Increased extracellular adenosine in Drosophila that are deficient in adenosine deaminase activates a release of energy stores leading to wasting and death.

Extracellular adenosine is an important signaling molecule in neuromodulation, immunomodulation and hypoxia. Adenosine dysregulation can cause various pathologies, exemplified by a deficiency in adenosine deaminase in severe combined immunodeficiency. We have established a Drosophila model to study the effects of increased adenosine in vivo by mutating the main Drosophila adenosine deaminase-related growth factor (ADGF-A). Using a genetic screen, we show here that the increased extracellular adenosine in the adgf-a mutant is associated with hyperglycemia and impairment in energy storage. The adenosine works in this regard through the adenosine receptor as an anti-insulin hormone in parallel to adipokinetic hormone, a glucagon counterpart in flies. If not regulated properly, this action can lead to a loss of energy reserves (wasting) and death of the organism. Because adenosine signaling is associated with the immune response and the response to stress in general, our results mark extracellular adenosine as a good candidate signal involved in the wasting syndrome that accompanies various human pathologies.