{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:18:46Z","timestamp":1791951526785,"version":"4.3.4"},"reference-count":71,"publisher":"SAGE Publications","issue":"7","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antioxidants &amp; Redox Signaling"],"published-print":{"date-parts":[[2015,9]]},"abstract":"<jats:p>\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Aims:<\/jats:italic>\n                    <\/jats:bold>\n                    Obesity is characterized by a low-grade systemic inflammatory state and adipose tissue (AT) dysfunction, which predispose individuals to the development of insulin resistance (IR) and metabolic disease. However, a subset of obese individuals, referred to as metabolically healthy obese (MHO) individuals, are protected from obesity-associated metabolic abnormalities. Here, we aim at identifying molecular factors and pathways in adipocytes that are responsible for the progression from the insulin-sensitive to the insulin-resistant, metabolically unhealthy obese (MUHO) phenotype.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Results:<\/jats:italic>\n                    <\/jats:bold>\n                    Proteomic analysis of paired samples of adipocytes from subcutaneous (SC) and omental (OM) human AT revealed that both types of cells are altered in the MUHO state. Specifically, the glutathione redox cycle and other antioxidant defense systems as well as the protein-folding machinery were dysregulated and endoplasmic reticulum stress was increased in adipocytes from IR subjects. Moreover, proteasome activity was also compromised in adipocytes of MUHO individuals, which was associated with enhanced accumulation of oxidized and ubiquitinated proteins in these cells. Proteasome activity was also impaired in adipocytes of diet-induced obese mice and in 3T3-L1 adipocytes exposed to palmitate. In line with these data, proteasome inhibition significantly impaired insulin signaling in 3T3-L1 adipocytes.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Innovation:<\/jats:italic>\n                    <\/jats:bold>\n                    This study provides the first evidence of the occurrence of protein homeostasis deregulation in adipocytes in human obesity, which, together with oxidative damage, interferes with insulin signaling in these cells.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    <\/jats:bold>\n                    Our results suggest that proteasomal dysfunction and impaired proteostasis in adipocytes, resulting from protein oxidation and\/or misfolding, constitute major pathogenic mechanisms in the development of IR in obesity.\n                    <jats:italic toggle=\"yes\">Antioxid. Redox Signal<\/jats:italic>\n                    . 23, 597\u2013612.\n                  <\/jats:p>","DOI":"10.1089\/ars.2014.5939","type":"journal-article","created":{"date-parts":[[2015,2,25]],"date-time":"2015-02-25T11:47:31Z","timestamp":1424864851000},"page":"597-612","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":69,"title":["Proteasome Dysfunction Associated to Oxidative Stress and Proteotoxicity in Adipocytes Compromises Insulin Sensitivity in Human Obesity"],"prefix":"10.1177","volume":"23","author":[{"given":"Alberto","family":"D\u00edaz-Ruiz","sequence":"first","affiliation":[{"name":"Instituto Maim\u00f3nides de Investigaci\u00f3n Biom\u00e9dica (IMIBIC)\/Reina Sofia University Hospital\/University of C\u00f3rdoba","place":["Spain"]},{"name":"Instituto de Salud Carlos III","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roc\u00edo","family":"Guzm\u00e1n-Ruiz","sequence":"additional","affiliation":[{"name":"Instituto Maim\u00f3nides de Investigaci\u00f3n Biom\u00e9dica (IMIBIC)\/Reina Sofia University Hospital\/University of C\u00f3rdoba","place":["Spain"]},{"name":"Instituto de Salud Carlos III","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia R.","family":"Moreno","sequence":"additional","affiliation":[{"name":"Instituto Maim\u00f3nides de Investigaci\u00f3n Biom\u00e9dica (IMIBIC)\/Reina Sofia University Hospital\/University of C\u00f3rdoba","place":["Spain"]},{"name":"Instituto de Salud Carlos III","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Garc\u00eda-Rios","sequence":"additional","affiliation":[{"name":"Instituto de Salud Carlos III","place":["Spain"]},{"name":"IMIBIC\/Reina Sofia University Hospital\/University of C\u00f3rdoba","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nieves","family":"Delgado-Casado","sequence":"additional","affiliation":[{"name":"Instituto de Salud Carlos III","place":["Spain"]},{"name":"IMIBIC\/Reina Sofia University Hospital\/University of C\u00f3rdoba","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Membrives","sequence":"additional","affiliation":[{"name":"IMIBIC\/Reina Sofia University Hospital","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"T\u00fanez","sequence":"additional","affiliation":[{"name":"IMIBIC\/Reina Sofia University Hospital\/University of C\u00f3rdoba","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajaa","family":"El Bekay","sequence":"additional","affiliation":[{"name":"Instituto de Salud Carlos III","place":["Spain"]},{"name":"Hospital Virgen de la Victoria","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 M.","family":"Fern\u00e1ndez-Real","sequence":"additional","affiliation":[{"name":"Instituto de Salud Carlos III","place":["Spain"]},{"name":"Institut d'Investigaci\u00f3 Biom\u00e9dica de Girona (IdIBGi)","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sulay","family":"Tovar","sequence":"additional","affiliation":[{"name":"Instituto de Salud Carlos III","place":["Spain"]},{"name":"University of Santiago de Compostela","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Di\u00e9guez","sequence":"additional","affiliation":[{"name":"Instituto de Salud Carlos III","place":["Spain"]},{"name":"University of Santiago de Compostela","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"Tinahones","sequence":"additional","affiliation":[{"name":"Instituto de Salud Carlos III","place":["Spain"]},{"name":"Hospital Virgen de la Victoria","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"V\u00e1zquez-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Instituto Maim\u00f3nides de Investigaci\u00f3n Biom\u00e9dica (IMIBIC)\/Reina Sofia University Hospital\/University of