Adenosine Receptors A2A and A2B Modulate Glucose and Lipid Homeostasis

Obesity is associated with both excessive lipolysis in adipose tissue and excessive glucose output from the liver. The resulting hyperglycemia and elevation of fatty acids help promote the development of insulin resistance and eventually diabetes. Therefore, developing methods to control blood glucose and lipid levels is critical for progression of obesity into diabetes. Adenosine, a nucleoside released from cells during metabolic stress or inflammation that functions as an autocrine or paracrine signal, may play an important role in this process. Administration of adenosine in mice promotes a pronounced and acute increase in blood glucose and non-esterified fatty acids (NEFA). Through pharmacological manipulation we determined that activation of adenosine receptors A2AR and A2BR are both individually sufficient to induce this release of glucose and lipid, while simultaneous inhibition of both receptors is required to ablate this effect. Importantly, we find that the A2AR/A2BR-mediated effects on metabolism are significantly more pronounced in the postprandial state compared with the postabsorptive state. Western blotting analysis of animals injected with adenosine has revealed a strong induction of PKA and its substrates in both adipose and liver tissue, suggesting adenosine is directly signaling on these organs. Together these data suggest that adenosine signaling via A2AR and A2BR are capable of regulating blood glucose and NEFA levels. We propose that blocking A2AR and A2BR during obesity will lower postprandial blood glucose and NEFA levels, and lead to an improvement of insulin resistance. AHA Predoctoral Fellowship 24PRE1240394 (AHA) NIH NIDDK- 1R01DK136126-01A1 This abstract was presented at the American Physiology Summit 2025 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.