Adenosine signaling in the CNS modulates lipid and glucose homeostasis in the periphery

Maintenance of lipid and glucose homeostasis in the blood is a highly dynamic process that changes in response to fasting and feeding. During a fasted state, sympathetic tone and glucagon signaling facilitate an increase in hepatic glucose production and lipolysis from adipose tissue to meet the energy needs of the body in lieu of nutrients coming from the gut. Postprandially, insulin is released which leads to stowing away excess glucose as glycogen in the liver, and excess lipid as triglycerides in the adipose tissue. Our studies uncover a potentially novel mechanism for glucose and lipid modulation via the adenosine receptors in the central nervous system. Postprandial intraperitoneal administration of adenosine produces an acute and profound increase of blood glucose and non-esterified fatty acids (NEFA). Pharmacological agonism and antagonism finds that adenosine receptors A2A and A2B are both individually sufficient but collectively necessary for this adenosine-mediated effect. That is, agonism of either receptor produces profound glucose and NEFA excursions, but simultaneous inhibition of both is required to block this effect. Floxed alleles of A2A and A2B were combined to produce double floxed (DKO) mouse-line and when crossed to Cre, found that global DKO (UBC-Cre) and neuron-specific DKO (Baf53b-Cre) were both sufficient to block the adenosine effect. Interestingly adipocyte-specific DKO (AdipoQ-Cre) had no effect on lipolysis, and liver-specific DKO (AAV8-TBG-Cre) had any effect on glucose production when challenged with adenosine. Inhibition of autonomic signaling via hexamethonium was sufficient to prevent the adenosine effect. Moreover, concomitant administration of α-AR and ß-AR receptor antagonists (phentolamine and propranolol, respectively) before an adenosine challenge was sufficient to block the adenosine effect. Together these data indicate that sympathetic neuronal activity is necessary for adenosine-mediated effects on metabolism. We propose that peripheral administration of adenosine leads to activation of both the A2A and A2B receptors in central sympathetic neurons, activates a sympathetic cascade back to the periphery, and increases hepatic glucose production and adipocyte lipolysis via release of norepinephrine and epinephrine onto the liver and adipose tissue, respectively. Curiously these effects are absent during the fasted state, indicating that adenosine specifically plays a role in postprandial metabolism and may oppose insulin action. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.