The effects of hypoxia in determining larval size in Drosophila melanogaster

In Drosophila, hypoxia systemically restricts larval growth, but the molecular mechanism through which it does so remains poorly characterized. We show that Sima, the alpha subunit of the Drosophila hypoxia‐inducible factor, accumulates in nuclei of larval fat body cells during hypoxia and inhibits systemic growth when overexpressed in this same tissue. Oxygen deprivation and overexpression of Sima in the fat body also cause the retention of Drosophila insulin‐like peptides (Dilps) in the larval brain, suggesting that an endocrine signal emanates from the fat body and is relayed to the brain to regulate Dilp secretion during an oxygen‐deprived state. Additionally, hypoxia and overexpression of Sima in the fat body cause lipid droplets to aggregate in this metabolic tissue but not in the larval oenocytes, a liver‐like cell type, unlike what is observed in starvation. Furthermore, hypoxia reduces total cholesterol, triglyceride, and free fatty acid levels in wild‐type larvae. Finally, ubiquitous overexpression of the wild‐type insulin receptor rescues hypoxic growth restriction, suggesting that hypoxia‐induced insulin resistance in peripheral tissues serves to inhibit systemic growth. Interestingly, one tissue that mediates hypoxic growth restriction is the larval trachea, as both overexpression of the wild‐type insulin receptor and activation of TOR (Target of rapamycin) signaling in this tissue rescue inhibition of larval growth under hypoxic conditions. Rearing wild‐type larvae in hypoxia also decreases the number of lipid droplets that stud the larval trachea, which is suggestive of a novel finding that lipid droplet mobilization to the larval trachea functions to promote growth. Collectively, our results suggest that coordination of larval size is dependent on the communication between many organs through the use of insulin signaling and alterations to lipid metabolism. These findings may be applicable to other instances in which an adaptive response to hypoxia is required.