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

  • Cell Metab. 2021 Mar 2;33(3):565-580.e7. doi: 10.1016/j.cmet.2021.02.007.
Suzhen Chen  1 ,  Xiaoxiao Liu  2 ,  Chao Peng  3 ,  Chang Tan  4 ,  Honglin Sun  5 ,  He Liu  5 ,  Yao Zhang  5 ,  Ping Wu  3 ,  Can Cui  6 ,  Chuchu Liu  5 ,  Di Yang  5 ,  Zhiqiang Li  7 ,  Junxi Lu  5 ,  Jian Guan  8 ,  Xisong Ke  6 ,  Renxiao Wang  9 ,  Xiaohai Bo  4 ,  Xiaojun Xu  10 ,  Junfeng Han  11 ,  Junli Liu  12
Affiliations
  • 1. Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China; Department of Otolaryngology Head and Neck Surgery & Center of Sleep Medicine, Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China. Electronic address: [email protected].
  • 2. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
  • 3. National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China.
  • 4. Department of Chemistry, Shanghai Normal University, 100 Guilin Road, Shanghai 200234, China.
  • 5. Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China.
  • 6. Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 7. Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University, Qingdao University, Qingdao, China.
  • 8. Department of Otolaryngology Head and Neck Surgery & Center of Sleep Medicine, Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China.
  • 9. State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
  • 10. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
  • 11. Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China. Electronic address: [email protected].
  • 12. Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China. Electronic address: [email protected].
PMID: 33657393 DOI: 10.1016/j.cmet.2021.02.007
Abstract

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.

Keywords
AMPK; CMap; Dlat; LiP-SMap; Ucp1; hyperforin; obesity; thermogenesis.
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