Metabolic dysfunction in mice with adipocyte specific ablation of the adenosine A2A receptor.

Abstract

It has been well established that adenosine plays a key role in the control of inflammation through G protein coupled receptors and recently shown that it can regulate thermogenesis. Here we investigated the specific requirements of the adenosine A2A receptor (A2AR) in mature adipocytes for thermogenic functionality and metabolic homeostasis. We generated fat tissue specific adenosine A2A receptor knock-out mice to assess the influence of signaling through this receptor on brown and beige fat functionality, obesity, insulin sensitivity, inflammation and liver function. Fat specific A2AR knock-out and wild type littermate mice were compared for potential differences in cold tolerance and energy metabolism. In addition, we measured glucose metabolism, AT inflammation and liver phenotypes in mice of the two genotypes after exposure to a diet rich in fat. Our results provide novel evidence indicating that loss of the adenosine A2A receptor specifically in adipocytes is associated with cold intolerance and decreased oxygen consumption. Furthermore, mice with fat specific ablation of the A2AR exposed to a diet rich in fat showed increased propensity to obesity, decreased insulin sensitivity, elevated adipose tissue inflammation and hepato-steatosis and -steatitis. Overall, our data provide novel evidence that A2AR in mature adipocytes safeguards metabolic homeostasis, suggesting the possibility of targeting this receptor selectively in fat for the treatment of metabolic disease.