{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T21:16:29Z","timestamp":1792185389775,"version":"4.4.0"},"reference-count":43,"publisher":"American Diabetes Association","issue":"1","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,1,1]]},"abstract":"<jats:p>Obesity-related insulin resistance is associated with an influx of pathogenic T cells into visceral adipose tissue (VAT), but the mechanisms regulating lymphocyte balance in such tissues are unknown. Here we describe an important role for the immune cytotoxic effector molecule perforin in regulating this process. Perforin-deficient mice (Prf1null) show early increased body weight and adiposity, glucose intolerance, and insulin resistance when placed on high-fat diet (HFD). Regulatory effects of perforin on glucose tolerance are mechanistically linked to the control of T-cell proliferation and cytokine production in inflamed VAT. HFD-fed Prf1null mice have increased accumulation of proinflammatory IFN-\u03b3\u2013producing CD4+ and CD8+ T cells and M1-polarized macrophages in VAT. CD8+ T cells from the VAT of Prf1null mice have increased proliferation and impaired early apoptosis, suggesting a role for perforin in the regulation of T-cell turnover during HFD feeding. Transfer of CD8+ T cells from Prf1null mice into CD8-deficient mice (CD8null) resulted in worsening of metabolic parameters compared with wild-type donors. Improved metabolic parameters in HFD natural killer (NK) cell\u2013deficient mice (NKnull) ruled out a role for NK cells as a single source of perforin in regulating glucose homeostasis. The findings support the importance of T-cell function in insulin resistance and suggest that modulation of lymphocyte homeostasis in inflamed VAT is one possible avenue for therapeutic intervention.<\/jats:p>","DOI":"10.2337\/db13-1524","type":"journal-article","created":{"date-parts":[[2014,7,22]],"date-time":"2014-07-22T01:32:56Z","timestamp":1405992776000},"page":"90-103","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":57,"title":["Perforin Is a Novel Immune Regulator of Obesity-Related Insulin Resistance"],"prefix":"10.2337","volume":"64","author":[{"given":"Xavier S.","family":"Revelo","sequence":"first","affiliation":[{"name":"Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue","family":"Tsai","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Lei","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Luck","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magar","family":"Ghazarian","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert","family":"Tsui","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally Y.","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Schroer","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia T.","family":"Luk","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria H.Y.","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tak W.","family":"Mak","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minna","family":"Woo","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada"},{"name":"Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn","family":"Winer","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada"},{"name":"Department of Pathology, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Winer","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada"},{"name":"Department of Pathology, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2014,7,21]]},"reference":[{"key":"2022031223031800300_B1","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/nm.2627","article-title":"The cellular and signaling networks linking the immune system and metabolism in disease","volume":"18","author":"Osborn","year":"2012","journal-title":"Nat Med"},{"key":"2022031223031800300_B2","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.cell.2013.01.041","article-title":"The origins and drivers of insulin resistance","volume":"152","author":"Johnson","year":"2013","journal-title":"Cell"},{"key":"2022031223031800300_B3","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1146\/annurev-physiol-021909-135846","article-title":"Macrophages, inflammation, and insulin resistance","volume":"72","author":"Olefsky","year":"2010","journal-title":"Annu Rev Physiol"},{"key":"2022031223031800300_B4","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"},{"key":"2022031223031800300_B5","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"},{"key":"2022031223031800300_B6","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":"2022031223031800300_B7","doi-asserted-by":"crossref","first-page":"16","DOI":"10.2337\/db06-1076","article-title":"Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity","volume":"56","author":"Lumeng","year":"2007","journal-title":"Diabetes"},{"key":"2022031223031800300_B8","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1038\/nm.1994","article-title":"Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice","volume":"15","author":"Liu","year":"2009","journal-title":"Nat