Insulin-like peptides play distinct roles in nutrient-dependent plasticity in Drosophila

The highly conserved insulin signaling pathway regulates growth and development time in response to nutrition across metazoans. The fruit fly, Drosophila melanogaster, has 7 insulin-like peptides, which bind to a single insulin receptor and are differentially expressed across development time, organs, and with nutritional conditions. However, whether individual insulin-like peptides play specific roles in controlling growth remains unknown. Recent studies have revealed that, in addition to the caloric content of the diet, the ratio of protein to carbohydrates in the diet plays a key role in regulating life history traits. Furthermore, individual insulin-like peptides vary in their expression profiles according to nutrient conditions. Whether these differences in expression have any functional significance to animal life history traits remains unclear. Here, we report that reducing the protein content of the larval diet through macronutrient restriction-where the calories lost from protein dilution are offset by increased carbohydrate content-results in a more pronounced developmental delay compared to caloric restriction-where both protein and carbohydrate concentrations are reduced. We further reveal that these two diet types result in notable differences in the expression levels of Drosophila insulin-like peptides 2, 3, and 5, and observe distinct phenotypic responses of individual insulin-like peptide mutants raised on each diet type. Taken together, our findings highlight the distinct roles of individual insulin-like peptides in regulating growth and development time in response to changes in dietary macronutrients, and provide key insights into the molecular mechanisms controlling nutritional plasticity in Drosophila.