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Deoxyschizandrin (DS), a natural lignan, occurs in <jats:italic>S. chinensis<\/jats:italic> fruit and has potent hepatoprotective effects, whereas its protective roles and mechanisms against obesity and non\u2010alcoholic fatty liver disease (NAFLD) are largely elusive. Here, we identified DS as a dual FXR\/TGR5 agonist using luciferase reporter and cyclic adenosine monophosphate\u00a0(cAMP) assays. DS was orally or intracerebroventricularly administrated to high\u2010fat diet\u2010induced obesity (DIO) mice, and methionine and choline\u2010deficient L\u2010amino acid diet (MCD diet)\u2010induced non\u2010alcoholic steatohepatitis to evaluate its protective effects. Exogenous leptin treatment was employed to investigate the sensitization effect of DS on leptin. The molecular mechanism of DS was explored by Western blot, quantitative real\u2010time PCR analysis, and ELISA. The results showed that DS activated FXR\/TGR5 signaling and effectively reduced NAFLD in DIO and MCD diet\u2010fed mice. DS countered obesity in DIO mice by promoting anorexia and energy expenditure and reversing leptin resistance, involving both peripheral and central TGR5 activation and leptin sensitization. Our findings indicate that DS may be a novel therapeutic approach for alleviating obesity and NAFLD through regulating FXR and TGR5 activities and leptin signaling.<\/jats:p>","DOI":"10.1002\/ptr.7770","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T18:16:40Z","timestamp":1677003400000},"page":"2771-2786","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Deoxyschizandrin ameliorates obesity and non\u2010alcoholic fatty liver disease: Involvement of dual <scp>Farnesyl X receptor<\/scp>\/<scp>G protein\u2010coupled bile acid receptor 1<\/scp> activation and leptin sensitization"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7090-262X","authenticated-orcid":false,"given":"Ming","family":"Gu","sequence":"first","affiliation":[{"name":"Institute of Digestive Disease, Longhua Hospital Shanghai University of Traditional Chinese Medicine  Shanghai China"},{"name":"School of Pharmacy Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaru","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Pharmacy Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujun","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Digestive Disease, Longhua Hospital Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0184-5641","authenticated-orcid":false,"given":"Shengjie","family":"Fan","sequence":"additional","affiliation":[{"name":"School of Pharmacy Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Pharmacy Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,2,21]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-019-0176-8"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.04.014"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2021.01.012"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2018.7"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.04.009"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.01.055"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00223.2019"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.06.012"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-17-0557"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2016.222"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.2.741"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3760"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-021-00507-z"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.plipres.2009.11.001"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.plipres.2021.101094"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)64849-5"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M015859"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.08.057"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.6743"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nutres.2019.01.001"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2015.02.022"},{"key":"e_1_2_10_23_1","volume-title":"Bile acid and receptors: Biology and drug discovery for nonalcoholic fatty liver disease","author":"Jiao T. 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