{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T16:08:51Z","timestamp":1790438931306,"version":"4.1.0"},"reference-count":66,"publisher":"The Endocrine Society","issue":"6","license":[{"start":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T00:00:00Z","timestamp":1616630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Grant-in-Aid for Scientific Research","award":["19K11764"],"award-info":[{"award-number":["19K11764"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The CX3CL1-CX3CR1 system plays an important role in disease progression by regulating inflammation both positively and negatively. We reported previously that C-C chemokine receptors 2 and 5 promote obesity-associated adipose tissue inflammation and insulin resistance. Here, we demonstrate that CX3CL1-CX3CR1 signaling is involved in adipose tissue inflammation and insulin resistance in obese mice via adipose tissue macrophage recruitment and M1\/M2 polarization. Cx3cl1 expression was persistently decreased in the epididymal white adipose tissue (eWAT) of high-fat diet-induced obese (DIO) mice, despite increased expression of other chemokines. Interestingly, in Cx3cr1\u2212\/\u2212 mice, glucose tolerance, insulin resistance, and hepatic steatosis induced by DIO or leptin deficiency were exacerbated. CX3CL1-CX3CR1 signaling deficiency resulted in reduced M2-polarized macrophage migration and an M1-dominant shift of macrophages within eWAT. Furthermore, transplantation of Cx3cr1\u2212\/\u2212 bone marrow was sufficient to impair glucose tolerance, insulin sensitivity, and regulation of M1\/M2 status. Moreover, Cx3cl1 administration in vivo led to the attenuation of glucose intolerance and insulin resistance. Thus, therapy targeting the CX3CL1-CX3CR1 system may be beneficial in the treatment of type 2 diabetes by regulating M1\/M2 macrophages.<\/jats:p>","DOI":"10.1210\/endocr\/bqab064","type":"journal-article","created":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T22:20:05Z","timestamp":1616710805000},"source":"Crossref","is-referenced-by-count":37,"title":["CX3CL1-CX3CR1 Signaling Deficiency Exacerbates Obesity-induced Inflammation and Insulin Resistance in Male Mice"],"prefix":"10.1210","volume":"162","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2714-6395","authenticated-orcid":false,"given":"Mayumi","family":"Nagashimada","sequence":"first","affiliation":[{"name":"Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Japan"},{"name":"Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Sawamoto","sequence":"additional","affiliation":[{"name":"Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinhua","family":"Ni","sequence":"additional","affiliation":[{"name":"Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Japan"},{"name":"College of Biological Engineering, Zhejiang University of Technology, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Kitade","sequence":"additional","affiliation":[{"name":"Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Nagata","sequence":"additional","affiliation":[{"name":"Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Xu","sequence":"additional","affiliation":[{"name":"Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masuko","family":"Kobori","sequence":"additional","affiliation":[{"name":"Food Research Institute, National Agriculture and Food Research Organization, Tsukuba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naofumi","family":"Mukaida","sequence":"additional","affiliation":[{"name":"Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichi","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuguhito","family":"Ota","sequence":"additional","affiliation":[{"name":"Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2021,3,25]]},"reference":[{"issue":"12","key":"2021121716530811400_OP-B1","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1172\/JCI200319451","article-title":"Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance","volume":"112","author":"Xu","year":"2003","journal-title":"J Clin Invest"},{"issue":"7121","key":"2021121716530811400_OP-B2","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature05485","article-title":"Inflammation and metabolic