A nutrient-sensitive enterokine coordinates developmental plasticity through inter-organ signalling

Animal survival in fluctuating environments depend on the ability to modulate their developmental pace in response to nutrient availability, a phenomenon known as developmental plasticity. In Drosophila larvae, we uncover a critical endocrine mechanism that coordinates this process under conditions of amino acid restriction. We identify the peptide hormone Limostatin as an enterokine, produced by a small population of midgut enteroendocrine cells, that acts systemically to inhibit the expression and release of dILP2, the major insulin-like peptide controlling developmental progression. Limostatin expression in enteroendocrine cells is triggered by reduced amino acid availability through an inter-organ relay involving the fat body and neuroendocrine insulin-producing cells in the brain. Limostatin participates in a feedback control loop that slows down developmental progression once systemic nutrient shortage is sensed. This gut-brain axis enables larvae to preserve viability under nutritional stress. Our findings define the larval gut as a nutrient-sensitive endocrine organ and position Limostatin as a key regulator of developmental plasticity. Our work expands the concept of decretins to include developmental pace control, suggesting that enterokines that regulate IGF signalling, rather than insulin release per se, may represent an evolutionarily conserved or convergent strategy in regulating developmental plasticity.