Caspase Induction and BCL2 Inhibition in Human Adipose Tissue

Abstract

OBJECTIVECell 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 METHODSThe 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.RESULTSSAT 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.CONCLUSIONSBody 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.

DBC1 is involved in adipocyte inflammation and is a possible marker of human adipose tissue senescence

“…However, the expressions of senescence‐related gene (BAX and TP53) markers were the best predictors of DBC1 gene expression variance in human adipose tissue. This information is novel and consistent with a recent study, in which senescence and proapoptotic markers were linked to adipose tissue inflammation and insulin resistance in morbidly obese patients . Supporting these associations, mice experiments using DBC1 KO mice revealed that DBC1 promotes adipose tissue senescence and inflammation .…”

Changes in Proteomic Profiles are Related to Changes in BMI and Fat Distribution During 10 Years of Aging

“…CASP‐8 is a cysteine protease involved in apoptosis and cell death, and this protein was implicated in the remodeling of the heart following myocardial injury, such as myocardial infarction . In subcutaneous, but not visceral, biopsies taken from humans with varying degrees of obesity, the expression of CASP‐8 was inversely related to the degree of obesity , but apart from that single prior study, human data relating CASP‐8 and obesity are lacking. Because cell cycle abnormalities, such as apoptosis regulation, have been postulated to play a major role in obesity‐related complications , we believe that it is worthwhile to further explore the connection between WHR and CASP‐8 found in the present study.…”

Intermedin protects against myocardial ischemia-reperfusion injury in hyperlipidemia rats

“…Numerous studies have shown that the Bcl-2 protein family plays an important role in the regulation of the apoptotic process, which could somehow cause diverse forms of intracellular damage and integrate the competing signals of death stimuli, and further determine cell survival (Adams and Cory, 1998;Babu et al, 2004). As a typical representative of this family, Bcl-2 has been reported to exert its anti-apoptotic effect by blocking the activation of caspase enzyme-associated signaling pathways, antagonizing the function of another family member Bax and so on (Adams and Cory, 1998;Henshall et al, 2002;Babu et al, 2004;Nieminen et al, 2013;Tinahones et al, 2013). Significantly, our study demonstrated that MI/R increased caspase-3 and Bax protein expression in hyperlipidemia animals, while the activity of Bcl-2 was decreased in the meantime, suggesting that hyperlipidemia rats showed exacerbated apoptosis after MI/R compared to non-hyperlipidemia rats.…”