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. RNA-seq profiling of intestine from spoki larvae with con and EcRi in enterocytes