{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T11:20:51Z","timestamp":1793532051462,"version":"4.5.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T00:00:00Z","timestamp":1676851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001691","name":"the Japan society for the promotion of science","doi-asserted-by":"crossref","award":["19K16659"],"award-info":[{"award-number":["19K16659"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"the Japan society for the promotion of science","doi-asserted-by":"crossref","award":["22K08614"],"award-info":[{"award-number":["22K08614"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"the Japan society for the promotion of science","doi-asserted-by":"crossref","award":["21K16329"],"award-info":[{"award-number":["21K16329"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Fatty acid\u2013binding protein 4 (FABP4) is a critical immune-metabolic modulator, mainly expressed in adipocytes and macrophages, secreted from adipocytes in association with lipolysis, and plays essential pathogenic roles in cardiovascular and metabolic diseases. We previously reported Chlamydia pneumoniae infecting murine 3T3-L1 adipocytes and causing lipolysis and FABP4 secretion in\u00a0vitro. However, it is still unknown whether C. pneumoniae intranasal lung infection targets white adipose tissues (WATs), induces lipolysis, and causes FABP4 secretion in\u00a0vivo. In this study, we demonstrate that C. pneumoniae lung infection causes robust lipolysis in WAT. Infection-induced WAT lipolysis was diminished in FABP4\u2212\/\u2212 mice or FABP4 inhibitor\u2013pretreated wild-type mice. Infection by C. pneumoniae in wild-type but not FABP4\u2212\/\u2212 mice induces the accumulation of TNF-\u03b1\u2013 and IL-6\u2013producing M1-like adipose tissue macrophages in WAT. Infection-induced WAT pathology is augmented by endoplasmic reticulum (ER) stress\/the unfolded protein response (UPR), which is abrogated by treatment with azoramide, a modulator of the UPR. C. pneumoniae lung infection is suggested to target WAT and induce lipolysis and FABP4 secretion in\u00a0vivo via ER stress\/UPR. FABP4 released from infected adipocytes may be taken up by other neighboring intact adipocytes or adipose tissue macrophages. This process can further induce ER stress activation and trigger lipolysis and inflammation, followed by FABP4 secretion, leading to WAT pathology. A better understanding of the role of FABP4 in C. pneumoniae infection\u2013induced WAT pathology will provide the basis for rational intervention measures directed at C. pneumoniae infection and metabolic syndrome, such as atherosclerosis, for which robust epidemiologic evidence exists.<\/jats:p>","DOI":"10.4049\/jimmunol.2200601","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T14:11:08Z","timestamp":1678284668000},"page":"1086-1097","source":"Crossref","is-referenced-by-count":9,"title":["<i>Chlamydia pneumoniae<\/i> Lung Infection in Mice Induces Fatty Acid\u2013Binding Protein 4\u2013Dependent White Adipose Tissue Pathology"],"prefix":"10.1093","volume":"210","author":[{"given":"Yusuke","family":"Kurihara","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University , Fukuoka,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3992-5604","authenticated-orcid":false,"given":"Nirwana Fitriani","family":"Walenna","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University , Fukuoka,","place":["Japan"]},{"name":"Department of Bacteriology, Graduate School of Medical Science, Kyushu University , Fukuoka,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8696-4959","authenticated-orcid":false,"given":"Kazunari","family":"Ishii","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University , Fukuoka,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshinori","family":"Soejima","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University , Fukuoka,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University , Fukuoka,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michinobu","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University , Fukuoka,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0616-0190","authenticated-orcid":false,"given":"Ryo","family":"Ozuru","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University , Fukuoka,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akinori","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University , Fukuoka,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9487-5566","authenticated-orcid":false,"given":"Ryota","family":"Itoh","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University , Fukuoka,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0145-3541","authenticated-orcid":false,"given":"Masato","family":"Furuhashi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine , Sapporo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6khan S","family":"Hotamisligil","sequence":"additional","affiliation":[{"name":"Sabri \u00dclker Center for Metabolic Research, Harvard T.H. Chan School of Public Health , Boston, MA"},{"name":"Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health , Boston, MA"},{"name":"Broad Institute of MIT and Harvard , Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3496-6087","authenticated-orcid":false,"given":"Kenji","family":"Hiromatsu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University , Fukuoka,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,2,20]]},"reference":[{"key":"2025021008032149600_r1","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1001\/jama.1943.02840030011003","article-title":"Insulin resistance due to infection in diabetes mellitus in man","volume":"121","author":"Greene","year":"1943","journal-title":"J. Am. Med. Assoc."},{"key":"2025021008032149600_r2","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/archinte.1932.00150190003001","article-title":"Decreased dextrose tolerance in acute infectious diseases","volume":"50","author":"Williams","year":"1932","journal-title":"Arch. Intern. Med."