title: Caspase induction and BCL2 inhibition in human adipose tissue: a potential relationship with insulin signaling alteration.
abstract: OBJECTIVE
  Cell death determines the onset of obesity and associated insulin resistance. Here, we analyze the relationship among obesity, adipose tissue apoptosis, and insulin signaling.
  
  
  METHODS
  The expression levels of initiator (CASP8/9) and effector (CASP3/7) caspases as well as antiapoptotic B-cell lymphoma (BCL)2 and inflammatory markers were assessed in visceral (VAT) and subcutaneous (SAT) adipose tissue from patients with different degrees of obesity and without insulin resistance or diabetes. Adipose tissue explants from lean subjects were cultured with TNF-α or IL-6, and the expression of apoptotic and insulin signaling components was analyzed and compared with basal expression levels in morbidly obese subjects.
  
  
  RESULTS
  SAT and VAT exhibited increased CASP3/7 and CASP8/9 expression levels and decreased BCL2 expression with BMI increase. These changes were accompanied by increased inflammatory cytokine mRNA levels and macrophage infiltration markers. In obese subjects, CASP3/7 activation and BCL2 downregulation correlated with the IRS-1/2-expression levels. Expression levels of caspases, BCL2, p21, p53, IRS-1/2, GLUT4, protein tyrosine phosphatase 1B, and leukocyte antigen-related phosphatase in TNF-α- or IL-6-treated explants from lean subjects were comparable with those found in adipose tissue samples from morbidly obese subjects. These insulin component expression levels were reverted with CASP3/7 inhibition in these TNF-α- or IL-6-treated explants.
  
  
  CONCLUSIONS
  Body fat mass increase is associated with CASP3/7 and BCL2 expression in adipose tissue. Moreover, this proapoptotic state correlated with insulin signaling, suggesting its potential contribution to the development of insulin resistance.
authors.affiliation: CIBER in Physiopathology of Obesity and Nutrition (CB06/03), Instituto de Salud Carlos III, Spain. fjtinahones@hotmail.com
authors.forename: Francisco José
authors.initials: FJ
authors.lastname: Tinahones
authors.forename: Leticia
authors.initials: L
authors.lastname: Coín Aragüez
authors.forename: Mora
authors.initials: M
authors.lastname: Murri
authors.forename: Wilfredo
authors.initials: W
authors.lastname: Oliva Olivera
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Mayas Torres
authors.forename: Nuria
authors.initials: N
authors.lastname: Barbarroja
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gomez Huelgas
authors.forename: Maria M
authors.initials: MM
authors.lastname: Malagón
authors.forename: Rajaa
authors.initials: R
authors.lastname: El Bekay
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D053179:Caspase 7 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050151:Subcutaneous Fat / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D015850:Interleukin-6; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C505407:CASP3 protein, human; C505520:CASP7 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D053453:Caspase 9