Abstract| Volume 37, SUPPLEMENT 4, S65-S66, October 2013

Disruption of Adipocyte Caspase 8 Protects Mice from Weight Gain and Glucose Intolerance

      Caspase 8 is a key initiator of death receptor-induced apoptosis, a pathway also implicated in important non-apoptotic functions, including adipose tissue inflammation. We have previously shown that caspase 8 plays an important role in pancreatic β-cells, both in diabetes-related apoptosis and in maintenance of β-cell mass with age. The aim of this study was to investigate the role of caspase 8 in adipocyte regulation of whole body energy and glucose homeostasis.
      We found that caspase 8 expression was increased in adipocytes from humans with obesity and diabetes. To further study the specific role of adipocyte caspase 8 in metabolism, we generated adipose tissue-specific caspase 8 knockout mice (aP2Cre+Casp8fl/fl ) using an adipocyte protein 2 (aP2) CRE-loxP recombination system, and placed these mice on high-fat diet (HFD) for 8 weeks.
      aP2Cre+Casp8fl/fl mice were protected from weight gain on HFD (–17% body weight, p≤0.05, n=10 males; –14% body weight, p≤0.05, n=10 females), with decreased fat pad weights, smaller adipocytes and decreased hepatic steatosis. Furthermore, these mice demonstrated improved glucose tolerance on intraperitoneal glucose tolerance testing (p≤0.05, n=9 males; p≤0.05, n=9 females) following HFD feeding, as well as decreased fasting insulin and leptin levels.
      This study demonstrates that caspase 8 plays an important role in adipose tissue regulation of whole body energy and glucose homeostasis, and disruption of adipocyte caspase 8 protects mice from obesity and diabetes.