disorders","volume":"444","author":"Hotamisligil","year":"2006","journal-title":"Nature"},{"issue":"6","key":"2021121716530811400_OP-B3","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1172\/JCI26498","article-title":"MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity","volume":"116","author":"Kanda","year":"2006","journal-title":"J Clin Invest"},{"issue":"3","key":"2021121716530811400_OP-B4","doi-asserted-by":"crossref","first-page":"165","DOI":"10.4093\/dmj.2013.37.3.165","article-title":"Chemokine systems link obesity to insulin resistance","volume":"37","author":"Ota","year":"2013","journal-title":"Diabetes Metab J"},{"issue":"7","key":"2021121716530811400_OP-B5","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.2337\/db11-1506","article-title":"CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1\/M2 status","volume":"61","author":"Kitade","year":"2012","journal-title":"Diabetes"},{"issue":"2","key":"2021121716530811400_OP-B6","doi-asserted-by":"crossref","first-page":"99","DOI":"10.4161\/adip.22420","article-title":"CCR5: A novel player in the adipose tissue inflammation and insulin resistance?","volume":"2","author":"Ota","year":"2013","journal-title":"Adipocyte"},{"issue":"4","key":"2021121716530811400_OP-B7","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0092-8674(00)80438-9","article-title":"Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion","volume":"91","author":"Imai","year":"1997","journal-title":"Cell"},{"issue":"4","key":"2021121716530811400_OP-B8","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1182\/blood-2008-07-170787","article-title":"CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival","volume":"113","author":"Landsman","year":"2009","journal-title":"Blood"},{"issue":"8","key":"2021121716530811400_OP-B9","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1084\/jem.188.8.1413","article-title":"Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow","volume":"188","author":"Fong","year":"1998","journal-title":"J Exp Med"},{"issue":"11","key":"2021121716530811400_OP-B10","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1161\/ATVBAHA.107.161174","article-title":"Chemokines in atherosclerosis: an update","volume":"28","author":"Zernecke","year":"2008","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"1","key":"2021121716530811400_OP-B11","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1172\/JCI28549","article-title":"Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques","volume":"117","author":"Tacke","year":"2007","journal-title":"J Clin Invest"},{"issue":"7","key":"2021121716530811400_OP-B12","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1161\/01.CIR.0000057548.68243.42","article-title":"Decreased atherosclerotic lesion formation in CX3CR1\/apolipoprotein E double knockout mice","volume":"107","author":"Combadi\u00e8re","year":"2003","journal-title":"Circulation"},{"issue":"10","key":"2021121716530811400_OP-B13","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1038\/aps.2013.92","article-title":"Chemokines and atherosclerosis: focus on the CX3CL1\/CX3CR1 pathway","volume":"34","author":"Apostolakis","year":"2013","journal-title":"Acta Pharmacol Sin"},{"issue":"8","key":"2021121716530811400_OP-B14","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1172\/JCI16790","article-title":"Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans","volume":"111","author":"McDermott","year":"2003","journal-title":"J Clin Invest"},{"issue":"11","key":"2021121716530811400_OP-B15","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.1002\/art.10622","article-title":"Migration of CX3CR1-positive T cells producing type 1 cytokines and cytotoxic molecules into the synovium of patients with rheumatoid arthritis","volume":"46","author":"Nanki","year":"2002","journal-title":"Arthritis Rheum"},{"issue":"7","key":"2021121716530811400_OP-B16","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1002\/1529-0131(200107)44:7<1568::AID-ART280>3.0.CO;2-1","article-title":"Fractalkine, a novel chemokine in rheumatoid arthritis and in rat adjuvant-induced arthritis","volume":"44","author":"Ruth","year":"2001","journal-title":"Arthritis Rheum"},{"issue":"1","key":"2021121716530811400_OP-B17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/2050-7771-2-1","article-title":"Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases","volume":"2","author":"Yang","year":"2014","journal-title":"Biomark