title: Preserved endothelial function in human obesity in the absence of insulin resistance.
abstract: BACKGROUND
  Insulin resistance (IR) is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular disease (CVD). On the other hand, obesity has long been related to IR and increased CVD. However it is not known if IR is a necessary condition for endothelial dysfunction in human obesity, allowing for preserved endothelial function in obese people when absent. Therefore, the purpose of the study was to assess the relationship between IR and endothelial dysfunction in human obesity and the mechanisms involved.
  
  
  METHODS
  Twenty non-insulin resistant morbid obese (NIR-MO), 32 insulin resistant morbid obese (IR-MO), and 12 healthy subjects were included. Serum concentrations of glucose, insulin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), resistin and adiponectin were determined. IR was evaluated by HOMA-index. Endothelium-dependent relaxation to bradykinin (BK) in mesenteric microvessels was assessed in wire myograph.
  
  
  RESULTS
  Serum IL-6, and TNF-α levels were elevated only in IR-MO patients while resistin was elevated and adiponectin reduced in all MO individuals. Mesenteric arteries from IR-MO, but not from NIR-MO subjects displayed blunted relaxation to BK. Vasodilatation was improved in IR-MO arteries by the superoxide scavenger, superoxide dismutase (SOD) or the mitochondrial-targeted SOD mimetic, mito-TEMPO. NADPH oxidase inhibitors (apocynin and VAS2870) and the nitric oxide synthase (NOS) cofactor, tetrahydrobiopterin failed to modify BK-induced vasodilatations. Superoxide generation was higher in vessels from IR-MO subjects and reduced by mito-TEMPO. Blockade of TNF-α with infliximab, but not inhibition of inducible NOS or cyclooxygenase, improved endothelial relaxation and decreased superoxide formation.
  
  
  CONCLUSIONS
  Endothelial dysfunction is observed in human morbid obesity only when insulin resistance is present. Mechanisms involved include augmented mitochondrial superoxide generation, and increased systemic inflammation mediated by TNF-α. These findings may explain the different vascular risk of healthy vs unhealthy obesity.
authors.forename: Mariam
authors.initials: M
authors.lastname: El Assar
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Ruiz de Adana
authors.forename: Javier
authors.initials: J
authors.lastname: Angulo
authors.forename: María Luz
authors.initials: ML
authors.lastname: Pindado Martínez
authors.forename: Alberto
authors.initials: A
authors.lastname: Hernández Matías
authors.affiliation: Fundación para la Investigación Biomédica, Hospital Universitario de Getafe, Madrid, Spain. leocadio.rodriguez@salud.madrid.org.
authors.forename: Leocadio
authors.initials: L
authors.lastname: Rodríguez-Mañas
mesh_terms: D052242:Adiponectin / Q000097:blood; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid / Q000503:physiopathology*; D052243:Resistin / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D007328:Insulin; D015850:Interleukin-6; D052243:Resistin; D014409:Tumor Necrosis Factor-alpha