title: Drosophilaneprilysins control insulin signaling and food intake via cleavage of regulatory peptides.
abstract: Insulin and IGF signaling are critical to numerous developmental and physiological processes, with perturbations being pathognomonic of various diseases, including diabetes. Although the functional roles of the respective signaling pathways have been extensively studied, the control of insulin production and release is only partially understood. Herein, we show that inDrosophilaexpression of insulin-like peptides is regulated by neprilysin activity. Concomitant phenotypes of altered neprilysin expression included impaired food intake, reduced body size, and characteristic changes in the metabolite composition. Ectopic expression of a catalytically inactive mutant did not elicit any of the phenotypes, which confirms abnormal peptide hydrolysis as a causative factor. A screen for corresponding substrates of the neprilysin identified distinct peptides that regulate insulin-like peptide expression, feeding behavior, or both. The high functional conservation of neprilysins and their substrates renders the characterized principles applicable to numerous species, including higher eukaryotes and humans.
authors.affiliation: Department of Developmental Biology, University of Osnabrück, Osnabrück, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hallier
authors.affiliation: Department of Developmental Biology, University of Osnabrück, Osnabrück, Germany.
authors.forename: Ronja
authors.initials: R
authors.lastname: Schiemann
authors.affiliation: Department of Developmental Biology, University of Osnabrück, Osnabrück, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Cordes
authors.affiliation: Department of Biomedical Research, Institute for Research in Biomedicine, Barcelona, Spain.
authors.forename: Jessica
authors.initials: J
authors.lastname: Vitos-Faleato
authors.affiliation: Department of Microbiology, University of Osnabrück, Osnabrück, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Walter
authors.affiliation: Department of Genetics, University of Osnabrück, Osnabrück, Germany.
authors.forename: Jürgen J
authors.initials: JJ
authors.lastname: Heinisch
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Malmendal
authors.affiliation: Department of Developmental Biology, University of Osnabrück, Osnabrück, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Paululat
authors.affiliation: Department of Developmental Biology, University of Osnabrück, Osnabrück, Germany.
authors.forename: Heiko
authors.identifier: 0000-0002-3304-4523
authors.initials: H
authors.lastname: Meyer
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D005247:Feeding Behavior; D015870:Gene Expression; D007328:Insulin / Q000378:metabolism*; D007814:Larva / Q000235:genetics / Q000502:physiology; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D030781:Organisms, Genetically Modified; D059748:Proteolysis; D015398:Signal Transduction
chemical_list: D029721:Drosophila Proteins; D007328:Insulin; D009479:Neuropeptides; C000624573:Nep4 protein, Drosophila; D015260:Neprilysin
keywords: D. melanogaster; developmental biology; epidemiology; feeding behavior; global health; insulin expression; insulin signaling; metallopeptidase; neprilysin; peptide metabolism; stem cells