancer landscape of subcutaneous adipose tissues by ChIP-seq analysis using antibodies against the H3K27ac histone modification. Motif enrichment analysis showed the Smad motif was significantly enriched in enhancers altered post-oxymatrine treatment. Further chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) analysis and luciferase reporter assays showed oxymatrine alters the binding of Smad3 on the enhancer regions of B-cell lymphoma 2 (Bcl2) and the enhancer activity of Bcl2.Together, our study highlighted oxymatrine could suppress high-fructose and high-fat diet-induced obesity by inhibiting the suppressor of mothers against decapentaplegic 3 (Smad3) binding on obesity-related enhancers.Copyright © 2023 Ren, Liu, Huang, Zhang, Fei, Yu, Hu, Zhen and Chen.