A propolis-derived small molecule ameliorates metabolic syndrome in obese mice by targeting the CREB/CRTC2 transcriptional complex

Yaqiong Chen, Jiang Wang, Yibing Wang, Pengfei Wang, Zan Zhou, Rong Wu, Qian Xu, Hanyun You, Yaxin Liu, Lei Wang, Lingqin Zhou, Yuting Wu, Lihong Hu (), Hong Liu () and Yi Liu ()
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Yaqiong Chen: Fudan University
Jiang Wang: Chinese Academy of Sciences
Yibing Wang: Chinese Academy of Sciences
Pengfei Wang: University of Chinese Academy of Sciences
Zan Zhou: University of Chinese Academy of Sciences
Rong Wu: University of Chinese Academy of Sciences
Qian Xu: the First Affiliated Hospital of Harbin Medical University
Hanyun You: Nanjing University of Chinese Medicine
Yaxin Liu: Fudan University
Lei Wang: Fudan University
Lingqin Zhou: Fudan University
Yuting Wu: Shanghai Institutes for Biological Sciences
Lihong Hu: Nanjing University of Chinese Medicine
Hong Liu: Chinese Academy of Sciences
Yi Liu: Fudan University

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-021-27533-9

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