},{"key":"2025021008032149600_r3","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/nrmicro796","article-title":"Chlamydia pneumoniae\u2014an infectious risk factor for atherosclerosis?","volume":"2","author":"Campbell","year":"2004","journal-title":"Nat. Rev. Microbiol."},{"key":"2025021008032149600_r4","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.2337\/dc05-2068","article-title":"Burden of infection and insulin resistance in healthy middle-aged men","volume":"29","author":"Fern\u00e1ndez-Real","year":"2006","journal-title":"Diabetes Care"},{"key":"2025021008032149600_r5","doi-asserted-by":"crossref","first-page":"2724","DOI":"10.1001\/jama.288.21.2724","article-title":"Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease","volume":"288","author":"Kalayoglu","year":"2002","journal-title":"JAMA"},{"key":"2025021008032149600_r6","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1086\/599796","article-title":"Acute Chlamydia pneumoniae reinfection accelerates the development of insulin resistance and diabetes in obese C57BL\/6 mice","volume":"200","author":"Wang","year":"2009","journal-title":"J. Infect. Dis."},{"key":"2025021008032149600_r7","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1056\/NEJMe058019","article-title":"Infection, antibiotics, and atherothrombosis\u2014end of the road or new beginnings?","volume":"352","author":"Anderson","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"2025021008032149600_r8","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3389\/fcimb.2014.00034","article-title":"Persistent C. pneumoniae infection in atherosclerotic lesions: rethinking the clinical trials","volume":"4","author":"Campbell","year":"2014","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"2025021008032149600_r9","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1056\/NEJMoa043528","article-title":"Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome","volume":"352","author":"Cannon","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"2025021008032149600_r10","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1056\/NEJMoa043526","article-title":"Azithromycin for the secondary prevention of coronary events","volume":"352","author":"Grayston","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"2025021008032149600_r11","doi-asserted-by":"crossref","first-page":"e20201416","DOI":"10.1084\/jem.20201416","article-title":"Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance","volume":"218","author":"He","year":"2021","journal-title":"J. Exp. Med."},{"key":"2025021008032149600_r12","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.2174\/138161208784246153","article-title":"Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity","volume":"14","author":"Heilbronn","year":"2008","journal-title":"Curr. Pharm. Des."},{"key":"2025021008032149600_r13","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/nrendo.2017.90","article-title":"Adapting to obesity with adipose tissue inflammation","volume":"13","author":"Reilly","year":"2017","journal-title":"Nat. Rev. Endocrinol."},{"key":"2025021008032149600_r14","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1100\/2011\/397971","article-title":"Macrophages, meta-inflammation, and immuno-metabolism","volume":"11","author":"Shapiro","year":"2011","journal-title":"ScientificWorldJournal"},{"key":"2025021008032149600_r15","doi-asserted-by":"crossref","first-page":"216","DOI":"10.5551\/jat.48710","article-title":"Fatty acid-binding protein 4 in cardiovascular and metabolic diseases","volume":"26","author":"Furuhashi","year":"2019","journal-title":"J. Atheroscler. Thromb."},{"key":"2025021008032149600_r16","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1038\/nrendo.2015.122","article-title":"Metabolic functions of FABPs\u2014mechanisms and therapeutic implications","volume":"11","author":"Hotamisligil","year":"2015","journal-title":"Nat. Rev. Endocrinol."},{"key":"2025021008032149600_r17","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1194\/jlr.S091793","article-title":"Adipokine FABP4 integrates energy stores and counterregulatory metabolic responses","volume":"60","author":"Prentice","year":"2019","journal-title":"J. Lipid Res."},{"key":"2025021008032149600_r18","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1038\/s41586-021-04137-3","article-title":"A hormone complex of FABP4 and nucleoside kinases regulates islet function","volume":"600","author":"Prentice","year":"2021","journal-title":"Nature"},{"key":"2025021008032149600_r19","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1038\/nature05844","article-title":"Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2","volume":"447","author":"Furuhashi","year":"2007","journal-title":"Nature"},{"key":"2025021008032149600_r20","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.2337\/diabetes.48.10.1987","article-title":"Altered insulin secretion associated with reduced lipolytic efficiency in aP2\u2212\/\u2212 mice","volume":"48","author":"Scheja","year":"1999","journal-title":"Diabetes"},{"key":"2025021008032149600_r21","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1038\/ng.3943","article-title":"Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease","volume":"49","author":"Zhao","year":"2017","journal-title":"Nat. Genet."},{"key":"2025021008032149600_r22","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.bbrc.2017.11.005","article-title":"Chlamydia pneumoniae exploits adipocyte lipid chaperone FABP4 to facilitate fat mobilization and intracellular growth in murine adipocytes","volume":"495","author":"Walenna","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025021008032149600_r23","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1074\/jbc.RA119.010683","article-title":"Chlamydia pneumoniae infection-induced endoplasmic reticulum stress causes fatty acid-binding protein 4 secretion in murine adipocytes","volume":"295","author":"Walenna","year":"2020","journal-title":"J. Biol. Chem."