KCS

Insulin/insulin growth factor signaling plays a central role in growth, metabolism, and aging in animals. However, up-stream regulatory signaling for the insulin transcription is not known. I present that Drosophila short neuropeptide F (sNPF) signaling regulates expression of Drosophila insulin like peptides (Dilps) through ERK activation in insulin producing cells and controls growth by regulating insulin receptor/FOXO signaling in the fat body insulin target tissue. The gain-of-function sNPF or sNPFR1 receptor mutant produced a bog body size through ERK mediated Dilps expression. When Drosophila CNS cells or rat pancreatic cells treated with sNPF or NPY peptide, a sNPF vertebrate ortholog, Dilps or insulin expression was increased by the activation of ERK. In the fat body cells of sNPF mutants, expression of translational inhibitor 4E-BP was increased by the down-regulation of Akt and nuclear localized FOXO, resulting in the reduction of cell size. Moreover, in sNPF mutants, high glucose levels of larval hemolymph were detected and lifespan was extended. Drosophila sNPF and evolutionary conserved mammalian NPY appear to regulate ERK mediated insulin expression and to thus systemically modulate growth, metabolism, and lifespan.