{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T04:05:16Z","timestamp":1783137916378,"version":"3.54.6"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,12,14]],"date-time":"2017-12-14T00:00:00Z","timestamp":1513209600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,12,14]],"date-time":"2017-12-14T00:00:00Z","timestamp":1513209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Common genetic variants at the <jats:italic>ARL15<\/jats:italic> locus are associated with plasma adiponectin, insulin and HDL cholesterol concentrations, obesity, and coronary atherosclerosis. The <jats:italic>ARL15<\/jats:italic> gene encodes a small GTP-binding protein whose function is currently unknown. In this study adipocyte-autonomous roles for ARL15 were investigated using conditional knockdown of <jats:italic>Arl15<\/jats:italic> in murine 3T3-L1 (pre)adipocytes. <jats:italic>Arl15<\/jats:italic> knockdown in differentiated adipocytes impaired adiponectin secretion but not adipsin secretion or insulin action, while in preadipocytes it impaired adipogenesis. In differentiated adipocytes GFP-tagged ARL15 localized predominantly to the Golgi with lower levels detected at the plasma membrane and intracellular vesicles, suggesting involvement in intracellular trafficking. Sequencing of <jats:italic>ARL15<\/jats:italic> in 375 severely insulin resistant patients identified four rare heterozygous variants, including an early nonsense mutation in a proband with femorogluteal lipodystrophy and non classical congenital adrenal hyperplasia, and an essential splice site mutation in a proband with partial lipodystrophy and a history of childhood yolk sac tumour. No nonsense or essential splice site mutations were found in 2,479 controls, while five such variants were found in the ExAC database. These findings provide evidence that ARL15 plays a role in adipocyte differentiation and adiponectin secretion, and raise the possibility that human ARL15 haploinsufficiency predisposes to lipodystrophy.<\/jats:p>","DOI":"10.1038\/s41598-017-17746-8","type":"journal-article","created":{"date-parts":[[2017,12,8]],"date-time":"2017-12-08T11:29:06Z","timestamp":1512732546000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["The metabolic syndrome- associated small G protein ARL15 plays a role in adipocyte differentiation and adiponectin secretion"],"prefix":"10.1038","volume":"7","author":[{"given":"Nuno","family":"Rocha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicity","family":"Payne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Huang-Doran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3859-8701","authenticated-orcid":false,"given":"Alison","family":"Sleigh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Fawcett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Stears","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Saudek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2199-4449","authenticated-orcid":false,"given":"Stephen","family":"O\u2019Rahilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5800-4520","authenticated-orcid":false,"given":"In\u00eas","family":"Barroso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6539-3069","authenticated-orcid":false,"given":"Robert K.","family":"Semple","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,12,14]]},"reference":[{"key":"17746_CR1","doi-asserted-by":"publisher","first-page":"e1000768","DOI":"10.1371\/journal.pgen.1000768","volume":"5","author":"JB Richards","year":"2009","unstructured":"Richards, J. B. et al. A genome-wide association study reveals variants in ARL15 that influence adiponectin levels. PLoS Genet. \n                           5, e1000768 (2009).","journal-title":"PLoS Genet."},{"key":"17746_CR2","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1016\/j.cmet.2016.04.011","volume":"23","author":"JH Stern","year":"2016","unstructured":"Stern, J. H., Rutkowski, J. M. & Scherer, P. E. Adiponectin, Leptin, and Fatty Acids in the Maintenance of Metabolic Homeostasis through Adipose Tissue Crosstalk. Cell Metab. \n                           23, 770\u201384 (2016).","journal-title":"Cell Metab."},{"key":"17746_CR3","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1038\/nature09270","volume":"466","author":"TM Teslovich","year":"2010","unstructured":"Teslovich, T. M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature \n                           466, 707\u201313 (2010).","journal-title":"Nature"},{"key":"17746_CR4","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1038\/ng.2797","volume":"45","author":"GC Global Lipids","year":"2013","unstructured":"Global Lipids, G. C. et al. Discovery and refinement of loci associated with lipid levels. Nat. Genet. \n                           45, 1274\u201383 (2013).","journal-title":"Nat. Genet."},{"key":"17746_CR5","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1038\/ng.2385","volume":"44","author":"RA Scott","year":"2012","unstructured":"Scott, R. A. et al. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat. Genet. \n                           44, 991\u20131005 (2012).","journal-title":"Nat. Genet."},{"key":"17746_CR6","doi-asserted-by":"publisher","first-page":"4378","DOI":"10.2337\/db14-0319","volume":"63","author":"RA Scott","year":"2014","unstructured":"Scott, R. A. et al. Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity. Diabetes \n                           63, 4378\u201387 (2014).","journal-title":"Diabetes"},{"key":"17746_CR7","doi-asserted-by":"publisher","first-page":"4369","DOI":"10.2337\/db14-0318","volume":"63","author":"H Yaghootkar","year":"2014","unstructured":"Yaghootkar, H. et al. Genetic evidence for a normal-weight \u2018metabolically obese\u2019 phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes. Diabetes \n                           63, 4369\u201377 (2014).","journal-title":"Diabetes"},{"key":"17746_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13357","volume":"7","author":"JS Ried","year":"2016","unstructured":"Ried, J. S. et al. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. Nat. Commun. \n                           7, 13357 (2016).","journal-title":"Nat. Commun."},{"key":"17746_CR9","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/nature14132","volume":"518","author":"D Shungin","year":"2015","unstructured":"Shungin, D. et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature \n                           518, 187\u2013196 (2015).","journal-title":"Nature"},{"key":"17746_CR10","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/j.ajhg.2010.09.014","volume":"87","author":"JT Glessner","year":"2010","unstructured":"Glessner, J. T. et al. A genome-wide study reveals copy number variants exclusive to childhood obesity cases. Am. J. Hum. Genet. \n                           87, 661\u20136 (2010).","journal-title":"Am. J. Hum. Genet."},{"key":"17746_CR11","doi-asserted-by":"publisher","first-page":"3219","DOI":"10.1210\/jc.2006-0166","volume":"91","author":"RK Semple","year":"2006","unstructured":"Semple, R. K. et al. Elevated plasma adiponectin in humans with genetically defective insulin receptors. J. Clin. Endocrinol. Metab. \n                           91, 3219\u20133223 (2006).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"17746_CR12","doi-asserted-by":"publisher","first-page":"9863","DOI":"10.1128\/MCB.24.22.9863-9872.2004","volume":"24","author":"JJ Rochford","year":"2004","unstructured":"Rochford, J. J. et al. ETO\/MTG8 Is an Inhibitor of C\/EBP Activity and a Regulator of Early Adipogenesis. Mol. Cell. Biol. \n                           24, 9863\u20139872 (2004).","journal-title":"Mol. Cell. Biol."},{"key":"17746_CR13","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1074\/mcp.M600437-MCP200","volume":"6","author":"JR Zavzavadjian","year":"2007","unstructured":"Zavzavadjian, J. R. et al. The alliance for cellular signaling plasmid collection: a flexible resource for protein localization studies and signaling pathway analysis. Mol. Cell. Proteomics \n                           6, 413\u201324 (2007).","journal-title":"Mol. Cell. Proteomics"},{"key":"17746_CR14","doi-asserted-by":"publisher","first-page":"4028","DOI":"10.1172\/JCI73264","volume":"124","author":"F Payne","year":"2014","unstructured":"Payne, F. et al. Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance. J. Clin. Invest. \n                           124, 4028\u201338 (2014).","journal-title":"J. Clin. Invest."},{"key":"17746_CR15","doi-asserted-by":"publisher","first-page":"13759","DOI":"10.1073\/pnas.0606179103","volume":"103","author":"K-J Shin","year":"2006","unstructured":"Shin, K.-J. et al. A single lentiviral vector platform for microRNA-based conditional RNA interference and coordinated transgene expression. Proc. Natl. Acad. Sci. USA \n                           103, 13759\u201364 (2006).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"17746_CR16","doi-asserted-by":"publisher","first-page":"925","DOI":"10.2337\/db10-1334","volume":"60","author":"I Huang-Doran","year":"2011","unstructured":"Huang-Doran, I. et al. Genetic defects in human pericentrin are associated with severe insulin resistance and diabetes. Diabetes \n                           60, 925\u201335 (2011).","journal-title":"Diabetes"},{"key":"17746_CR17","first-page":"315","volume":"119","author":"RK Semple","year":"2009","unstructured":"Semple, R. K. et al. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J. Clin. Invest. \n                           119, 315\u201322 (2009).","journal-title":"J. Clin. Invest."},{"key":"17746_CR18","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1002\/jmri.22580","volume":"34","author":"SB Reeder","year":"2011","unstructured":"Reeder, S. B., Cruite, I., Hamilton, G. & Sirlin, C. B. Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy. J. Magn. Reson. Imaging \n                           34, 729\u201349 (2011).","journal-title":"J. Magn. Reson. Imaging"},{"key":"17746_CR19","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1111\/j.1464-5491.1995.tb02058.x","volume":"12","author":"DRR Williams","year":"1995","unstructured":"Williams, D. R. R. et al. Undiagnosed Glucose Intolerance in the Community: the Isle of Ely Diabetes Project. Diabet. Med. \n                           12, 30\u201335 (1995).","journal-title":"Diabet. Med."},{"key":"17746_CR20","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1042\/BJ20081438","volume":"414","author":"JG Donaldson","year":"2008","unstructured":"Donaldson, J. G. Arfs and membrane lipids: sensing, generating and responding to membrane curvature. Biochem. J. \n                           414, e1\u2013e2 (2008).","journal-title":"Biochem. J."