{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:56:31Z","timestamp":1760241391387,"version":"build-2065373602"},"reference-count":46,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,2,8]],"date-time":"2018-02-08T00:00:00Z","timestamp":1518048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DK035816","HL092969","HL88420"],"award-info":[{"award-number":["DK035816","HL092969","HL88420"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Obesity is a chronic inflammatory state characterized by altered levels of adipose tissue immune cell populations. Natural killer T (NKT) cells are CD1d restricted lymphocyte subsets that recognize lipid antigens whose level decreases in obese adipose tissue. However, studies in mice with deficiency or increased levels of NKT cells have yielded contradictory results, so the exact role of these cells in obesity and adipose tissue inflammation is not yet established. We previously showed that Ldlr\u2212\/\u2212 mice with excess invariant NKT (iNKT) cells demonstrate significant weight gain, adiposity, metabolic abnormalities, and atherosclerosis. The current study evaluates the effects of NKT cell deficiency on obesity, associated metabolic changes, and atherosclerosis in J\u03b118\u2212\/\u2212Ldlr\u2212\/\u2212 (lacking iNKT cells) and Cd1d\u2212\/\u2212Ldlr\u2212\/\u2212 (lacking invariant and type II NKT cells) mice, and control mice were fed an obesogenic diet (high fat, sucrose, cholesterol) for 16 weeks. Contrary to expectations, Ja18\u2212\/\u2212Ldlr\u2212\/\u2212 mice gained significantly more weight than Ldlr\u2212\/\u2212 or Cd1d\u2212\/\u2212Ldlr\u2212\/\u2212 mice, developed hypertriglyceridemia, and had worsened adipose tissue inflammation. All the mice developed insulin resistance and hepatic triglyceride accumulation. Ja18\u2212\/\u2212Ldlr\u2212\/\u2212 mice also had increased atherosclerotic lesion area. Our findings suggest that iNKT cells exacerbates the metabolic, inflammatory, and atherosclerotic features of diet-induced obesity. Further work is required to unravel the paradox of an apparently similar effect of iNKT cell surplus and depletion on obesity.<\/jats:p>","DOI":"10.3390\/ijms19020510","type":"journal-article","created":{"date-parts":[[2018,2,9]],"date-time":"2018-02-09T12:46:27Z","timestamp":1518180387000},"page":"510","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Deficiency of Invariant Natural Killer T Cells Does Not Protect Against Obesity but Exacerbates Atherosclerosis in Ldlr\u2212\/\u2212 Mice"],"prefix":"10.3390","volume":"19","author":[{"given":"Savitha","family":"Subramanian","sequence":"first","affiliation":[{"name":"Diabetes Obesity Center for Excellence, Division of Metabolism, Endocrinology and Nutrition, University of Washington, 850 Republican Street Box 35805, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leela","family":"Goodspeed","sequence":"additional","affiliation":[{"name":"Diabetes Obesity Center for Excellence, Division of Metabolism, Endocrinology and Nutrition, University of Washington, 850 Republican Street Box 35805, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shari","family":"Wang","sequence":"additional","affiliation":[{"name":"Diabetes Obesity Center for Excellence, Division of Metabolism, Endocrinology and Nutrition, University of Washington, 850 Republican Street Box 35805, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yilei","family":"Ding","sequence":"additional","affiliation":[{"name":"Diabetes Obesity Center for Excellence, Division of Metabolism, Endocrinology and Nutrition, University of Washington, 850 Republican Street Box 35805, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Division of Cardiology, University of Washington, Seattle, WA 98195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Godfrey","family":"Getz","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5903-2205","authenticated-orcid":false,"given":"Alan","family":"Chait","sequence":"additional","affiliation":[{"name":"Diabetes Obesity Center for Excellence, Division of Metabolism, Endocrinology and Nutrition, University of Washington, 850 Republican Street Box 35805, Seattle, WA 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Reardon","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1038\/ni.2683","article-title":"Regulatory T cells in nonlymphoid tissues","volume":"14","author":"Burzyn","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.cmet.2013.05.008","article-title":"Immunological goings-on in visceral adipose tissue","volume":"17","author":"Mathis","year":"2013","journal-title":"Cell Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.tem.2012.05.011","article-title":"Adipose tissue-resident immune cells: Key players in immunometabolism","volume":"23","author":"Schipper","year":"2012","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.cell.2015.02.022","article-title":"Immune regulation of metabolic homeostasis in health and disease","volume":"161","author":"Brestoff","year":"2015","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1172\/JCI88876","article-title":"Role of innate and adaptive immunity in obesity-associated metabolic disease","volume":"127","author":"McLaughlin","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"229","DOI":"10.4093\/dmj.2017.41.4.229","article-title":"Unusual suspects in the development of obesity-induced inflammation and insulin resistance: NK cells, iNKT cells, and ILCs","volume":"41","author":"Bonamichi","year":"2017","journal-title":"Diabetes Metab. