A nutrient-sensitive enterokine coordinates developmental plasticity through inter-organ signaling.

Animal survival in fluctuating environments depends 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 larval midgut enteroendocrine cells, that acts systemically to inhibit the expression and release of dIlp2, a major insulin-like peptide controlling developmental progression. Limostatin expression and secretion by 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. In turn, Limostatin participates in a feedback control loop that slows down developmental progression once systemic nutrient shortage is sensed. This bidirectional 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 signaling, rather than insulin release per se, may represent an evolutionarily conserved or convergent strategy in regulating developmental plasticity.