(VP107) THE ADIPOCYTE-SPECIFIC ROLE OF CASPASE-8 SIGNALING IN ADIPOSITY

Background: Adipocyte death occurs in prolonged overnutrition and obesity. This is hypothesized to be a potent inducer of adipose tissue inflammation, which is associated with loss of glucose control, a hallmark of type 2 diabetes. Caspase-8 is a key effector in the apoptotic pathway and possesses additional non-apoptotic roles, including promoting activation of pro-inflammatory nuclear factor κB signaling. Previously, we demonstrated that caspase-8 expression is increased in adipose tissue of mice and humans with obesity and insulin resistance, highlighting a critical role of caspase-8 in these settings. Additionally, we demonstrated that adipose tissue-specific disruption of caspase-8 using an adipocyte protein 2 (aP2)-CreLoxP recombination system reduced weight gain on high fat diet (HFD), and improved adiposity, glucose tolerance, and adipose tissue inflammation in mice. To further this work, the objective of this study was to investigate the role of caspase-8 more specifically in adipocytes and in the regulation of adipose tissue homeostasis.

METHODS AND RESULTS: Mice with adipocyte-specific disruption of caspase-8 were generated using the alternate adiponectin-Cre-LoxP recombination system (adipoqCre+Casp8fl/fl), which is highly specific to adipocytes. Littermates were used as controls. Mice were placed on 16-20 weeks of 60% high fat diet (HFD) as a model of diet-induced obesity.

In line with previous findings, caspase-8 protein levels were increased in perigonadal fat of diet-induced obese wild-type mice fed HFD compared to lean controls fed normal chow diet. Mice with adipocyte-specific disruption of caspase-8 exhibited decreased adiposity, specifically decreased inguinal, perigonadal, and perirenal fat pad weight compared to littermate controls. These mice also had increased interscapular (brown) fat pad weight. In parallel, increased expression of genes associated with adipose tissue thermogenesis was observed in perigonadal fat of mice with caspase-8 disruption. Furthermore, in keeping with changes in adiposity, Lep gene expression was also decreased in perigonadal fat of these mice.

Conclusion: Findings from this study demonstrate an adipocyte-specific role of caspase-8 in regulating adiposity. Both aP2-Cre and adiponectin-Cre-mediated disruption of caspase-8 in adipose tissue and adipocytes show an important role of caspase-8 in diet-induced obesity. Disruption of adipocyte caspase-8 may be an interesting therapeutic target for obesity or type 2 diabetes, both of which are major healthcare issues.