A(2B) Adenosine Receptors Prevent Insulin Resistance by Inhibiting Adipose Tissue Inflammation via Maintaining Alternative Macrophage Activation

Obesity causes increased classical and decreased alternative macrophage activation, which in turn cause insulin resistance in target organs. Because A(2B) adenosine receptors (ARs) are important regulators of macrophage activation, we examined the role of A(2B) ARs in adipose tissue inflammation and insulin resistance. A(2B) AR deletion impaired glucose and lipid metabolism in mice fed chow but not a high-fat diet, which was paralleled by dysregulation of the adipokine system, and increased classical macrophage activation and inhibited alternative macrophage activation. The expression of alternative macrophage activation–specific transcriptions factors, including CCAAT/enhancer-binding protein-β, interferon regulatory factor 4, and peroxisome proliferator–activated receptor-γ, was decreased in adipose tissue of A(2B) AR–deficient mice. Furthermore, in in vitro studies, we found that stimulation of A(2B) ARs suppressed free fatty acid–induced deleterious inflammatory and metabolic activation of macrophages. Moreover, AR activation upregulated the interleukin-4–induced expression of CCAAT/enhancer-binding protein-β, interferon regulatory factor 4, and peroxisome proliferator–activated receptor-γ in macrophages. Altogether, our results indicate that therapeutic strategies targeting A(2B) ARs hold promise for preventing adipose tissue inflammation and insulin resistance.