Breakdown of excessive amounts of adenosine triphosphate (ATP), the main energy source of a cell, leads to the formation of extracellular adenosine, an important signaling molecule involved in multiple pathways that regulate neuronal and immunological function. Adenosine is either actively produced by certain cells or is released from damaged tissue, particularly when cells are starved of oxygen. Adenosine levels are tightly regulated at all points throughout its production, release, uptake and degradation, and disruptions in control that result in excessively high levels are associated with a number of human pathologies, including severe combined immunodeficiency (SCID).
The diversity in the regulation and function of adenosine (both of which differ in a tissue- and cell-specific manner) means that it has been difficult to unravel its exact role at the molecular level. In addition, data obtained in vitro, or in tissue culture, might not be relevant to whole organisms, and mammalian model systems are overly complicated. It would therefore be very useful to have a simpler model.
The authors previously showed that, in Drosophila, increasing extracellular adenosine by knocking out the adenosine deaminase gene (adgf-a) is fatal. Here, they demonstrate that larvae with increased adenosine are hyperglycemic, and cannot accumulate energy stores in the form of glycogen for their further development; in diet-restrictive conditions, these effects lead to death of the fly. Death can be prevented by mutating AdoR, the Drosophila adenosine receptor gene, which shows that the signaling function of adenosine is required for the lethal phenotype. The disruption of glucose metabolism is probably due to adenosine directly acting to stimulate glucose release in parallel with adipokinetic hormone, the Drosophila counterpart of glucagon.
Implications and future directions
The identification of extracellular adenosine as a stimulator of glucose release in Drosophila supports a recent study in rats suggesting that stress-induced release of extracellular adenosine has a strong anti-insulin effect. The machinery of adenosine signaling seems to be well conserved between flies and mammals, making Drosophila a potentially useful model in which to study the effects of extracellular adenosine on energy metabolism. The link between excess adenosine and glucose metabolism might be of clinical importance because there is frequently a harmful early-phase hyperglycemia in severely traumatized patients. A second intriguing observation concerns the inability of adgf-a mutants to store glycogen; if this effect is conserved in mammals, it could be important in the molecularly unexplored phenomenon of wasting, which is caused by a progressive loss of energy reserves during certain infections.