C\u00f3rdoba","place":["Spain"]},{"name":"Instituto de Salud Carlos III","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"L\u00f3pez-Miranda","sequence":"additional","affiliation":[{"name":"Instituto de Salud Carlos III","place":["Spain"]},{"name":"IMIBIC\/Reina Sofia University Hospital\/University of C\u00f3rdoba","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda M.","family":"Malag\u00f3n","sequence":"additional","affiliation":[{"name":"Instituto Maim\u00f3nides de Investigaci\u00f3n Biom\u00e9dica (IMIBIC)\/Reina Sofia University Hospital\/University of C\u00f3rdoba","place":["Spain"]},{"name":"Instituto de Salud Carlos III","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2015,9,1]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.12.9047"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI58719"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M110.006924"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00110.2014"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc12-s064"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20100285"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M700198-MCP200"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2013.02.005"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-011-1211-9"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2014.5851"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.2008.01959.x"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a004374"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0705799105"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.2337\/db13-1383"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2012.05.008"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2011.08.001"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2012.10.004"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2010.03.019"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2005.7.1040"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/biof.5520060210"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2458-9-88"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00523.2006"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-08-2543"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01137"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.02.034"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2014.12.009"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.09.004"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2013.5815"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2941"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00699.2010"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.3945\/jn.108.098269"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-1575"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00638-X"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.08.039"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M409028200"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.05.008"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.11.6373"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.092"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1467-789X.2012.01033.x"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M504611200"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.2337\/db11-1652"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2921"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60761-756-3_18"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201000350"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M111.008094"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0053836"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-397863-9.00006-7"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/ijo.2010.216"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022931"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3350637"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)02083-1"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.02.017"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pop.2009.01.009"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2013.08.012"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2011.03.031"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.48.7.1359"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.7400074"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/oby.2008.419"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-2339"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)37568-3"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2009.07.004"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2010.11.006"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.11.012"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00017.2012"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2001232"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.05.006"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2091-9-S1-S6"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200319451"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.2174\/1389203053545453"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-010-9199-8"},{"key":"e_1_3_3_72_2","first-page":"33","article-title":"Integration of ER stress, oxidative stress and the inflammatory response in health and disease","volume":"3","author":"Zhang K","year":"2010","unstructured":"Zhang K. Integration of ER stress, oxidative stress and the inflammatory response in health and disease. Int J Clin Exp Med, 3: 33\u201340, 2010.","journal-title":"Int J Clin Exp Med"}],"container-title":["Antioxidants &amp; Redox Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/ars.2014.5939","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/ars.2014.5939","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/ars.2014.5939","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:53:27Z","timestamp":1777377207000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/ars.2014.5939"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,9]]},"references-count":71,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2015,9]]}},"alternative-id":["10.1089\/ars.2014.5939"],"URL":"https:\/\/doi.org\/10.1089\/ars.2014.5939","relation":{},"ISSN":["1523-0864","1557-7716"],"issn-type":[{"value":"1523-0864","type":"print"},{"value":"1557-7716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,9]]}}}