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nri3369","article-title":"Invariant natural killer T cells: An innate activation scheme linked to diverse effector functions","volume":"13","author":"Brennan","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.it.2012.08.009","article-title":"Invariant natural killer T cells as sensors and managers of inflammation","volume":"34","author":"Parekh","year":"2013","journal-title":"Trends Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1146\/annurev.immunol.25.022106.141711","article-title":"The biology of NKT cells","volume":"25","author":"Bendelac","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nri3328","article-title":"Recognition of CD1d-restricted antigens by natural killer t cells","volume":"12","author":"Rossjohn","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1128\/MCB.00552-12","article-title":"A novel function of adipocytes in lipid antigen presentation to iNKT cells","volume":"33","author":"Huh","year":"2013","journal-title":"Mol. Cell. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"28473","DOI":"10.1038\/srep28473","article-title":"Adipocyte-specific Cd1d-deficiency mitigates diet-induced obesity and insulin resistance in mice","volume":"6","author":"Satoh","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.molimm.2015.06.009","article-title":"Endogenous ligands of natural killer T cells are alpha-linked glycosylceramides","volume":"68","author":"Kain","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13433","DOI":"10.1073\/pnas.1415357111","article-title":"Activation of iNKT cells by a distinct constituent of the endogenous glucosylceramide fraction","volume":"111","author":"Brennan","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.4049\/jimmunol.1501019","article-title":"Identification of a potent microbial lipid antigen for diverse NKT cells","volume":"195","author":"Wolf","year":"2015","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.immuni.2012.06.016","article-title":"Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production","volume":"37","author":"Lynch","year":"2012","journal-title":"Immunity"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1194\/jlr.M041020","article-title":"Increased levels of invariant natural killer T lymphocytes worsen metabolic abnormalities and atherosclerosis in obese mice","volume":"54","author":"Subramanian","year":"2013","journal-title":"J. Lipid Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1002\/eji.200939349","article-title":"Invariant NKT cells and CD1d(+) cells amass in human omentum and are depleted in patients with cancer and obesity","volume":"39","author":"Lynch","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"E1143","DOI":"10.1073\/pnas.1200498109","article-title":"Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice","volume":"109","author":"Wu","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/ni.3047","article-title":"Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of T(reg) cells and macrophages in adipose tissue","volume":"16","author":"Lynch","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3725","DOI":"10.1172\/JCI72308","article-title":"IL-10-producing NKT10 cells are a distinct regulatory invariant nkt cell subset","volume":"124","author":"Sag","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kotas, M.E., Lee, H.Y., Gillum, M.P., Annicelli, C., Guigni, B.A., Shulman, G.I., and Medzhitov, R. (2011). Impact of CD1d deficiency on metabolism. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025478"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.1172\/JCI62739","article-title":"Natural killer T cells in adipose tissue prevent insulin resistance","volume":"122","author":"Schipper","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Satoh, M., Andoh, Y., Clingan, C.S., Ogura, H., Fujii, S., Eshima, K., Nakayama, T., Taniguchi, M., Hirata, N., and Ishimori, N. (2012). Type II NKT cells stimulate diet-induced obesity by mediating adipose tissue inflammation, steatohepatitis and insulin resistance. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030568"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1161\/ATVBAHA.112.301105","article-title":"Lack of invariant natural killer T cells affects lipid metabolism in adipose tissue of diet-induced obese mice","volume":"33","author":"Strodthoff","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Mantell, B.S., Stefanovic-Racic, M., Yang, X., Dedousis, N., Sipula, I.J., and O\u2019Doherty, R.M. (2011). Mice lacking NKT cells but with a complete complement of CD8+ T-cells are not protected against the metabolic abnormalities of diet-induced obesity. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019831"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Martin-Murphy, B.V., You, Q., Wang, H., de La Houssaye, B.A., Reilly, T.P., Friedman, J.E., and Ju, C. (2014). Mice lacking natural killer T cells are more susceptible to metabolic alterations following high fat diet feeding. