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

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.

• Authors: 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, Yi Liu
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 246 (01 11 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 35017472 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Blood Glucose
• Crtc2 protein, mouse
• Transcription Factors
• Propolis
• CREB-Binding Protein
• Crebbp protein, mouse

Topics

• Animals
• Blood Glucose
• Brazil
• CREB-Binding Protein (genetics, metabolism)
• Drug Delivery Systems
• Drug Development
• Drug Discovery
• Gluconeogenesis
• Insulin Resistance
• Liver (metabolism)
• Metabolic Syndrome (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Mice, Obese (genetics, metabolism)
• Obesity (metabolism)
• Propolis (genetics, metabolism)
• Transcription Factors (genetics, metabolism)