Neuropeptide ACP facilitates lipid oxidation and utilization during long-term flight in locusts

Long-term flight depends heavily on intensive energy metabolism in animals; however, the neuroendocrine mechanisms underlying efficient substrate utilization remain elusive. Here, we report that the adipokinetic hormone/corazonin-related peptide (ACP) can facilitate muscle lipid utilization in a famous long-term migratory flighting species, Locusta migratoria. By peptidomic analysis and RNAi screening, we identified brain-derived ACP as a key flight-related neuropeptide. ACP gene expression increased notably upon sustained flight. CRISPR/Cas9-mediated knockout of ACP gene and ACP receptor gene (ACPR) significantly abated prolonged flight of locusts. Transcriptomic and metabolomic analyses further revealed that genes and metabolites involved in fatty acid transport and oxidation were notably downregulated in the flight muscle of ACP mutants. Finally, we demonstrated that a fatty-acid-binding protein (FABP) mediated the effects of ACP in regulating muscle lipid metabolism during long-term flight in locusts. Our results elucidated a previously undescribed neuroendocrine mechanism underlying efficient energy utilization associated with long-term flight.