Med"},{"key":"2022031223031800300_B9","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1194\/jlr.M800132-JLR200","article-title":"Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding","volume":"49","author":"Elgazar-Carmon","year":"2008","journal-title":"J Lipid Res"},{"key":"2022031223031800300_B10","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1038\/nm.2885","article-title":"Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase","volume":"18","author":"Talukdar","year":"2012","journal-title":"Nat Med"},{"key":"2022031223031800300_B11","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1038\/nm.2001","article-title":"Normalization of obesity-associated insulin resistance through immunotherapy","volume":"15","author":"Winer","year":"2009","journal-title":"Nat Med"},{"key":"2022031223031800300_B12","first-page":"366","article-title":"Association between specific adipose tissue CD4+ T-cell populations and insulin resistance in obese individuals","volume-title":"Gastroenterology","author":"Fabbrini","year":"2013"},{"key":"2022031223031800300_B13","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/nm.1964","article-title":"CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity","volume":"15","author":"Nishimura","year":"2009","journal-title":"Nat Med"},{"key":"2022031223031800300_B14","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/nm.2353","article-title":"B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies","volume":"17","author":"Winer","year":"2011","journal-title":"Nat Med"},{"key":"2022031223031800300_B15","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.4049\/jimmunol.1000021","article-title":"Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance","volume":"185","author":"Yang","year":"2010","journal-title":"J Immunol"},{"key":"2022031223031800300_B16","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1038\/nri1983","article-title":"Perforin-mediated target-cell death and immune homeostasis","volume":"6","author":"Voskoboinik","year":"2006","journal-title":"Nat Rev Immunol"},{"key":"2022031223031800300_B17","doi-asserted-by":"crossref","first-page":"3262","DOI":"10.1002\/(SICI)1521-4141(199910)29:10<3262::AID-IMMU3262>3.0.CO;2-A","article-title":"Homeostatic regulation of CD8+ T cells by perforin","volume":"29","author":"K\u00e4gi","year":"1999","journal-title":"Eur J Immunol"},{"key":"2022031223031800300_B18","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1146\/annurev-med-041610-134208","article-title":"Familial and acquired hemophagocytic lymphohistiocytosis","volume":"63","author":"Janka","year":"2012","journal-title":"Annu Rev Med"},{"key":"2022031223031800300_B19","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1182\/blood-2011-06-363994","article-title":"Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation","volume":"119","author":"Chen","year":"2012","journal-title":"Blood"},{"key":"2022031223031800300_B20","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1182\/blood-2010-12-324533","article-title":"Perforin is a critical physiologic regulator of T-cell activation","volume":"118","author":"Lykens","year":"2011","journal-title":"Blood"},{"key":"2022031223031800300_B21","doi-asserted-by":"crossref","first-page":"5184","DOI":"10.1182\/blood-2013-04-495309","article-title":"Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8(+) T cells and dendritic cells","volume":"121","author":"Terrell","year":"2013","journal-title":"Blood"},{"key":"2022031223031800300_B22","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1073\/pnas.0509054103","article-title":"Perforin-dependent elimination of dendritic cells regulates the expansion of antigen-specific CD8+ T cells in vivo","volume":"103","author":"Yang","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031223031800300_B23","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nmeth.1806","article-title":"A guide to analysis of mouse energy metabolism","volume":"9","author":"Tsch\u00f6p","year":"2012","journal-title":"Nat Methods"},{"key":"2022031223031800300_B24","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1194\/jlr.M500294-JLR200","article-title":"Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans","volume":"46","author":"Cinti","year":"2005","journal-title":"J Lipid Res"},{"key":"2022031223031800300_B25","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1084\/jem.183.5.2143","article-title":"Development of insulitis without diabetes in transgenic mice lacking perforin-dependent cytotoxicity","volume":"183","author":"K\u00e4gi","year":"1996","journal-title":"J Exp Med"},{"key":"2022031223031800300_B26","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.4049\/jimmunol.170.4.2221","article-title":"Perforin-dependent brain-infiltrating cytotoxic CD8+ T lymphocytes mediate experimental cerebral malaria pathogenesis","volume":"170","author":"Nitcheu","year":"2003","journal-title":"J Immunol"},{"key":"2022031223031800300_B27","first-page":"229","article-title":"Reduction of viral myocarditis in mice