The TGF-/Activin ligand daw regulates sugar and pH homeostasis in Drosophila melanogaster. Arpan Ghosh, Michael O'Connor. Gen Cell & Development, Univ Minnesota Twin Cities, Minneapolis, MN.

   TGF-/Activin ligands regulate a plethora of biological processes in all multicellular organisms and consequently have emerged as potential therapeutic solutions for multiple conditions. Our study aims at understanding the role of TGF- signaling in regulating metabolism by studying the metabolic consequences of manipulating TGF- signaling in Drosophila melanogaster. We show that Drosophila TGF-/Activin ligand dawdle (daw) dose-dependently regulates sugar and pH homeostasis in the fly larvae. daw nulls show significantly higher circulating sugar concentration, whereas over-expression of daw leads to a significant drop in hemolymph sugar. This diabetic phenotype of daw mutants is caused by a block in the release of Insulin from the Insulin producing cells since dIlp mRNA expression remains unchanged, but DIlp peptides accumulate in the IPCs. These mutants also show higher total triacylglycerol, glycogen and glucose, all hallmarks of insulin resistance in Drosophila larvae. Additionally, high-throughput GC/MS metabolomic analysis showed significant increase in multiple sugar metabolism intermediates in daw mutants, indicating a potential involvement of daw in regulating peripheral sugar metabolism. daw null mutants also show a significant drop in hemolymph pH that can be rescued by ectopic expression of daw. Challenging the daw mutants with high sugar and/or low pH food conditions lead to a severe drop in larval viability highlighting potential physiological significance of altered sugar and pH homeostasis in these mutants. While acidification (pH ~4.3) of food by any acid increased daw lethality, Propionic acid (PA) in particular most severely affected larval viability. The mechanism by which PA causes this acidity-independent effect may involve the role of PA as a metabolite or signaling molecule. Collectively, our study shows widespread involvement of TGF- signaling in metabolism and homeostasis in Drosophila and opens up the possibility of using this model organism to develop mechanistic paradigms for how TGF- signaling might regulate metabolism.