{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:49:12Z","timestamp":1788544152520,"version":"build-2803163510"},"reference-count":40,"publisher":"Bioscientifica","issue":"2","content-domain":{"domain":["jme.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:p>Browning of white adipose tissue has been proven to be a potential target to fight against obesity and its metabolic commodities, making the exploration of molecules involved in browning process important. Among those browning agents reported recently, FGF21 play as a quite promising candidate for treating obesity for its obvious enhancement of thermogenic capacity in adipocyte and significant improvement of metabolic disorders in both mice and human. However, whether other members of fibroblast growth factor (FGF) family play roles in adipose thermogenesis and obese development is still an open question. Here, we examined the mRNA expression of all FGF family members in three adipose tissues of male C57BL\/6 mice and found that FGF9 is highly expressed in adipose tissue and decreased under cold stress. Furthermore, FGF9 treatment inhibited thermogenic genes in the process of beige adipocytes differentiation from stromal vascular fraction (SVF) in a dose-dependent manner. Similar results were obtained with FGF9 overexpression. Consistently, knockdown of FGF9 in SVF cells by using lentiviral shRNA increased thermogenic genes in differentiated beige adipocytes. RNA sequencing analysis revealed a significant increment of hypoxia-inducible factor (HIF) pathway in the early stage of beige adipocytes differentiation under FGF9 treatment, which was validated by real-time PCR. FGF9 expression was increased in subcutaneous WAT of obese human and mice. This study shows that adipose-derived FGF9 play as an inhibitory role in the browning of white adipocytes. Activation of hypoxia signaling at early stage of adipose browning process may contribute to this anti-thermogenic effect of FGF9.<\/jats:p>","DOI":"10.1530\/jme-18-0151","type":"journal-article","created":{"date-parts":[[2018,11,28]],"date-time":"2018-11-28T06:41:47Z","timestamp":1543387307000},"page":"79-90","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-6","source":"Crossref","is-referenced-by-count":25,"title":["FGF9 inhibits browning program of white adipocytes and associates with human obesity"],"prefix":"10.1530","volume":"62","author":[{"given":"Yingkai","family":"Sun","sequence":"first","affiliation":[{"name":"1Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Wang","sequence":"additional","affiliation":[{"name":"1Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoqian","family":"Zhao","sequence":"additional","affiliation":[{"name":"1Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Li","sequence":"additional","affiliation":[{"name":"1Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Liu","sequence":"additional","affiliation":[{"name":"1Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyun","family":"Tang","sequence":"additional","affiliation":[{"name":"2State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhugang","family":"Wang","sequence":"additional","affiliation":[{"name":"2State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqing","family":"Wang","sequence":"additional","affiliation":[{"name":"1Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixin","family":"Liu","sequence":"additional","affiliation":[{"name":"1Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Ning","sequence":"additional","affiliation":[{"name":"1Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiqiu","family":"Wang","sequence":"additional","affiliation":[{"name":"1Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Hong","sequence":"additional","affiliation":[{"name":"1Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"ref151","doi-asserted-by":"crossref","first-page":"12983","DOI":"10.1074\/jbc.M110.215889","article-title":"Thermogenic activation induces FGF21 expression and release in brown adipose tissue","volume":"286","year":"2011","journal-title":"Journal of Biological Chemistry"},{"key":"ref361","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1146\/annurev-nutr-071812-161156","article-title":"Hypoxia and adipocyte physiology: implications for adipose tissue dysfunction in obesity","volume":"34","year":"2014","journal-title":"Annual Review of Nutrition"},{"key":"ref201","doi-asserted-by":"crossref","first-page":"e187","DOI":"10.1371\/journal.pbio.0040187","article-title":"Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination","volume":"4","year":"2006","journal-title":"PLOS Biology"},{"key":"ref01","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/j.devcel.2012.04.018","article-title":"FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man","volume":"22","year":"2012","journal-title":"Developmental Cell"},{"key":"ref281","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/hep.22627","article-title":"Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression","volume":"49","year":"2009","journal-title":"Hepatology"},{"key":"ref71","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1242\/dev.128.11.2095","article-title":"Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme","volume":"128","year":"2001","journal-title":"Development"},{"key":"ref351","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physrev.00017.2012","article-title":"Hypoxia and adipose tissue function and dysfunction in obesity","volume":"93","year":"2013","journal-title":"Physiological Reviews"},{"key":"ref391","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1038\/ncb2867","article-title":"Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch","volume":"15","year":"2013","journal-title":"Nature Cell Biology"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"12553","DOI":"10.1073\/pnas.1006962107","article-title":"Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway","volume":"107","year":"2010","journal-title":"PNAS"},{"key":"ref181","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s00109-016-1480-6","article-title":"Adipose HIF-1alpha causes obesity by suppressing brown adipose tissue thermogenesis","volume":"95","year":"2017","journal-title":"Journal of Molecular Medicine"},{"key":"ref331","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1093\/hmg\/ddx029","article-title":"A point mutation in Fgf9 impedes joint interzone formation leading to multiple synostoses syndrome","volume":"26","year":"2017","journal-title":"Human Molecular Genetics"},{"key":"ref191","first-page":"437.e435","article-title":"Long-term cold adaptation does not require FGF21 or UCP1","volume":"26","year":"2017","journal-title":"Cell Metabolism"},{"key":"ref81","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/nrd.2015.9","article-title":"Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23","volume":"15","year":"2016","journal-title":"Nature Reviews Drug Discovery"},{"key":"ref121","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.cmet.2013.08.005","article-title":"The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes","volume":"18","year":"2013","journal-title":"Cell