The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity
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...
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| Veröffentlicht in: | Cell metabolism 2021-03, Vol.33 (3), p.565-580.e7 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1016/j.cmet.2021.02.007 |
| format | Article |
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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.</description><identifier>ISSN: 1550-4131</identifier><identifier>EISSN: 1932-7420</identifier><identifier>DOI: 10.1016/j.cmet.2021.02.007</identifier><identifier>PMID: 33657393</identifier><language>eng</language><publisher>United States</publisher><subject>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</subject><ispartof>Cell metabolism, 2021-03, Vol.33 (3), p.565-580.e7</ispartof><rights>Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c347t-d3a1203bda1d6808ac4efefcf94f507d49fac209a3f1d6fe29bd24805d6edd5f3</citedby><cites>FETCH-LOGICAL-c347t-d3a1203bda1d6808ac4efefcf94f507d49fac209a3f1d6fe29bd24805d6edd5f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33657393$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Suzhen</creatorcontrib><creatorcontrib>Liu, Xiaoxiao</creatorcontrib><creatorcontrib>Peng, Chao</creatorcontrib><creatorcontrib>Tan, Chang</creatorcontrib><creatorcontrib>Sun, Honglin</creatorcontrib><creatorcontrib>Liu, He</creatorcontrib><creatorcontrib>Zhang, Yao</creatorcontrib><creatorcontrib>Wu, Ping</creatorcontrib><creatorcontrib>Cui, Can</creatorcontrib><creatorcontrib>Liu, Chuchu</creatorcontrib><creatorcontrib>Yang, Di</creatorcontrib><creatorcontrib>Li, Zhiqiang</creatorcontrib><creatorcontrib>Lu, Junxi</creatorcontrib><creatorcontrib>Guan, Jian</creatorcontrib><creatorcontrib>Ke, Xisong</creatorcontrib><creatorcontrib>Wang, Renxiao</creatorcontrib><creatorcontrib>Bo, Xiaohai</creatorcontrib><creatorcontrib>Xu, Xiaojun</creatorcontrib><creatorcontrib>Han, Junfeng</creatorcontrib><creatorcontrib>Liu, Junli</creatorcontrib><title>The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity</title><title>Cell metabolism</title><addtitle>Cell Metab</addtitle><description>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.</description><subject>Adipose Tissue, Brown - metabolism</subject><subject>Adipose Tissue, White - metabolism</subject><subject>AMP-Activated Protein Kinases - metabolism</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Cold Temperature</subject><subject>Dihydrolipoyllysine-Residue Acetyltransferase - chemistry</subject><subject>Dihydrolipoyllysine-Residue Acetyltransferase - metabolism</subject><subject>Humans</subject><subject>Hypericum - chemistry</subject><subject>Hypericum - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Obese</subject><subject>Mitochondrial Proteins - chemistry</subject><subject>Mitochondrial Proteins - metabolism</subject><subject>Molecular Docking Simulation</subject><subject>Obesity - drug therapy</subject><subject>Obesity - metabolism</subject><subject>Obesity - pathology</subject><subject>Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism</subject><subject>Phloroglucinol - analogs & derivatives</subject><subject>Phloroglucinol - chemistry</subject><subject>Phloroglucinol - metabolism</subject><subject>Phloroglucinol - pharmacology</subject><subject>Phloroglucinol - therapeutic use</subject><subject>Signal Transduction - drug effects</subject><subject>Terpenes - chemistry</subject><subject>Terpenes - metabolism</subject><subject>Terpenes - pharmacology</subject><subject>Terpenes - therapeutic use</subject><subject>Thermogenesis - drug effects</subject><subject>Thermogenesis - genetics</subject><subject>Uncoupling Protein 1 - genetics</subject><subject>Uncoupling Protein 1 - metabolism</subject><subject>Up-Regulation - drug