},{"key":"2025021008032149600_r24","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1126\/science.274.5291.1377","article-title":"Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein","volume":"274","author":"Hotamisligil","year":"1996","journal-title":"Science"},{"key":"2025021008032149600_r25","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.bbrc.2014.08.128","article-title":"Chlamydia pneumoniae harness host NLRP3 inflammasome-mediated caspase-1 activation for optimal intracellular growth in murine macrophages","volume":"452","author":"Itoh","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025021008032149600_r26","doi-asserted-by":"crossref","first-page":"e0233152","DOI":"10.1371\/journal.pone.0233152","article-title":"Examination of ex-vivo viability of human adipose tissue slice culture","volume":"15","author":"Schopow","year":"2020","journal-title":"PLoS One"},{"key":"2025021008032149600_r27","doi-asserted-by":"crossref","first-page":"292ra98","DOI":"10.1126\/scitranslmed.aaa9134","article-title":"Phenotypic assays identify azoramide as a small-molecule modulator of the unfolded protein response with antidiabetic activity","volume":"7","author":"Fu","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"2025021008032149600_r28","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1038\/nm.2067","article-title":"Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. [Published erratum appears in 2010 Nat. Med. 16: 237.]","volume":"15","author":"Erbay","year":"2009","journal-title":"Nat. Med."},{"key":"2025021008032149600_r29","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/sj.gene.6364285","article-title":"Genetic analysis of susceptibility to Chlamydia trachomatis in mouse","volume":"7","author":"Bernstein-Hanley","year":"2006","journal-title":"Genes Immun."},{"key":"2025021008032149600_r30","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1038\/ncb2865","article-title":"A CREB3-ARF4 signalling pathway mediates the response to Golgi stress and susceptibility to pathogens","volume":"15","author":"Reiling","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"2025021008032149600_r31","first-page":"2640","article-title":"Adipocyte\/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice","volume":"118","author":"Furuhashi","year":"2008","journal-title":"J. Clin. Invest."},{"key":"2025021008032149600_r32","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1111\/jcmm.12384","article-title":"Endoplasmic reticulum stress in adipose tissue augments lipolysis","volume":"19","author":"Bogdanovic","year":"2015","journal-title":"J. Cell. Mol. Med."},{"key":"2025021008032149600_r33","doi-asserted-by":"crossref","first-page":"6240","DOI":"10.1074\/jbc.M111.299115","article-title":"Lipolysis response to endoplasmic reticulum stress in adipose cells","volume":"287","author":"Deng","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2025021008032149600_r34","doi-asserted-by":"crossref","first-page":"100440","DOI":"10.1016\/j.jbc.2021.100440","article-title":"Inflammation promotes adipocyte lipolysis via IRE1 kinase","volume":"296","author":"Foley","year":"2021","journal-title":"J. Biol. Chem."},{"key":"2025021008032149600_r35","doi-asserted-by":"crossref","first-page":"C822","DOI":"10.1152\/ajpcell.00519.2020","article-title":"In vitro and ex vivo models of adipocytes","volume":"320","author":"Dufau","year":"2021","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"2025021008032149600_r36","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1007\/s12020-019-02157-8","article-title":"Exogenous FABP4 interferes with differentiation, promotes lipolysis and inflammation in adipocytes","volume":"67","author":"Dou","year":"2020","journal-title":"Endocrine"},{"key":"2025021008032149600_r37","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1126\/science.1128294","article-title":"Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes","volume":"313","author":"Ozcan","year":"2006","journal-title":"Science"},{"key":"2025021008032149600_r38","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1172\/JCI29881","article-title":"Obesity induces a phenotypic switch in adipose tissue macrophage polarization","volume":"117","author":"Lumeng","year":"2007","journal-title":"J. Clin. Invest."},{"key":"2025021008032149600_r39","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.atherosclerosis.2016.04.012","article-title":"Exogenous FABP4 induces endoplasmic reticulum stress in HepG2 liver cells","volume":"249","author":"Bosquet","year":"2016","journal-title":"Atherosclerosis"},{"key":"2025021008032149600_r40","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/ni.3709","article-title":"The metabolic ER stress sensor IRE1\u03b1 suppresses alternative activation of macrophages and impairs energy expenditure in obesity","volume":"18","author":"Shan","year":"2017","journal-title":"Nat. Immunol."},{"key":"2025021008032149600_r41","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.cellimm.2018.12.008","article-title":"ER-stress regulates macrophage polarization through pancreatic EIF-2alpha kinase","volume":"336","author":"Yang","year":"2019","journal-title":"Cell. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/210\/8\/1086\/61469729\/ji2200601.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/210\/8\/1086\/61469729\/ji2200601.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T08:07:25Z","timestamp":1739174845000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/210\/8\/1086\/7932639"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,20]]},"references-count":41,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2023,4,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.2200601","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,4]]},"published":{"date-parts":[[2023,2,20]]}}}