{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T01:41:40Z","timestamp":1780105300727,"version":"3.54.0"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,4,30]],"date-time":"2020-04-30T00:00:00Z","timestamp":1588204800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,4,30]],"date-time":"2020-04-30T00:00:00Z","timestamp":1588204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003625","name":"Ministry of Health and Welfare","doi-asserted-by":"publisher","award":["#HI19C0577"],"award-info":[{"award-number":["#HI19C0577"]}],"id":[{"id":"10.13039\/501100003625","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Inflammation and remodelling of orbital tissue associated with enhanced adipogenesis commonly occur in Graves\u2019 ophthalmopathy (GO), however, the underlying mechanisms that link immune cells and adipocytes in orbital inflammation are not well-known. The primary aim of this study was to elucidate how a genetically determined shift in the T-cell repertoire toward self-reactive T-cells could drive orbital adipogenesis. To induce the T-cell-mediated autoimmune response, SKG mice were intraperitoneally injected with zymosan A once at 8 weeks of age. After three months, orbital magnetic resonance imaging (MRI), histopathologic studies, and <jats:italic>in vitro<\/jats:italic> analyses were performed to evaluate inflammation and adipogenesis. The eyes of the zymosan A-treated SKG mice displayed proptosis and blepharitis. A detailed analysis of orbital adipose tissue showed enhanced orbital adipogenesis and cellular infiltration compared to controls. In addition, increased secretion of adipokines and other cytokines in the periorbital tissue was observed, together with elevated serum concentration of inflammatory cytokines. Orbital adipogenesis was enhanced in zymosan A-treated SKG mice, a novel mouse model for GO-like inflammatory adipose phenotypes most likely induced by T-cell mediated autoimmune responses. This mouse model gives us the opportunity to examine the underlying molecular mechanisms of enhanced adipogenesis in GO, ultimately providing a potential therapeutic target alternative to conventional GO treatment.<\/jats:p>","DOI":"10.1038\/s41598-020-64402-9","type":"journal-article","created":{"date-parts":[[2020,4,30]],"date-time":"2020-04-30T10:03:55Z","timestamp":1588241035000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Enhanced orbital adipogenesis in a mouse model of T-cell-mediated autoimmunity, zymosan A-treated SKG mice: Implications for Graves\u2019 ophthalmopathy"],"prefix":"10.1038","volume":"10","author":[{"given":"Sera","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae-Young","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaeryung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung In","family":"Woo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon-Duck","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jisang","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae-Young","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoon-Suk","family":"Cha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Hui","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,4,30]]},"reference":[{"key":"64402_CR1","doi-asserted-by":"publisher","first-page":"1552","DOI":"10.1056\/NEJMra1510030","volume":"375","author":"TJ Smith","year":"2016","unstructured":"Smith, T. J. & Hegedus, L. Graves\u2019 Disease. N. Engl. J. Med. 375, 1552\u20131565 (2016).","journal-title":"N. Engl. J. Med."},{"key":"64402_CR2","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1056\/NEJMra0905750","volume":"362","author":"RS Bahn","year":"2010","unstructured":"Bahn, R. S. Graves\u2019 ophthalmopathy. N. Engl. J. Med. 362, 726\u2013738 (2010).","journal-title":"N. Engl. J. Med."},{"key":"64402_CR3","first-page":"477","volume":"92","author":"GB Bartley","year":"1994","unstructured":"Bartley, G. B. The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Trans. Am. Ophthalmol. Soc. 92, 477\u2013588 (1994).","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"64402_CR4","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1089\/105072502761016476","volume":"12","author":"WM Wiersinga","year":"2002","unstructured":"Wiersinga, W. M. & Bartalena, L. Epidemiology and prevention of Graves\u2019 ophthalmopathy. Thyroid 12, 855\u2013860 (2002).","journal-title":"Thyroid"},{"key":"64402_CR5","doi-asserted-by":"publisher","DOI":"10.1186\/s40842-016-0037-5","volume":"2","author":"P Novaes","year":"2016","unstructured":"Novaes, P., Diniz Grisolia, A. B. & Smith, T. J. Update on thyroid-associated Ophthalmopathy with a special emphasis on the ocular surface. Clin. Diabetes Endocrinol. 