Res"},{"issue":"6372","key":"2021121716530811400_OP-B18","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1126\/science.aao1503","article-title":"CX3CR1+ mononuclear phagocytes control immunity to intestinal fungi","volume":"359","author":"Leonardi","year":"2018","journal-title":"Science"},{"issue":"12","key":"2021121716530811400_OP-B19","doi-asserted-by":"crossref","first-page":"4787","DOI":"10.1172\/JCI59150","article-title":"CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice","volume":"121","author":"Medina-Contreras","year":"2011","journal-title":"J Clin Invest"},{"issue":"2","key":"2021121716530811400_OP-B20","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.cell.2013.03.001","article-title":"The fractalkine\/CX3CR1 system regulates \u03b2 cell function and insulin secretion","volume":"153","author":"Lee","year":"2013","journal-title":"Cell"},{"key":"2021121716530811400_OP-B21","doi-asserted-by":"crossref","first-page":"14556","DOI":"10.1038\/ncomms14556","article-title":"Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice","volume":"8","author":"Dorfman","year":"2017","journal-title":"Nat Commun"},{"key":"2021121716530811400_OP-B22","doi-asserted-by":"crossref","DOI":"10.1016\/j.jid.2020.02.023","article-title":"Pivotal involvement of the CX3CL1-CX3CR1 axis for the recruitment of M2 tumor-associated macrophages in skin carcinogenesis","author":"Ishida","year":"2020","journal-title":"J Invest Dermatol"},{"issue":"6","key":"2021121716530811400_OP-B23","doi-asserted-by":"crossref","first-page":"4283","DOI":"10.4049\/jimmunol.180.6.4283","article-title":"Protective roles of the fractalkine\/CX3CL1-CX3CR1 interactions in alkali-induced corneal neovascularization through enhanced antiangiogenic factor expression","volume":"180","author":"Lu","year":"2008","journal-title":"J Immunol"},{"key":"2021121716530811400_OP-B24","doi-asserted-by":"crossref","first-page":"17192","DOI":"10.1038\/srep17192","article-title":"Astaxanthin prevents and reverses diet-induced insulin resistance and steatohepatitis in mice: a comparison with vitamin E","volume":"5","author":"Ni","year":"2015","journal-title":"Sci Rep"},{"issue":"3","key":"2021121716530811400_OP-B25","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1210\/en.2014-1776","article-title":"Prevention and reversal of lipotoxicity-induced hepatic insulin resistance and steatohepatitis in mice by an antioxidant carotenoid, \u03b2-cryptoxanthin","volume":"156","author":"Ni","year":"2015","journal-title":"Endocrinology"},{"key":"2021121716530811400_OP-B26"},{"key":"2021121716530811400_OP-B27"},{"key":"2021121716530811400_OP-B28"},{"key":"2021121716530811400_OP-B29"},{"key":"2021121716530811400_OP-B30"},{"key":"2021121716530811400_OP-B31"},{"key":"2021121716530811400_OP-B32"},{"key":"2021121716530811400_OP-B33"},{"key":"2021121716530811400_OP-B34"},{"key":"2021121716530811400_OP-B35"},{"key":"2021121716530811400_OP-B36"},{"key":"2021121716530811400_OP-B37"},{"key":"2021121716530811400_OP-B38"},{"key":"2021121716530811400_OP-B39"},{"key":"2021121716530811400_OP-B40"},{"key":"2021121716530811400_OP-B41"},{"issue":"12","key":"2021121716530811400_OP-B42","doi-asserted-by":"crossref","first-page":"3239","DOI":"10.2337\/db08-0872","article-title":"Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes","volume":"57","author":"Lumeng","year":"2008","journal-title":"Diabetes"},{"key":"2021121716530811400_OP-B43"},{"key":"2021121716530811400_OP-B44"},{"key":"2021121716530811400_OP-B45"},{"key":"2021121716530811400_OP-B46"},{"key":"2021121716530811400_OP-B47"},{"key":"2021121716530811400_OP-B48"},{"key":"2021121716530811400_OP-B49"},{"key":"2021121716530811400_OP-B50"},{"key":"2021121716530811400_OP-B51"},{"key":"2021121716530811400_OP-B52"},{"key":"2021121716530811400_OP-B53"},{"issue":"10","key":"2021121716530811400_OP-B54","doi-asserted-by":"crossref","first-page":"2966","DOI":"10.2337\/db16-0317","article-title":"DPP-4 inhibition by linagliptin attenuates obesity-related inflammation and insulin resistance by regulating M1\/M2 macrophage polarization","volume":"65","author":"Zhuge","year":"2016","journal-title":"Diabetes"},{"key":"2021121716530811400_OP-B55","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/B978-0-12-411619-1.00016-1","article-title":"Flow