Remote-control of AMPK via extracellular adenosine controls tissue growth

AMPK is a regulator of cellular catabolism that is activated by AMP. Since AMP accumulates in cells with low ATP, AMPK is considered a stress activated kinase. Here, while studying organ growth during Drosophila development, we find that AMPK is activated by a signaling metabolite not related to stress. We find that the two main physiological inputs that regulate organ growth rates during development - the hormone ecdysone and dietary protein - both regulate expression in the intestine of an enzyme, adenosine deaminase. This leads to changes in the levels of adenosine in circulation. Circulating adenosine acts as a signaling molecule by entering into cells, becoming phosphorylated to adenosine mono-phosphate (AMP) and activating AMPK to inhibit organ growth. Thus AMPK activity is regulated developmentally, and AMPK in one tissue such as the wing can be remote-controlled by another tissue such as the intestine via circulating adenosine. Interestingly, this mechanism accounts for half of the effect of dietary protein on tissue growth rates in Drosophila. Overall design: RNA-seq profiling of intestine from spoki larvae with con and EcRi in enterocytes