2, 19 (2016).","journal-title":"Clin. Diabetes Endocrinol."},{"key":"64402_CR6","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1530\/EJE-14-0712","volume":"172","author":"E Sisti","year":"2015","unstructured":"Sisti, E. et al. Intravenous glucocorticoid therapy for Graves\u2019 ophthalmopathy and acute liver damage: an epidemiological study. Eur. J. Endocrinol. 172, 269\u2013276 (2015).","journal-title":"Eur. J. Endocrinol."},{"key":"64402_CR7","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1038\/nature02119","volume":"426","author":"N Sakaguchi","year":"2003","unstructured":"Sakaguchi, N. et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426, 454\u2013460 (2003).","journal-title":"Nature"},{"key":"64402_CR8","doi-asserted-by":"crossref","unstructured":"Jeong, H. et al. Spondyloarthritis features in zymosan-induced SKG mice. Joint Bone Spine (2017).","DOI":"10.1016\/j.jbspin.2017.11.008"},{"key":"64402_CR9","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/0092-8674(92)90598-7","volume":"71","author":"AC Chan","year":"1992","unstructured":"Chan, A. C., Iwashima, M., Turck, C. W. & Weiss, A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell 71, 649\u2013662 (1992).","journal-title":"Cell"},{"key":"64402_CR10","doi-asserted-by":"publisher","first-page":"5862","DOI":"10.1210\/jc.2004-1108","volume":"89","author":"MR Velaga","year":"2004","unstructured":"Velaga, M. R. et al. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves\u2019 disease. J. Clin. Endocrinol. Metab. 89, 5862\u20135865 (2004).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"64402_CR11","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1186\/s13075-015-0725-z","volume":"17","author":"EJ Lee","year":"2015","unstructured":"Lee, E. J. et al. Investigation of the relationship between the onset of arthritis and uveitis in genetically predisposed SKG mice. Arthritis Res. Ther. 17, 218 (2015).","journal-title":"Arthritis Res. Ther."},{"key":"64402_CR12","doi-asserted-by":"publisher","first-page":"365","DOI":"10.14348\/molcells.2014.0074","volume":"37","author":"JY Huh","year":"2014","unstructured":"Huh, J. Y., Park, Y. J., Ham, M. & Kim, J. B. Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. Mol. Cell 37, 365\u2013371 (2014).","journal-title":"Mol. Cell"},{"key":"64402_CR13","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.cell.2014.12.011","volume":"160","author":"MW Lee","year":"2015","unstructured":"Lee, M. W. et al. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160, 74\u201387 (2015).","journal-title":"Cell"},{"key":"64402_CR14","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1172\/JCI78362","volume":"125","author":"L Sidossis","year":"2015","unstructured":"Sidossis, L. & Kajimura, S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J. Clin. Invest. 125, 478\u2013486 (2015).","journal-title":"J. Clin. Invest."},{"key":"64402_CR15","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1038\/nature14115","volume":"519","author":"JR Brestoff","year":"2015","unstructured":"Brestoff, J. R. et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242\u2013246 (2015).","journal-title":"Nature"},{"key":"64402_CR16","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.immuni.2015.01.001","volume":"42","author":"M Uhm","year":"2015","unstructured":"Uhm, M. & Saltiel, A. R. White, brown, and beige; type 2 immunity gets hot. Immunity 42, 15\u201317 (2015).","journal-title":"Immunity"},{"key":"64402_CR17","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1007\/s12016-016-8562-7","volume":"52","author":"M Ungerer","year":"2017","unstructured":"Ungerer, M., Fassbender, J., Li, Z., Munch, G. & Holthoff, H. P. Review of Mouse Models of Graves\u2019 Disease and Orbitopathy-Novel Treatment by Induction of Tolerance. Clin. Rev. Allergy Immunol. 