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Proteasome Dysfunction Associated to Oxidative Stress and Proteotoxicity in Adipocytes Compromises Insulin Sensitivity in Human Obesity
dc.contributor.author | Díaz-Ruiz, A. | |
dc.contributor.author | Guzmán-Ruiz, R. | |
dc.contributor.author | Moreno, N. R. | |
dc.contributor.author | García-Rios, A. | |
dc.contributor.author | Delgado-Casado, N. | |
dc.contributor.author | Membrives, A. | |
dc.contributor.author | Túnez, I. | |
dc.contributor.author | El Bekay, R. | |
dc.contributor.author | Fernández-Real, J. M. | |
dc.contributor.author | Tovar Carro, Sulay | |
dc.contributor.author | Diéguez González, Carlos | |
dc.contributor.author | Tinahones, F. J. | |
dc.contributor.author | Vázquez-Martínez, R. | |
dc.contributor.author | López-Miranda, J. | |
dc.contributor.author | Malagón, M | |
dc.date.accessioned | 2017-06-07T07:34:53Z | |
dc.date.available | 2017-06-07T07:34:53Z | |
dc.date.issued | 2015 | |
dc.identifier.issn | 1523-0864 | |
dc.identifier.uri | http://hdl.handle.net/20.500.11940/8185 | |
dc.description.abstract | AIMS: 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. RESULTS: 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. INNOVATION: 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. CONCLUSION: 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. | |
dc.description.sponsorship | IMIBIC/Universidad de Córdoba-SCAI (ProteoRed, PRB2-ISCIII) | |
dc.description.sponsorship | MINECO/FEDER | |
dc.description.sponsorship | Junta de Andalucía/FEDER | |
dc.description.sponsorship | CIBERobn(Instituto de Salud Carlos III) | |
dc.language.iso | eng | |
dc.subject.mesh | 3T3-L1 Cells | |
dc.subject.mesh | Adipocytes | |
dc.subject.mesh | Adult | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Disease Models, Animal | |
dc.subject.mesh | Endoplasmic Reticulum Stress | |
dc.subject.mesh | Female | |
dc.subject.mesh | Gene Expression Regulation | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Insulin Resistance | |
dc.subject.mesh | Male | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Obesity, Metabolically Benign | |
dc.subject.mesh | Omentum | |
dc.subject.mesh | Oxidative Stress | |
dc.subject.mesh | Palmitic Acid | |
dc.subject.mesh | Proteasome Endopeptidase Complex | |
dc.subject.mesh | Subcutaneous Fat | |
dc.subject.mesh | Unfolded Protein Response | |
dc.title | Proteasome Dysfunction Associated to Oxidative Stress and Proteotoxicity in Adipocytes Compromises Insulin Sensitivity in Human Obesity | |
dc.type | Artigo | es |
dc.authorsophos | Díaz-Ruiz, A. | |
dc.authorsophos | Guzmán-Ruiz, R. | |
dc.authorsophos | Moreno, N. R. | |
dc.authorsophos | García-Rios, A. | |
dc.authorsophos | Delgado-Casado, N. | |
dc.authorsophos | Membrives, A. | |
dc.authorsophos | Túnez, I. | |
dc.authorsophos | El Bekay, R. | |
dc.authorsophos | Fernández-Real, J. M. | |
dc.authorsophos | Tovar, S. | |
dc.authorsophos | Diéguez, C. | |
dc.authorsophos | Tinahones, F. J. | |
dc.authorsophos | Vázquez-Martínez, R. | |
dc.authorsophos | López-Miranda, J. | |
dc.authorsophos | Malagón, M. M. | |
dc.identifier.doi | 10.1089/ars.2014.5939 | |
dc.identifier.isi | 360045800001 | |
dc.identifier.pmid | 25714483 | |
dc.identifier.sophos | 19528 | |
dc.issue.number | 7 | |
dc.journal.title | ANTIOXIDANTS & REDOX SIGNALING | |
dc.organization | Servizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI)::EOXI de Santiago::IDIS.- Instituto de investigaciones sanitarias de Santiago | |
dc.page.initial | 597 | |
dc.page.final | 612 | |
dc.relation.projectID | info:eu-repo/grantAgreement/IMIBIC/University of Cordoba-SCAI (ProteoRed, PRB2-ISCIII)/PT13/0001 | |
dc.relation.projectID | info:eu-repo/grantAgreement/MINECO/FEDER/BFU2010-17116 | |
dc.relation.projectID | info:eu-repo/grantAgreement/MINECO/FEDER/BFU2013-44229-R | |
dc.relation.projectID | info:eu-repo/grantAgreement/Junta de Andalucia/FEDER/CTS-6606 | |
dc.relation.projectID | info:eu-repo/grantAgreement/Junta de Andalucia/FEDER/PI-0200/2013 | |
dc.rights.accessRights | openAccess | |
dc.typesophos | Artículo Original | |
dc.volume.number | 23 |
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