{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T20:13:06Z","timestamp":1790107986926,"version":"4.0.1"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T00:00:00Z","timestamp":1691107200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Emerging evidence demonstrates that the high-fructose and high-fat diet (HFHF) induced obesity and fatty liver disease has become one of the most common metabolic disorders worldwide. Therefore, innovative investigations on compounds targeting obesity and fatty liver diseases are urgently needed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The high-throughput natural compounds screen was performed to screen the important compounds. A rat HFHF model was constructed, the regulatory function of Oxymatrine in HFHF-induced obesity was further explored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified Oxymatrine, a natural compound extracted from <jats:italic>Sophora flavescens<\/jats:italic>, showed a potential compacity in high-fat diet-induced fatty liver disease. We found that oxymatrine significantly inhibited HFHF-induced obesity using a rat HFHF model. Additionally, we found that oxymatrine altered the enhancer landscape of subcutaneous adipose tissues by ChIP-seq analysis using antibodies against the H3K27ac histone modification. Motif enrichment analysis showed the Smad motif was significantly enriched in enhancers altered post-oxymatrine treatment. Further chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) analysis and luciferase reporter assays showed oxymatrine alters the binding of Smad3 on the enhancer regions of B-cell lymphoma 2 (Bcl2) and the enhancer activity of Bcl2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Together, our study highlighted oxymatrine could suppress high-fructose and high-fat diet-induced obesity by inhibiting the suppressor of mothers against decapentaplegic 3 (Smad3) binding on obesity-related enhancers.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1145575","type":"journal-article","created":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T16:27:02Z","timestamp":1691166422000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Oxymatrine relieves high-fructose\/fat-induced obesity via reprogramming the activity of lipid metabolism-related enhancer"],"prefix":"10.3389","volume":"14","author":[{"given":"Luping","family":"Ren","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehua","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xitong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Fei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijuan","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfeng","family":"Zhen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuchun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/advances\/nmz053","article-title":"Dairy foods, obesity, and metabolic health: the role of the food matrix compared with single nutrients","volume":"10","author":"Mozaffarian","year":"2019","journal-title":"Adv Nutr"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-020-00655-y","article-title":"Sugar and artificially sweetened beverages and risk of obesity, type 2 diabetes mellitus, hypertension, and all-cause mortality: a dose-response meta-analysis of prospective cohort studies","volume":"35","author":"Qin","year":"2020","journal-title":"Eur J Epidemiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.09.004","article-title":"\u201cSweet death\u201d: fructose as a metabolic toxin that targets the gut-liver axis","volume":"33","author":"Febbraio","year":"2021","journal-title":"Cell Metab"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-021-00472-y","article-title":"Dietary carbohydrates and fats in nonalcoholic fatty liver disease","volume":"18","author":"Yki-Jarvinen","year":"2021","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2101-7","article-title":"Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate","volume":"579","author":"Zhao","year":"2020","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1039\/D0FO02653K","article-title":"Taxifolin ameliorate high-fat-diet feeding plus acute ethanol binge-induced steatohepatitis through inhibiting inflammatory caspase-1-dependent pyroptosis","volume":"12","author":"Zhan","year":"2020","journal-title":"Food Funct"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.585066","article-title":"Naringin attenuates high fat diet induced non-alcoholic fatty liver disease and gut bacterial dysbiosis in mice","volume":"11","author":"Mu","year":"2020","journal-title":"Front Microbiol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"105291","DOI":"10.1016\/j.phrs.2020.105291","article-title":"Corylin reduces obesity and insulin resistance and promotes adipose tissue browning through SIRT-1 and beta3-AR activation","volume":"164","author":"Chen","year":"2021","journal-title":"Pharmacol Res"},{"key":"B9","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.ejphar.2013.06.013","article-title":"Oxymatrine attenuates hepatic steatosis in non-alcoholic fatty liver disease rats fed with high fructose diet through inhibition of sterol regulatory element binding transcription factor 1 (Srebf1) and activation of peroxisome proliferator activated receptor alpha (Ppar\u03b1)","volume":"714","author":"Shi","year":"2013","journal-title":"Eur J Pharmacol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2013.1512","article-title":"Oxymatrine ameliorates non-alcoholic fatty liver disease in rats through peroxisome proliferator-activated receptor-\u03b1 activation","volume":"8","author":"Shi","year":"2013","journal-title":"Mol Med Rep"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00216","article-title":"Hepatic proteomic changes and Sirt1\/AMPK signaling activation by oxymatrine treatment in rats with non-alcoholic steatosis","volume":"11","author":"Xu","year":"2020","journal-title":"Front