Glycolytic disruption restricts Drosophila melanogaster larval growth via the cytokine Upd3.

Drosophila larval growth requires efficient conversion of dietary nutrients into biomass. Lactate dehydrogenase (Ldh) and glycerol-3-phosphate dehydrogenase (Gpdh1) support this larval metabolic program by cooperatively promoting glycolytic flux. Consistent with their cooperative functions, the loss of both enzymes, but not either single enzyme alone, induces a developmental arrest. However, Ldh and Gpdh1 exhibit complex and often mutually exclusive expression patterns, suggesting that the lethal phenotypes exhibited by Gpdh1; Ldh double mutants could be mediated non-autonomously. Supporting this possibility, we find that the developmental arrest displayed by double mutants extends beyond simple metabolic disruption and instead stems, in part, from changes in systemic growth factor signaling. Specifically, we demonstrate that the simultaneous loss of Gpdh1 and Ldh results in elevated expression of Upd3, a cytokine involved in Jak/Stat signaling. Furthermore, we show that upd3 loss-of-function mutations suppress the Gpdh1; Ldh larval arrest phenotype, indicating that Upd3 signaling restricts larval development in response to decreased glycolytic flux. Together, our findings reveal a mechanism by which metabolic disruptions can modulate systemic growth factor signaling.