title: Proteasome Dysfunction Associated to Oxidative Stress and Proteotoxicity in Adipocytes Compromises Insulin Sensitivity in Human Obesity.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 1 Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica (IMIBIC)/Reina Sofia University Hospital/University of Córdoba , Córdoba, Spain .|2 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III , Córdoba, Spain .
authors.forename: Alberto
authors.initials: A
authors.lastname: Díaz-Ruiz
authors.affiliation: 1 Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica (IMIBIC)/Reina Sofia University Hospital/University of Córdoba , Córdoba, Spain .|2 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III , Córdoba, Spain .
authors.forename: Rocío
authors.initials: R
authors.lastname: Guzmán-Ruiz
authors.affiliation: 1 Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica (IMIBIC)/Reina Sofia University Hospital/University of Córdoba , Córdoba, Spain .|2 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III , Córdoba, Spain .
authors.forename: Natalia R
authors.initials: NR
authors.lastname: Moreno
authors.affiliation: 2 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III , Córdoba, Spain .|3 Lipids and Atherosclerosis Unit, IMIBIC/Reina Sofia University Hospital/University of Córdoba , Córdoba, Spain .
authors.forename: Antonio
authors.initials: A
authors.lastname: García-Rios
authors.affiliation: 2 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III , Córdoba, Spain .|3 Lipids and Atherosclerosis Unit, IMIBIC/Reina Sofia University Hospital/University of Córdoba , Córdoba, Spain .
authors.forename: Nieves
authors.initials: N
authors.lastname: Delgado-Casado
authors.affiliation: 4 Unidad de Gestión Clínica de Cirugía General y Digestivo. Sección de Obesidad, IMIBIC/Reina Sofia University Hospital , Córdoba, Spain .
authors.forename: Antonio
authors.initials: A
authors.lastname: Membrives
authors.affiliation: 5 Department of Biochemistry and Molecular Biology, IMIBIC/Reina Sofia University Hospital/University of Córdoba , Córdoba, Spain .
authors.forename: Isaac
authors.initials: I
authors.lastname: Túnez
authors.affiliation: 2 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III , Córdoba, Spain .|6 Biomedical Research Laboratory, Endocrinology Department, Hospital Virgen de la Victoria , Málaga, Spain .
authors.forename: Rajaa
authors.initials: R
authors.lastname: El Bekay
authors.affiliation: 2 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III , Córdoba, Spain .|7 Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona (IdIBGi) , Girona, Spain .
authors.forename: José M
authors.initials: JM
authors.lastname: Fernández-Real
authors.affiliation: 2 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III , Córdoba, Spain .|8 Department of Physiology, School of Medicine-CIMUS-Instituto de Investigaciones Sanitarias (IDIS), University of Santiago de Compostela , Santiago de Compostela, A Coruña, Spain .
authors.forename: Sulay
authors.initials: S
authors.lastname: Tovar
authors.affiliation: 2 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III , Córdoba, Spain .|8 Department of Physiology, School of Medicine-CIMUS-Instituto de Investigaciones Sanitarias (IDIS), University of Santiago de Compostela , Santiago de Compostela, A Coruña, Spain .
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.affiliation: 2 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III , Córdoba, Spain .|6 Biomedical Research Laboratory, Endocrinology Department, Hospital Virgen de la Victoria , Málaga, Spain .
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Tinahones
authors.affiliation: 1 Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica (IMIBIC)/Reina Sofia University Hospital/University of Córdoba , Córdoba, Spain .|2 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III , Córdoba, Spain .
authors.forename: Rafael
authors.initials: R
authors.lastname: Vázquez-Martínez
authors.affiliation: 2 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III , Córdoba, Spain .|3 Lipids and Atherosclerosis Unit, IMIBIC/Reina Sofia University Hospital/University of Córdoba , Córdoba, Spain .
authors.forename: José
authors.initials: J
authors.lastname: López-Miranda
authors.affiliation: 1 Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica (IMIBIC)/Reina Sofia University Hospital/University of Córdoba , Córdoba, Spain .|2 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III , Córdoba, Spain .
authors.forename: María M
authors.initials: MM
authors.lastname: Malagón
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000818:Animals; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D000067329:Obesity, Metabolically Benign / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009852:Omentum / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D019308:Palmitic Acid / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D050151:Subcutaneous Fat / Q000378:metabolism / Q000473:pathology; D056811:Unfolded Protein Response
chemical_list: D019308:Palmitic Acid; D046988:Proteasome Endopeptidase Complex