Pharmacol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020005698","article-title":"A PML\/RAR\u03b1 direct target atlas redefines transcriptional deregulation in acute promyelocytic leukemia","volume":"137","author":"Tan","year":"2021","journal-title":"Blood"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2016.05.003","article-title":"Non-alcoholic fatty liver disease and dyslipidemia: an update","volume":"65","author":"Katsiki","year":"2016","journal-title":"Metabolism: Clin Exp"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.01.019","article-title":"Fructose and sugar: a major mediator of non-alcoholic fatty liver disease","volume":"68","author":"Jensen","year":"2018","journal-title":"J Hepatol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.nutres.2018.11.003","article-title":"Fructose threshold for inducing organ damage in a rat model of nonalcoholic fatty liver disease","volume":"62","author":"Fakhoury-Sayegh","year":"2019","journal-title":"Nutr Res (New York N.Y.)"},{"key":"B16","doi-asserted-by":"publisher","first-page":"104541","DOI":"10.1016\/j.phrs.2019.104541","article-title":"Oxymatrine exerts organ- and tissue-protective effects by regulating inflammation, oxidative stress, apoptosis, and fibrosis: from bench to bedside","volume":"151","author":"Lan","year":"2020","journal-title":"Pharmacol Res"},{"key":"B17","doi-asserted-by":"publisher","first-page":"118090","DOI":"10.1016\/j.lfs.2020.118090","article-title":"Oxymatrine alleviated hepatic lipid metabolism via regulating miR-182 in non-alcoholic fatty liver disease","volume":"257","author":"Zhang","year":"2020","journal-title":"Life Sci"},{"key":"B18","doi-asserted-by":"publisher","first-page":"153270","DOI":"10.1016\/j.phymed.2020.153270","article-title":"The water extract of sophorae tonkinensis radix et rhizoma alleviates non-alcoholic fatty liver disease and its mechanism","volume":"77","author":"Zhao","year":"2020","journal-title":"Phytomed: Int J Phytother Phytopharmacol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1629","DOI":"10.1038\/srep01629","article-title":"Oxymatrine prevents NF-kappaB nuclear translocation and ameliorates acute intestinal inflammation","volume":"3","author":"Guzman","year":"2013","journal-title":"Sci Rep"},{"key":"B20","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.bbrc.2011.02.106","article-title":"The roles of transforming growth factor-beta and Smad3 signaling in adipocyte differentiation and obesity","volume":"407","author":"Tsurutani","year":"2011","journal-title":"Biochem Biophys Res Commun"},{"key":"B21","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.cmet.2011.04.013","article-title":"Protection from obesity and diabetes by blockade of TGF-beta\/Smad3 signaling","volume":"14","author":"Yadav","year":"2011","journal-title":"Cell Metab"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.2337\/db10-0801","article-title":"Smad3 deficiency in mice protects against insulin resistance and obesity induced by a high-fat diet","volume":"60","author":"Tan","year":"2011","journal-title":"Diabetes"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-019-4938-6","article-title":"Synergistic activation of thermogenic adipocytes by a combination of PPARgamma activation, SMAD3 inhibition and adrenergic receptor activation ameliorates metabolic abnormalities in rodents","volume":"62","author":"Matsumoto","year":"2019","journal-title":"Diabetologia"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.clml.2020.11.004","article-title":"BCL2 expression in first-line diffuse Large b-cell lymphoma identifies a patient population with poor prognosis","volume":"21","author":"Punnoose","year":"2020","journal-title":"Clin lymphoma Myeloma Leukemia"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.4238\/2014.May.23.10","article-title":"Roles of Fas\/Fasl, bcl-2\/Bax, and caspase-8 in rat nonalcoholic fatty liver disease pathogenesis","volume":"13","author":"Li","year":"2014","journal-title":"Genet Mol Res"},{"key":"B26","doi-asserted-by":"publisher","first-page":"818","DOI":"10.3390\/ijms22020818","article-title":"Empagliflozin attenuates non-alcoholic fatty liver disease (NAFLD) in high fat diet fed ApoE((-\/-)) mice by activating autophagy and reducing ER stress and apoptosis","volume":"22","author":"Nasiri-Ansari","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00236-20","article-title":"Elevated miR-183 impairs trophoblast migration and invasiveness by downregulating FOXP1 expression and elevating GNG7 expression during pre-eclampsia","volume":"41","author":"Lai","year":"2020","journal-title":"Mol Cell Biol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1038\/s41420-021-00536-7","article-title":"Exosomes secreted by palmitic acid-treated hepatocytes promote LX-2 cell activation by transferring miRNA-107","volume":"7","author":"Wang","year":"2021","journal-title":"Cell Death Discov"},{"key":"B29","doi-asserted-by":"publisher","first-page":"5070","DOI":"10.1038\/s41467-019-12988-8","article-title":"Foxp1 controls brown\/beige adipocyte differentiation and thermogenesis through regulating beta3-AR desensitization","volume":"10","author":"Liu","year":"2019","journal-title":"Nat Commun"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aax9605","article-title":"CTNNB1\/\u03b2-catenin dysfunction contributes to adiposity by regulating the cross-talk of mature adipocytes and preadipocytes","volume":"6","author":"Chen","year":"2020","journal-title":"Sci Adv"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1145575\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T16:27:05Z","timestamp":1691166425000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1145575\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,4]]},"references-count":30,"alternative-id":["10.3389\/fendo.2023.1145575"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1145575","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,4]]},"article-number":"1145575"}}