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

• Published in: Cell metabolism 2021-03, Vol.33 (3), p.565-580.e7
• Main Authors: Chen, Suzhen, Liu, Xiaoxiao, Peng, Chao, Tan, Chang, Sun, Honglin, Liu, He, Zhang, Yao, Wu, Ping, Cui, Can, Liu, Chuchu, Yang, Di, Li, Zhiqiang, Lu, Junxi, Guan, Jian, Ke, Xisong, Wang, Renxiao, Bo, Xiaohai, Xu, Xiaojun, Han, Junfeng, Liu, Junli
• Format: Article
• Language: English
• Subjects: Adipose Tissue, Brown - metabolism; Adipose Tissue, White - metabolism; AMP-Activated Protein Kinases - metabolism; Animals; Binding Sites; Cold Temperature; Dihydrolipoyllysine-Residue Acetyltransferase - chemistry; Dihydrolipoyllysine-Residue Acetyltransferase - metabolism; Humans; Hypericum - chemistry; Hypericum - metabolism; Mice; Mice, Inbred C57BL; Mice, Obese; Mitochondrial Proteins - chemistry; Mitochondrial Proteins - metabolism; Molecular Docking Simulation; Obesity - drug therapy; Obesity - metabolism; Obesity - pathology; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Phloroglucinol - analogs & derivatives; Phloroglucinol - chemistry; Phloroglucinol - metabolism; Phloroglucinol - pharmacology; Phloroglucinol - therapeutic use; Signal Transduction - drug effects; Terpenes - chemistry; Terpenes - metabolism; Terpenes - pharmacology; Terpenes - therapeutic use; Thermogenesis - drug effects; Thermogenesis - genetics; Uncoupling Protein 1 - genetics; Uncoupling Protein 1 - metabolism; Up-Regulation - drug effects
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2021.02.007

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.