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

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

doi:10.1016/j.cmet.2021.02.007

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.

Authors

Suzhen Chen¹, Xiaoxiao Liu², Chao Peng³, Chang Tan⁴, Honglin Sun⁵, He Liu⁵, Yao Zhang⁵, Ping Wu³, Can Cui⁶, Chuchu Liu⁵, Di Yang⁵, Zhiqiang Li⁷, Junxi Lu⁵, Jian Guan⁸, Xisong Ke⁶, Renxiao Wang⁹, Xiaohai Bo⁴, Xiaojun Xu¹⁰, Junfeng Han¹¹, Junli Liu¹²

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: cszdream@163.com.
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: 1020122236@cpu.edu.cn.
¹¹ Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China. Electronic address: tjhjf@163.com.
¹² Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 200233 Shanghai, China. Electronic address: liujunli@sjtu.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism
Adipose Tissue, Brown / metabolism*
Adipose Tissue, White / 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

Substances

Mitochondrial Proteins
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Terpenes
Uncoupling Protein 1
Phloroglucinol
Dihydrolipoyllysine-Residue Acetyltransferase
Dlat protein, mouse
AMP-Activated Protein Kinases
hyperforin