effects</subject><issn>1550-4131</issn><issn>1932-7420</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMtu1TAURS0EoqXwAwyQh0wSju08rodVeVUtgkEZW459nPgqiYPtIO7f46sWRmdLZ689WIS8ZVAzYN2HY20WzDUHzmrgNUD_jFwyKXjVNxyel9y2UDVMsAvyKqUjgOiEFC_JhRBd25d4SfLDhHSbTjmYCRdv9Eyn04bRhehXmqMfR4yJ5gnjEkZcMflEy0dbv4WENPuUdqS_vaaafpx1rq6__bijyY-rnv06Uv2nADlQs8eBhqHw-fSavHB6Tvjm6V6Rn58_Pdx8re6_f7m9ub6vjGj6XFmhGQcxWM1sd4CDNg06dMbJxrXQ20Y6bThILVwpOORysLw5QGs7tLZ14oq8f9zdYvi1Y8pq8cngPOsVw54Ub2QPvZR9W6r8sWpiSCmiU1v0i44nxUCdbaujOttWZ9sKuCq2C_TuaX8fFrT_kX96xV_a9H87</recordid><startdate>20210302</startdate><enddate>20210302</enddate><creator>Chen, Suzhen</creator><creator>Liu, Xiaoxiao</creator><creator>Peng, Chao</creator><creator>Tan, Chang</creator><creator>Sun, Honglin</creator><creator>Liu, He</creator><creator>Zhang, Yao</creator><creator>Wu, Ping</creator><creator>Cui, Can</creator><creator>Liu, Chuchu</creator><creator>Yang, Di</creator><creator>Li, Zhiqiang</creator><creator>Lu, Junxi</creator><creator>Guan, Jian</creator><creator>Ke, Xisong</creator><creator>Wang, Renxiao</creator><creator>Bo, Xiaohai</creator><creator>Xu, Xiaojun</creator><creator>Han, Junfeng</creator><creator>Liu, Junli</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20210302</creationdate><title>The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c347t-d3a1203bda1d6808ac4efefcf94f507d49fac209a3f1d6fe29bd24805d6edd5f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adipose Tissue, Brown - metabolism</topic><topic>Adipose Tissue, White - metabolism</topic><topic>AMP-Activated Protein Kinases - metabolism</topic><topic>Animals</topic><topic>Binding Sites</topic><topic>Cold Temperature</topic><topic>Dihydrolipoyllysine-Residue Acetyltransferase - chemistry</topic><topic>Dihydrolipoyllysine-Residue Acetyltransferase - metabolism</topic><topic>Humans</topic><topic>Hypericum - chemistry</topic><topic>Hypericum - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Obese</topic><topic>Mitochondrial Proteins - chemistry</topic><topic>Mitochondrial Proteins - metabolism</topic><topic>Molecular Docking Simulation</topic><topic>Obesity - drug therapy</topic><topic>Obesity - metabolism</topic><topic>Obesity - pathology</topic><topic>Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism</topic><topic>Phloroglucinol - analogs & derivatives</topic><topic>Phloroglucinol - chemistry</topic><topic>Phloroglucinol - metabolism</topic><topic>Phloroglucinol - pharmacology</topic><topic>Phloroglucinol - therapeutic use</topic><topic>Signal Transduction - drug effects</topic><topic>Terpenes - chemistry</topic><topic>Terpenes - metabolism</topic><topic>Terpenes - pharmacology</topic><topic>Terpenes - therapeutic use</topic><topic>Thermogenesis - drug effects</topic><topic>Thermogenesis - genetics</topic><topic>Uncoupling Protein 1 - genetics</topic><topic>Uncoupling Protein 1 - metabolism</topic><topic>Up-Regulation - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Suzhen</creatorcontrib><creatorcontrib>Liu, Xiaoxiao</creatorcontrib><creatorcontrib>Peng, Chao</creatorcontrib><creatorcontrib>Tan, Chang</creatorcontrib><creatorcontrib>Sun, Honglin</creatorcontrib><creatorcontrib>Liu, He</creatorcontrib><creatorcontrib>Zhang, Yao</creatorcontrib><creatorcontrib>Wu, Ping</creatorcontrib><creatorcontrib>Cui, Can</creatorcontrib><creatorcontrib>Liu, Chuchu</creatorcontrib><creatorcontrib>Yang, Di</creatorcontrib><creatorcontrib>Li, Zhiqiang</creatorcontrib><creatorcontrib>Lu, Junxi</creatorcontrib><creatorcontrib>Guan, Jian</creatorcontrib><creatorcontrib>Ke, Xisong</creatorcontrib><creatorcontrib>Wang, Renxiao</creatorcontrib><creatorcontrib>Bo, Xiaohai</creatorcontrib><creatorcontrib>Xu, Xiaojun</creatorcontrib><creatorcontrib>Han, Junfeng</creatorcontrib><creatorcontrib>Liu, Junli</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cell metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Suzhen</au><au>Liu, Xiaoxiao</au><au>Peng, Chao</au><au>Tan, Chang</au><au>Sun, Honglin</au><au>Liu, He</au><au>Zhang, Yao</au><au>Wu, Ping</au><au>Cui, Can</au><au>Liu, Chuchu</au><au>Yang, Di</au><au>Li, Zhiqiang</au><au>Lu, Junxi</au><au>Guan, Jian</au><au>Ke, Xisong</au><au>Wang, Renxiao</au><au>Bo, Xiaohai</au><au>Xu, Xiaojun</au><au>Han, Junfeng</au><au>Liu, Junli</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity</atitle><jtitle>Cell metabolism</jtitle><addtitle>Cell Metab</addtitle><date>2021-03-02</date><risdate>2021</risdate><volume>33</volume><issue>3</issue><spage>565</spage><epage>580.e7</epage><pages>565-580.e7</pages><issn>1550-4131</issn><eissn>1932-7420</eissn><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.</abstract><cop>United States</cop><pmid>33657393</pmid><doi>10.1016/j.cmet.2021.02.007</doi><oa>free_for_read</oa></addata></record> |
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| 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 |
| title | The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity |
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