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0080949"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"R41","DOI":"10.1530\/JOE-13-0516","article-title":"Interplay between the immune system and adipose tissue in obesity","volume":"223","author":"Exley","year":"2014","journal-title":"J. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1161\/ATVBAHA.107.157685","article-title":"Dietary cholesterol worsens adipose tissue macrophage accumulation and atherosclerosis in obese LDL receptor-deficient mice","volume":"28","author":"Subramanian","year":"2008","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.2353\/ajpath.2007.060188","article-title":"Characterization of the natural killer T-cell response in an adoptive transfer model of atherosclerosis","volume":"170","author":"VanderLaan","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2351","DOI":"10.1161\/01.ATV.0000147112.84168.87","article-title":"Quantitative and qualitative differences in proatherogenic NKT cells in apolipoprotein E-deficient mice","volume":"24","author":"Major","year":"2004","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1084\/jem.20030997","article-title":"CD1d-dependent activation of NKT cells aggravates atherosclerosis","volume":"199","author":"Tupin","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1182\/blood-2003-10-3485","article-title":"Natural killer T cells accelerate atherogenesis in mice","volume":"104","author":"Nakai","year":"2004","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1161\/01.ATV.0000153046.59370.13","article-title":"Transient role for CD1d-restricted natural killer T cells in the formation of atherosclerotic lesions","volume":"25","author":"Aslanian","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1093\/cvr\/cvn005","article-title":"Deficiency of invariant Valpha 14 natural killer T cells decreases atherosclerosis in LDL receptor null mice","volume":"78","author":"Rogers","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1038\/nm.2002","article-title":"Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters","volume":"15","author":"Feuerer","year":"2009","journal-title":"Nat. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Deiuliis, J., Shah, Z., Shah, N., Needleman, B., Mikami, D., Narula, V., Perry, K., Hazey, J., Kampfrath, T., and Kollengode, M. (2011). Visceral adipose inflammation in obesity is associated with critical alterations in Tregulatory cell numbers. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016376"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/ni.3203","article-title":"A new mouse strain for the analysis of invariant NKT cell function","volume":"16","author":"Chandra","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1241214","DOI":"10.1126\/science.1241214","article-title":"Gut microbiota from twins discordant for obesity modulate metabolism in mice","volume":"341","author":"Ridaura","year":"2013","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3341","DOI":"10.2337\/db13-0844","article-title":"Assessing the human gut microbiota in metabolic diseases","volume":"62","author":"Karlsson","year":"2013","journal-title":"Diabetes"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1172\/JCI36509","article-title":"CD1d-dependent regulation of bacterial colonization in the intestine of mice","volume":"119","author":"Nieuwenhuis","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1161\/CIRCRESAHA.108.182998","article-title":"Proinflammatory phenotype of perivascular adipocytes: Influence of high-fat feeding","volume":"104","author":"Chatterjee","year":"2009","journal-title":"Circ. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.atherosclerosis.2011.07.012","article-title":"Perivascular visceral adipose tissue induces atherosclerosis in apolipoprotein E deficient mice","volume":"219","author":"Ohman","year":"2011","journal-title":"Atherosclerosis"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1161\/ATVBAHA.114.303029","article-title":"Perivascular adipose tissue in vascular function and disease: A review of current research and animal models","volume":"34","author":"Brown","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A simple method for the isolation and purification of total lipides from animal tissues","volume":"226","author":"Folch","year":"1957","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1161\/01.CIR.0000136819.93989.E1","article-title":"Increase in serum amyloid A evoked by dietary cholesterol is associated with increased atherosclerosis in mice","volume":"110","author":"Lewis","year":"2004","journal-title":"Circulation"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/2\/510\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:54:14Z","timestamp":1760194454000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/2\/510"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,8]]},"references-count":46,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2018,2]]}},"alternative-id":["ijms19020510"],"URL":"https:\/\/doi.org\/10.3390\/ijms19020510","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2018,2,8]]}}}