Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China.
State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China.
Nat Commun. 2022 Jan 11;13(1):246. doi: 10.1038/s41467-021-27533-9.
The molecular targets and mechanisms of propolis ameliorating metabolic syndrome are not fully understood. Here, we report that Brazilian green propolis reduces fasting blood glucose levels in obese mice by disrupting the formation of CREB/CRTC2 transcriptional complex, a key regulator of hepatic gluconeogenesis. Using a mammalian two-hybrid system based on CREB-CRTC2, we identify artepillin C (APC) from propolis as an inhibitor of CREB-CRTC2 interaction. Without apparent toxicity, APC protects mice from high fat diet-induced obesity, decreases fasting glucose levels, enhances insulin sensitivity and reduces lipid levels in the serum and liver by suppressing CREB/CRTC2-mediated both gluconeogenic and SREBP transcriptions. To develop more potential drugs from APC, we designed and found a novel compound, A57 that exhibits higher inhibitory activity on CREB-CRTC2 association and better capability of improving insulin sensitivity in obese animals, as compared with APC. In this work, our results indicate that CREB/CRTC2 is a suitable target for developing anti-metabolic syndrome drugs.
蜂胶改善代谢综合征的分子靶点和机制尚不完全清楚。在这里，我们报告称，巴西绿蜂胶通过破坏 CREB/CRTC2 转录复合物的形成来降低肥胖小鼠的空腹血糖水平，CREB/CRTC2 转录复合物是肝糖异生的关键调节因子。我们使用基于 CREB-CRTC2 的哺乳动物双杂交系统，鉴定出蜂胶中的 artepillin C (APC) 是 CREB-CRTC2 相互作用的抑制剂。APC 没有明显的毒性，可保护小鼠免受高脂肪饮食诱导的肥胖，降低空腹血糖水平，增强胰岛素敏感性，并通过抑制 CREB/CRTC2 介导的糖异生和 SREBP 转录来降低血清和肝脏中的脂质水平。为了从 APC 开发更多有潜力的药物，我们设计并发现了一种新型化合物 A57，与 APC 相比，它对 CREB-CRTC2 结合具有更高的抑制活性，并且在肥胖动物中改善胰岛素敏感性的能力更强。在这项工作中，我们的结果表明 CREB/CRTC2 是开发抗代谢综合征药物的合适靶点。