cytometry analyses of adipose tissue macrophages","volume":"537","author":"Cho","year":"2014","journal-title":"Methods Enzymol"},{"issue":"6","key":"2021121716530811400_OP-B56","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1002\/ijc.28779","article-title":"Crucial involvement of the CCL3-CCR5 axis-mediated fibroblast accumulation in colitis-associated carcinogenesis in mice","volume":"135","author":"Sasaki","year":"2014","journal-title":"Int J Cancer"},{"issue":"5","key":"2021121716530811400_OP-B57","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.2337\/db10-0956","article-title":"Fractalkine is a novel human adipochemokine associated with type 2 diabetes","volume":"60","author":"Shah","year":"2011","journal-title":"Diabetes"},{"issue":"1","key":"2021121716530811400_OP-B58","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/oby.2010.125","article-title":"Association of common polymorphisms in the fractalkine receptor (CX3CR1) with obesity","volume":"19","author":"Sirois-Gagnon","year":"2011","journal-title":"Obesity (Silver Spring)"},{"issue":"5461","key":"2021121716530811400_OP-B59","doi-asserted-by":"crossref","first-page":"2274","DOI":"10.1126\/science.287.5461.2274","article-title":"Rapid progression to AIDS in HIV+ individuals with a structural variant of the chemokine receptor CX3CR1","volume":"287","author":"Faure","year":"2000","journal-title":"Science"},{"issue":"12","key":"2021121716530811400_OP-B60","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1172\/JCI200319246","article-title":"Obesity is associated with macrophage accumulation in adipose tissue","volume":"112","author":"Weisberg","year":"2003","journal-title":"J Clin Invest"},{"issue":"1","key":"2021121716530811400_OP-B61","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S1074-7613(03)00174-2","article-title":"Blood monocytes consist of two principal subsets with distinct migratory properties","volume":"19","author":"Geissmann","year":"2003","journal-title":"Immunity"},{"issue":"5","key":"2021121716530811400_OP-B62","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/icb.2008.19","article-title":"Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T-cell responses","volume":"86","author":"Geissmann","year":"2008","journal-title":"Immunol Cell Biol"},{"key":"2021121716530811400_OP-B63","doi-asserted-by":"crossref","first-page":"514","DOI":"10.3389\/fimmu.2014.00514","article-title":"From monocytes to M1\/M2 macrophages: phenotypical vs. functional differentiation","volume":"5","author":"Italiani","year":"2014","journal-title":"Front Immunol"},{"issue":"6","key":"2021121716530811400_OP-B64","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1038\/oby.2012.7","article-title":"CX3CR1 deficiency does not influence trafficking of adipose tissue macrophages in mice with diet-induced obesity","volume":"20","author":"Morris","year":"2012","journal-title":"Obesity (Silver Spring)"},{"issue":"7","key":"2021121716530811400_OP-B65","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1038\/sj.gt.3300947","article-title":"Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA","volume":"6","author":"Liu","year":"1999","journal-title":"Gene Ther"},{"issue":"4","key":"2021121716530811400_OP-B66","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1172\/JCI94330","article-title":"Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function","volume":"128","author":"Riopel","year":"2018","journal-title":"J Clin Invest"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/advance-article-pdf\/doi\/10.1210\/endocr\/bqab064\/36730491\/bqab064.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/162\/6\/bqab064\/41809175\/bqab064.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/162\/6\/bqab064\/41809175\/bqab064.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T13:52:57Z","timestamp":1639749177000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/doi\/10.1210\/endocr\/bqab064\/6188411"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,25]]},"references-count":66,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,6,1]]}},"URL":"https:\/\/doi.org\/10.1210\/endocr\/bqab064","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,6,1]]},"published":{"date-parts":[[2021,3,25]]},"article-number":"bqab064"}}