PSUN336 Dietary sugar and protein differentially regulate the insulin and IGF1 homologs Dilp2 and Dilp6 in Drosophila.

Growth deficits are frequently seen among children in resource-poor settings where malnutrition and chronic enteric infections are common. The insulin/IGF1 signaling pathway promotes cell and organismal growth across the animal kingdom. To better understand how malnutrition and infection impair growth, we investigated insulin/IGF1 signaling under such conditions using Drosophila as a model organism. In Drosophila, seven insulin-like peptides (Dilps) activate the insulin/IGF signaling pathway through a single known insulin receptor. Major circulating Dilps include Dilp2, produced from neurosecretory insulin-producing cells in the brain, and Dilp6, produced by the fat body, a functional analog of liver. Like insulin, mature Dilp2 lacks a C-peptide, whereas this sequence is retained in the IGF1 homolog Dilp6. We previously reported that bacterial infection and innate immune signaling negatively regulate whole-animal growth in Drosophila larvae by reducing circulating Dilp6 but not Dilp2. Here we asked whether Dilp2 and Dilp6 also respond differently to dietary sugar and protein, as secretion of insulin-like hormones is rigidly regulated by dietary nutrients. We used dual-epitope tagged Dilp2 and Dilp6 alleles to measure endogenous, circulating Dilp2 or Dilp6 in larvae. We find that circulating Dilp2 decreased by 60% after six hours of starvation on non-nutritive agar, and we observed a 90% decrease in Dilp2 from fed levels after 24 hours of starvation. In contrast, circulating Dilp6 was only reduced by 33% after 24 hours of starvation. Next, we asked whether Dilp2 and Dilp6 respond to specific dietary nutrients by adding yeast extract (to mimic the wild protein source) and/or sucrose to agar. Hemolymph Dilp2 was recovered to 73% of fed levels by the addition of yeast extract; addition of sucrose did not increase Dilp2 levels above the starved condition. Although the circulating level of Dilp6 was not strongly reduced by starvation, hemolymph Dilp6 was increased 40% by a sucrose-only diet compared with the normal, fed condition. Surprisingly, a yeast extract-only diet led to a 70% inhibition of circulating Dilp6 compared with the normal fed state. Addition of sucrose to the yeast diet led to a dose-dependent increase in Dilp6, suggesting that this hormone responds to the ratio of sugar to protein in the diet. Together, these data suggest that Dilp2 and Dilp6 secretion is controlled by distinct environmental conditions ranging from infection to dietary composition. An open question is how these two hormones carry distinct information to target organs despite binding to the single known insulin receptor encoded in the Drosophila genome. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.