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Published on: January 4, 2018
A propolis-derived small molecule ameliorates metabolic syndrome in obese mice by targeting the CREB/CRTC2
Yaqiong Chen1, Jiang Wang2, Yibing Wang2,3
1Key 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.
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.
Insights
Brazilian green propolis and its compound, artepillin C (APC), lower blood glucose by inhibiting the CREB/CRTC2 complex. A new compound, A57, shows even greater potential for treating metabolic syndrome.
Area of Science:
- Biochemistry
- Pharmacology
- Metabolic Research
Background:
- Metabolic syndrome is a growing health concern with complex underlying mechanisms.
- The precise molecular targets of propolis in ameliorating metabolic syndrome remain largely unidentified.
- Hepatic gluconeogenesis, regulated by the CREB/CRTC2 transcriptional complex, is a key factor in glucose homeostasis.
Purpose of the Study:
- To elucidate the molecular mechanisms by which Brazilian green propolis improves metabolic parameters.
- To identify specific compounds within propolis that inhibit key regulators of metabolic pathways.
- To evaluate the therapeutic potential of propolis-derived compounds and novel analogs for metabolic syndrome.
Main Methods:
- Utilized a mammalian two-hybrid system to screen for inhibitors of the CREB/CRTC2 interaction.
- Administered Brazilian green propolis and identified compounds to diet-induced obese mice.
- Assessed effects on fasting blood glucose, insulin sensitivity, serum and liver lipid levels, and gene expression (gluconeogenic and SREBP pathways).
Main Results:
- Brazilian green propolis effectively reduces fasting blood glucose levels in obese mice.
- Artepillin C (APC), a propolis compound, was identified as a direct inhibitor of the CREB/CRTC2 transcriptional complex.
- APC treatment improved insulin sensitivity, reduced obesity, and lowered lipid levels by suppressing CREB/CRTC2-mediated gluconeogenic and SREBP transcriptions.
- A novel derivative, A57, demonstrated enhanced inhibition of CREB/CRTC2 association and superior insulin-sensitizing effects compared to APC.
Conclusions:
- The CREB/CRTC2 transcriptional complex is a critical target for managing hepatic gluconeogenesis and metabolic dysfunction.
- Artepillin C from Brazilian green propolis represents a promising natural compound for metabolic syndrome intervention.
- The development of novel CREB/CRTC2 inhibitors, such as A57, holds significant potential for future anti-metabolic syndrome drug discovery.
