The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity.

Cell metabolism 2021 Mar 02

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Stimulation of adipose tissue thermogenesis is regarded as a promising avenue in the treatment of obesity. However, pharmacologic engagement of this process has proven difficult. Using the Connectivity Map (CMap) approach, we identified the phytochemical hyperforin (HPF) as an anti-obesity agent. We found that HPF efficiently promoted thermogenesis by stimulating AMPK and PGC-1α via a Ucp1-dependent pathway. Using LiP-SMap (limited proteolysis-mass spectrometry) combined with a microscale thermophoresis assay and molecular docking analysis, we confirmed dihydrolipoamide S-acetyltransferase (Dlat) as a direct molecular target of HPF. Ablation of Dlat significantly attenuated HPF-mediated adipose tissue browning both in vitro and in vivo. Furthermore, genome-wide association study analysis indicated that a variation in DLAT is significantly associated with obesity in humans. These findings suggest that HPF is a promising lead compound in the pursuit of a pharmacological approach to promote energy expenditure in the treatment of obesity. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Suzhen Chen, Xiaoxiao Liu, Chao Peng, Chang Tan, Honglin Sun, He Liu, Yao Zhang, Ping Wu, Can Cui, Chuchu Liu, Di Yang, Zhiqiang Li, Junxi Lu, Jian Guan, Xisong Ke, Renxiao Wang, Xiaohai Bo, Xiaojun Xu, Junfeng Han, Junli Liu. The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity. Cell metabolism. 2021 Mar 02;33(3):565-580.e7