52, 182\u2013193 (2017).","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"64402_CR18","doi-asserted-by":"publisher","first-page":"1673","DOI":"10.1210\/en.2015-1829","volume":"157","author":"U Berchner-Pfannschmidt","year":"2016","unstructured":"Berchner-Pfannschmidt, U. et al. Comparative Assessment of Female Mouse Model of Graves\u2019 Orbitopathy Under Different Environments, Accompanied by Proinflammatory Cytokine and T-Cell Responses to Thyrotropin Hormone Receptor Antigen. Endocrinology 157, 1673\u20131682 (2016).","journal-title":"Endocrinology"},{"key":"64402_CR19","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1210\/en.2014-1813","volume":"156","author":"HP Holthoff","year":"2015","unstructured":"Holthoff, H. P. et al. Prolonged TSH receptor A subunit immunization of female mice leads to a long-term model of Graves\u2019 disease, tachycardia, and cardiac hypertrophy. Endocrinology 156, 1577\u20131589 (2015).","journal-title":"Endocrinology"},{"key":"64402_CR20","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1136\/bjophthalmol-2015-307399","volume":"100","author":"JJ Khong","year":"2016","unstructured":"Khong, J. J., McNab, A. A., Ebeling, P. R., Craig, J. E. & Selva, D. Pathogenesis of thyroid eye disease: review and update on molecular mechanisms. Br. J. Ophthalmol. 100, 142\u2013150 (2016).","journal-title":"Br. J. Ophthalmol."},{"key":"64402_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-31253-4","volume":"8","author":"A Schluter","year":"2018","unstructured":"Schluter, A. et al. Graves\u2019 orbitopathy occurs sex-independently in an autoimmune hyperthyroid mouse model. Sci. Rep. 8, 13096 (2018).","journal-title":"Sci. Rep."},{"key":"64402_CR22","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1111\/cei.13075","volume":"191","author":"A Schluter","year":"2018","unstructured":"Schluter, A. et al. Genetic immunization with mouse thyrotrophin hormone receptor plasmid breaks self-tolerance for a murine model of autoimmune thyroid disease and Graves\u2019 orbitopathy. Clin. Exp. Immunol. 191, 255\u2013267 (2018).","journal-title":"Clin. Exp. Immunol."},{"key":"64402_CR23","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.jcjo.2015.05.012","volume":"50","author":"YS Kim","year":"2015","unstructured":"Kim, Y. S., Kwak, A. Y., Lee, S. Y., Yoon, J. S. & Jang, S. Y. Meibomian gland dysfunction in Graves\u2019 orbitopathy. Can. J. Ophthalmol. 50, 278\u2013282 (2015).","journal-title":"Can. J. Ophthalmol."},{"key":"64402_CR24","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.ajo.2018.12.006","volume":"200","author":"MY Adil","year":"2019","unstructured":"Adil, M. Y. et al. Meibomian gland morphology is a sensitive early indicator of Meibomian gland dysfunction. Am. J. Ophthalmol. 200, 16\u201325 (2019).","journal-title":"Am. J. Ophthalmol."},{"key":"64402_CR25","doi-asserted-by":"crossref","unstructured":"Jankauskiene, J. & Jarusaitiene, D. Assessment of visual acuity, refraction changes, and proptosis in different ages of patients with thyroid diseases. International journal of endocrinology 2012 (2012).","DOI":"10.1155\/2012\/643275"},{"key":"64402_CR26","doi-asserted-by":"publisher","first-page":"244","DOI":"10.3109\/01676831003664319","volume":"29","author":"ET Detorakis","year":"2010","unstructured":"Detorakis, E. T., Drakonaki, E., Papadaki, E., Pallikaris, I. G. & Tsilimbaris, M. K. Effective orbital volume and eyeball position: an MRI study. Orbit 29, 244\u2013249 (2010).","journal-title":"Orbit"},{"key":"64402_CR27","first-page":"2002","volume":"29","author":"M Pfaffle","year":"2001","unstructured":"Pfaffle, M. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, 2002\u20132007 (2001).","journal-title":"Nucleic Acids Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64402-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64402-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64402-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T09:39:06Z","timestamp":1670319546000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64402-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,30]]},"references-count":27,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["64402"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-64402-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,30]]},"assertion":[{"value":"30 May 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 April 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7329"}}