Metabolism"},{"key":"ref161","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.2337\/db11-0174","article-title":"Disruption of hypoxia-inducible factor 1 in adipocytes improves insulin sensitivity and decreases adiposity in high-fat diet-fed mice","volume":"60","year":"2011","journal-title":"Diabetes"},{"key":"ref381","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1056\/NEJMoa0808949","article-title":"Functional brown adipose tissue in healthy adults","volume":"360","year":"2009","journal-title":"New England Journal of Medicine"},{"key":"ref401","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.bbrc.2007.07.032","article-title":"Hypoxia increases expression of selective facilitative glucose transporters (GLUT) and 2-deoxy-D-glucose uptake in human adipocytes","volume":"361","year":"2007","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"ref131","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/nrendo.2017.78","article-title":"FGF1 - a new weapon to control type 2 diabetes mellitus","volume":"13","year":"2017","journal-title":"Nature Reviews Endocrinology"},{"key":"ref341","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1210\/endo.143.5.8850","article-title":"Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity","volume":"143","year":"2002","journal-title":"Endocrinology"},{"key":"ref101","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1146\/annurev-physiol-021115-105339","article-title":"Understanding the Physiology of FGF21","volume":"78","year":"2016","journal-title":"Annual Review of Physiology"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.devcel.2010.08.010","article-title":"FGF9 suppresses meiosis and promotes male germ cell fate in mice","volume":"19","year":"2010","journal-title":"Developmental Cell"},{"key":"ref211","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1126\/science.1198363","article-title":"FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis","volume":"331","year":"2011","journal-title":"Science"},{"key":"ref261","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1172\/JCI200419081","article-title":"Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism","volume":"113","year":"2004","journal-title":"Journal of Clinical Investigation"},{"key":"ref111","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.cell.2007.01.047","article-title":"HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells","volume":"129","year":"2007","journal-title":"Cell"},{"key":"ref291","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/nature13540","article-title":"Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer","volume":"513","year":"2014","journal-title":"Nature"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"736","DOI":"10.2119\/molmed.2011.00075","article-title":"Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21","volume":"17","year":"2011","journal-title":"Molecular Medicine"},{"key":"ref271","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/s41588-018-0088-x","article-title":"Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition","volume":"50","year":"2018","journal-title":"Nature Genetics"},{"key":"ref371","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1038\/nature07221","article-title":"New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure","volume":"454","year":"2008","journal-title":"Nature"},{"key":"ref221","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/wdev.176","article-title":"The Fibroblast Growth Factor signaling pathway","volume":"4","year":"2015","journal-title":"Wiley Interdisciplinary Reviews: Developmental Biology"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/nrendo.2013.204","article-title":"Adipose tissue browning and metabolic health","volume":"10","year":"2014","journal-title":"Nature Reviews Endocrinology"},{"key":"ref171","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/nature10998","article-title":"A PPARgamma-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis","volume":"485","year":"2012","journal-title":"Nature"},{"key":"ref241","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.cmet.2013.01.015","article-title":"EBF2 determines and maintains brown adipocyte identity","volume":"17","year":"2013","journal-title":"Cell Metabolism"},{"key":"ref311","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.cmet.2016.02.001","article-title":"A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects","volume":"23","year":"2016","journal-title":"Cell Metabolism"},{"key":"ref141","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/nrm3528","article-title":"Exploring mechanisms of FGF signalling through the lens of structural biology","volume":"14","year":"2013","journal-title":"Nature Reviews Molecular Cell Biology"},{"key":"ref321","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1146\/annurev-biochem-052110-115718","article-title":"Adipogenesis: from stem cell to adipocyte","volume":"81","year":"2012","journal-title":"Annual Review of Biochemistry"},{"key":"ref231","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.cmet.2011.03.019","article-title":"FGF15\/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1alpha pathway","volume":"13","year":"2011","journal-title":"Cell Metabolism"},{"key":"ref251","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.cmet.2016.01.006","article-title":"FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues","volume":"23","year":"2016","journal-title":"Cell Metabolism"},{"key":"ref301","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1038\/cr.2012.94","article-title":"The PPARgamma-FGF1 axis: an unexpected mediator of adipose tissue homeostasis","volume":"22","year":"2012","journal-title":"Cell Research"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/S0092-8674(03)00928-0","article-title":"Neural tissue in ascidian embryos is induced by FGF9\/16\/20, acting via a combination of maternal GATA and Ets transcription factors","volume":"115","year":"2003","journal-title":"Cell"},{"key":"ref91","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1101\/gad.177857.111","article-title":"FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis","volume":"26","year":"2012","journal-title":"Genes and Development"}],"container-title":["Journal of Molecular Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/jme.bioscientifica.com\/view\/journals\/jme\/62\/2\/JME-18-0151.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/jme.bioscientifica.com\/downloadpdf\/journals\/jme\/62\/2\/JME-18-0151.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:53:36Z","timestamp":1784555616000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/jme\/article\/62\/2\/79-90\/14396"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2]]},"references-count":40,"journal-issue":{"issue":"2"},"URL":"https:\/\/doi.org\/10.1530\/jme-18-0151","relation":{},"ISSN":["0952-5041","1479-6813"],"issn-type":[{"value":"0952-5041","type":"print"},{"value":"1479-6813","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2]]}}}