Mladenova Saveta G, Savova Martina S, Marchev Andrey S, Ferrante Claudio, Orlando Giustino, Wabitsch Martin, Georgiev Milen I
BB-NCIPD Ltd., BB-National Centre of Infectious and Parasitic Diseases, Ministry of Health, 1000 Sofia, Bulgaria.
Department of Plant Cell Biotechnology, Center of Plant Systems Biology and Biotechnology, 4000, Plovdiv, Bulgaria; Laboratory of Metabolomics, Department of Biotechnology, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 139 Ruski Blvd, 4000 Plovdiv, Bulgaria.
Biomed Pharmacother. 2022 May;149:112908. doi: 10.1016/j.biopha.2022.112908. Epub 2022 Apr 1.
Obesity is a global health burden for which we do not yet have effective treatments for prevention or therapy. Plants are an invaluable source of bioactive leads possessing anti-adipogenic potential. Ethnopharmacological use of Ononis spinosa L. roots (OSR) for treatment of obesity and metabolic disorders requires а scientific rationale. The current study examined the anti-adipogenic capacity of OSR and its secondary metabolites ononin (ONON) and maackiain (MACK) in human adipocytes as an in vitro model of obesity. Both ONON and MACK diminished lipid accumulation during adipocyte differentiation. Molecular docking analysis exposed the potential interactions between MACK or ONON and target regulatory adipogenic proteins. Furthermore, results from an RT-qPCR analysis disclosed significant upregulation of AMPK by MACK and ONON treatment. In addition, ONON increased SIRT1, PI3K and ACC mRNA expression, while MACK notably downregulated CEBPA, AKT, SREBP1, ACC and ADIPOQ. The protein level of PI3K, C/EBPα, PPARγ and adiponectin was reduced upon MACK treatment in a concentration-dependent manner. Similarly, ONON suppressed PI3K, PPARγ and adiponectin protein abundance. Finally, our study provides evidence that ONON exerts anti-adipogenic effect by upregulation of SIRT1 and inhibition of PI3K, PPARγ and adiponectin, while MACK induced strong inhibitory effect on adipogenesis via hampering PI3K, PPARγ/C/EBPα signaling and anti-lipogenic effect through downregulation of SREBP1 and ACC. Even though OSR does not hamper adipogenic differentiation, it could be exploited as a source of natural leads with anti-adipogenic potential. The multidirectional mechanism of action of MACK warrant further validation in the context of in vivo obesity models.
肥胖是一种全球健康负担，目前我们尚未有有效的预防或治疗方法。植物是具有抗脂肪生成潜力的生物活性先导化合物的宝贵来源。刺芒柄花根（OSR）在民族药理学上用于治疗肥胖和代谢紊乱需要科学依据。本研究以人脂肪细胞作为肥胖的体外模型，研究了OSR及其次生代谢产物芒柄花苷（ONON）和紫铆因（MACK）的抗脂肪生成能力。ONON和MACK均减少了脂肪细胞分化过程中的脂质积累。分子对接分析揭示了MACK或ONON与靶标调节脂肪生成蛋白之间的潜在相互作用。此外，RT-qPCR分析结果显示，MACK和ONON处理后AMPK显著上调。此外，ONON增加了SIRT1、PI3K和ACC的mRNA表达，而MACK显著下调了CEBPA、AKT、SREBP1、ACC和ADIPOQ。MACK处理后，PI3K、C/EBPα、PPARγ和脂联素的蛋白水平呈浓度依赖性降低。同样，ONON抑制了PI3K、PPARγ和脂联素的蛋白丰度。最后，我们的研究表明，ONON通过上调SIRT1以及抑制PI3K、PPARγ和脂联素发挥抗脂肪生成作用，而MACK通过阻碍PI3K、PPARγ/C/EBPα信号传导对脂肪生成产生强烈抑制作用，并通过下调SREBP1和ACC发挥抗脂肪生成作用。尽管OSR不会阻碍脂肪生成分化，但它可以作为具有抗脂肪生成潜力的天然先导化合物来源加以利用。MACK的多向作用机制值得在体内肥胖模型中进一步验证。
