Adenosine A2A and A2B receptor signaling in neurons promotes glucose and fatty acid release in the postprandial state

Adenosine is a widely distributed signaling molecule whose levels rise during conditions of metabolic stress, hypoxia, or inflammation. Adenosine is a homeostatic regulator of neuronal, cardiovascular, immune, and metabolic functions through activation of adenosine receptors. Here, we show that administration of adenosine rapidly elicits an immediate and pronounced excursion of glucose and non-esterified fatty acids (NEFA) in mice refed for four hours but is greatly attenuated in fasted mice. This adenosine-mediated postprandial response suggests that adenosine is a potent regulator of postprandial nutrient handling. Selective agonists and antagonists of A2A and A2B adenosine receptors demonstrate that activation of either is sufficient to evoke adenosines metabolic response, but both receptors must be inhibited simultaneously to abolish it. Adenosine strongly stimulates hepatic glucose production and adipose lipolysis, and this catabolic activity depends on sympathetic nerve activity as it requires autonomic signal transmission and is inhibited by blocking adrenergic receptors. Genetic ablation studies identify A2A and A2B receptors expressed on neurons, likely central neurons, as the primary site of action for mediating adenosines effects on whole-body metabolism. Collectively, these data demonstrate that acute adenosine administration promotes centrally mediated metabolic effects, particularly during the postprandial period. Rigorous dissection of signaling pathways shows that A2A and A2B receptors are individually sufficient and collectively necessary for adenosine-mediated glucose and fatty acid excursion.