Caspase Induction and BCL2 Inhibition in Human Adipose Tissue:A potential relationship with insulin signaling alteration

Francisco José Tinahones, MD, PHD, Leticia Coín Aragüez, BSC, Mora Murri, PHD, Wilfredo Oliva Olivera, BSC, María Dolores Mayas Torres, PHD, Nuria Barbarroja, PHD, Ricardo Huelgas Gomez, MD, PHD, Maria del Mar Malagón, PHD and Rajaa El Bekay, PHD

Published online before print November 27, 2012, doi: 10.2337/dc12-0194

Diabetes Care November 27, 2012

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.

RESEARCH DESIGN AND 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.