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.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
Cell Metab. 2021 Mar 2;33(3):565-580.e7. 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.
刺激脂肪组织产热被认为是治疗肥胖症的一种很有前途的方法。然而，这种过程的药理学参与已被证明是困难的。我们使用连接组学（CMap）方法，将植物化学物质贯叶金丝桃素（HPF）鉴定为一种抗肥胖剂。我们发现 HPF 通过 Ucp1 依赖性途径刺激 AMPK 和 PGC-1α，有效地促进产热。使用 LiP-SMap（有限蛋白酶解-质谱）结合微尺度热泳实验和分子对接分析，我们证实二氢硫辛酰胺 S-乙酰转移酶（Dlat）是 HPF 的直接分子靶标。Dlat 的消融显著减弱了 HPF 介导的体外和体内脂肪组织褐变。此外，全基因组关联研究分析表明，DLAT 的变异与人类肥胖显著相关。这些发现表明，HPF 是一种很有前途的先导化合物，可用于寻找促进能量消耗的药理学方法来治疗肥胖症。