},{"key":"17746_CR21","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1016\/S0955-0674(99)80067-2","volume":"11","author":"P Chavrier","year":"1999","unstructured":"Chavrier, P. & Goud, B. The role of ARF and Rab GTPases in membrane transport. Current Opinion in Cell Biology \n                           11, 466\u2013475 (1999).","journal-title":"Current Opinion in Cell Biology"},{"key":"17746_CR22","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/nrm1910","volume":"7","author":"C D\u2019Souza-Schorey","year":"2006","unstructured":"D\u2019Souza-Schorey, C. & Chavrier, P. ARF proteins: roles in membrane traffic and beyond. Nat. Rev. Mol. Cell Biol. \n                           7, 347\u2013358 (2006).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"17746_CR23","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1146\/annurev.cellbio.23.090506.123209","volume":"23","author":"AK Gillingham","year":"2007","unstructured":"Gillingham, A. K. & Munro, S. The small G proteins of the Arf family and their regulators. Annu. Rev. Cell Dev. Biol. \n                           23, 579\u2013611 (2007).","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"17746_CR24","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1016\/j.bbrc.2006.02.102","volume":"342","author":"M Clarke","year":"2006","unstructured":"Clarke, M., Ewart, M. A., Santy, L. C., Prekeris, R. & Gould, G. W. ACRP30 is secreted from 3T3-L1 adipocytes via a Rab11-dependent pathway. Biochem. Biophys. Res. Commun. \n                           342, 1361\u20131367 (2006).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"17746_CR25","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1083\/jcb.116.5.1071","volume":"116","author":"RD Klausner","year":"1992","unstructured":"Klausner, R. D., Donaldson, J. G. & Lippincott-Schwartz, J. Brefeldin A: insights into the control of membrane traffic and organelle structure. J. Cell Biol. \n                           116, 1071\u201380 (1992).","journal-title":"J. Cell Biol."},{"key":"17746_CR26","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1111\/j.1600-0854.2005.00282.x","volume":"6","author":"T Szul","year":"2005","unstructured":"Szul, T. et al. Dissection of membrane dynamics of the ARF-guanine nucleotide exchange factor GBF1. Traffic \n                           6, 374\u201385 (2005).","journal-title":"Traffic"},{"key":"17746_CR27","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/S1097-2765(00)80455-4","volume":"3","author":"A Peyroche","year":"1999","unstructured":"Peyroche, A. et al. Brefeldin A acts to stabilize an abortive ARF-GDP-Sec. 7 domain protein complex: involvement of specific residues of the Sec. 7 domain. Mol. Cell \n                           3, 275\u201385 (1999).","journal-title":"Mol. Cell"},{"key":"17746_CR28","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.bbadis.2007.12.003","volume":"1782","author":"L Xie","year":"2008","unstructured":"Xie, L., O\u2019Reilly, C. P., Chapes, S. K. & Mora, S. Adiponectin and leptin are secreted through distinct trafficking pathways in adipocytes. Biochim. Biophys. Acta - Mol. Basis Dis. \n                           1782, 99\u2013108 (2008).","journal-title":"Biochim. Biophys. Acta - Mol. Basis Dis."},{"key":"17746_CR29","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/bjc.1990.272","volume":"62","author":"CR Pinkerton","year":"1990","unstructured":"Pinkerton, C. R. et al. \u2018JEB\u2019\u2013a carboplatin based regimen for malignant germ cell tumours in children. Br. J. Cancer \n                           62, 257\u201362 (1990).","journal-title":"Br. J. Cancer"},{"key":"17746_CR30","doi-asserted-by":"publisher","first-page":"7253","DOI":"10.1074\/jbc.M511313200","volume":"281","author":"L Xie","year":"2006","unstructured":"Xie, L. et al. Intracellular trafficking and secretion of adiponectin is dependent on GGA-coated vesicles. J. Biol. Chem. \n                           281, 7253\u20137259 (2006).","journal-title":"J. Biol. Chem."},{"key":"17746_CR31","doi-asserted-by":"publisher","first-page":"5313","DOI":"10.1242\/jcs.143610","volume":"126","author":"JE Casanova","year":"2013","unstructured":"Casanova, J. E. et al. Meeting report - Arf and Rab family G proteins. J. Cell Sci. \n                           126, 5313\u20136 (2013).","journal-title":"J. Cell Sci."},{"key":"17746_CR32","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nature19057","volume":"536","author":"M Lek","year":"2016","unstructured":"Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature \n                           536, 285\u2013291 (2016).","journal-title":"Nature"},{"key":"17746_CR33","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/ng.2892","volume":"46","author":"M Kircher","year":"2014","unstructured":"Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet \n                           46, 310\u2013315 (2014).","journal-title":"Nat Genet"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-17746-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-17746-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-17746-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T16:23:21Z","timestamp":1671812601000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-17746-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12,14]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["17746"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-17746-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12,14]]},"assertion":[{"value":"22 June 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 November 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 December 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"17593"}}