lacking perforin","volume":"110","author":"Koike","year":"2001","journal-title":"Res Commun Mol Pathol Pharmacol"},{"key":"2022031223031800300_B28","first-page":"1799","article-title":"Expression of granzyme B in human articular chondrocytes","volume":"30","author":"Horiuchi","year":"2003","journal-title":"J Rheumatol"},{"key":"2022031223031800300_B29","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1172\/JCI200422422","article-title":"Molecular mediators of hepatic steatosis and liver injury","volume":"114","author":"Browning","year":"2004","journal-title":"J Clin Invest"},{"key":"2022031223031800300_B30","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1182\/blood-2003-01-0183","article-title":"IL-15 induces antigen-independent expansion and differentiation of human naive CD8+ T cells in vitro","volume":"102","author":"Alves","year":"2003","journal-title":"Blood"},{"key":"2022031223031800300_B31","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1084\/jem.180.4.1395","article-title":"Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor","volume":"180","author":"Carson","year":"1994","journal-title":"J Exp Med"},{"key":"2022031223031800300_B32","doi-asserted-by":"crossref","first-page":"e39553","DOI":"10.1371\/journal.pone.0039553","article-title":"Interleukin-15 treatment induces weight loss independent of lymphocytes","volume":"7","author":"Barra","year":"2012","journal-title":"PLoS ONE"},{"key":"2022031223031800300_B33","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":"2022031223031800300_B34","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/nri911","article-title":"Functional significance of the perforin\/granzyme cell death pathway","volume":"2","author":"Trapani","year":"2002","journal-title":"Nat Rev Immunol"},{"key":"2022031223031800300_B35","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1161\/ATVBAHA.113.302077","article-title":"Essential role of CD11a in CD8+ T-cell accumulation and activation in adipose tissue","volume":"34","author":"Jiang","year":"2014","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2022031223031800300_B36","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1172\/JCI6266","article-title":"Perforin-independent beta-cell destruction by diabetogenic CD8(+) T lymphocytes in transgenic nonobese diabetic mice","volume":"103","author":"Amrani","year":"1999","journal-title":"J Clin Invest"},{"key":"2022031223031800300_B37","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1172\/JCI38388","article-title":"Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice","volume":"120","author":"Wueest","year":"2010","journal-title":"J Clin Invest"},{"key":"2022031223031800300_B38","doi-asserted-by":"crossref","first-page":"3428","DOI":"10.1074\/jbc.M109.074252","article-title":"Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis","volume":"285","author":"Alkhouri","year":"2010","journal-title":"J Biol Chem"},{"key":"2022031223031800300_B39","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1194\/jlr.M038638","article-title":"Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis","volume":"54","author":"Giordano","year":"2013","journal-title":"J Lipid Res"},{"key":"2022031223031800300_B40","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/369031a0","article-title":"Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice","volume":"369","author":"K\u00e4gi","year":"1994","journal-title":"Nature"},{"key":"2022031223031800300_B41","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1038\/ni.1787","article-title":"The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development","volume":"10","author":"Gascoyne","year":"2009","journal-title":"Nat Immunol"},{"key":"2022031223031800300_B42","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1258\/ebm.2012.011272","article-title":"High frequency of activated natural killer and natural killer T-cells in patients with new onset of type 2 diabetes mellitus","volume":"237","author":"Guo","year":"2012","journal-title":"Exp Biol Med (Maywood)"},{"key":"2022031223031800300_B43","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/ijo.2009.133","article-title":"Depot-specific differences in inflammatory mediators and a role for NK cells and IFN-gamma in inflammation in human adipose tissue","volume":"33","author":"O\u2019Rourke","year":"2009","journal-title":"Int J Obes (Lond)"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/64\/1\/90\/577668\/90.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/64\/1\/90\/577668\/90.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:39:12Z","timestamp":1667407152000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/64\/1\/90\/34690\/Perforin-Is-a-Novel-Immune-Regulator-of-Obesity"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,7,21]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2014,7,21]]},"published-print":{"date-parts":[[2015,1,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db13-1524","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,7,21]]}}}