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Drosophila neprilysins 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 in Drosophila expression 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.
PMID
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Authors

Mayor MeshTerms
Keywords

D. melanogaster

developmental biology

epidemiology

feeding behavior

global health

insulin expression

insulin signaling

metallopeptidase

neprilysin

peptide metabolism

stem cells

Journal Title elife
Publication Year Start




PMID- 27919317
OWN - NLM
STAT- In-Data-Review
DA  - 20161206
LR  - 20170220
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 5
DP  - 2016 Dec 06
TI  - Drosophila neprilysins control insulin signaling and food intake via cleavage of 
      regulatory peptides.
LID - 10.7554/eLife.19430 [doi]
LID - e19430 [pii]
AB  - 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 in
      Drosophila expression 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.
FAU - Hallier, Benjamin
AU  - Hallier B
AD  - Department of Developmental Biology, University of Osnabruck, Osnabruck, Germany.
FAU - Schiemann, Ronja
AU  - Schiemann R
AD  - Department of Developmental Biology, University of Osnabruck, Osnabruck, Germany.
FAU - Cordes, Eva
AU  - Cordes E
AD  - Department of Developmental Biology, University of Osnabruck, Osnabruck, Germany.
FAU - Vitos-Faleato, Jessica
AU  - Vitos-Faleato J
AD  - Department of Biomedical Research, Institute for Research in Biomedicine,
      Barcelona, Spain.
FAU - Walter, Stefan
AU  - Walter S
AD  - Department of Microbiology, University of Osnabruck, Osnabruck, Germany.
FAU - Heinisch, Jurgen J
AU  - Heinisch JJ
AD  - Department of Genetics, University of Osnabruck, Osnabruck, Germany.
FAU - Malmendal, Anders
AU  - Malmendal A
AD  - Department of Cellular and Molecular Medicine, University of Copenhagen,
      Copenhagen, Denmark.
FAU - Paululat, Achim
AU  - Paululat A
AD  - Department of Developmental Biology, University of Osnabruck, Osnabruck, Germany.
FAU - Meyer, Heiko
AU  - Meyer H
AUID- ORCID: http://orcid.org/0000-0002-3304-4523
AD  - Department of Developmental Biology, University of Osnabruck, Osnabruck, Germany.
LA  - eng
PT  - Journal Article
DEP - 20161206
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
PMC - PMC5140268
OTO - NOTNLM
OT  - D. melanogaster
OT  - developmental biology
OT  - epidemiology
OT  - feeding behavior
OT  - global health
OT  - insulin expression
OT  - insulin signaling
OT  - metallopeptidase
OT  - neprilysin
OT  - peptide metabolism
OT  - stem cells
EDAT- 2016/12/07 06:00
MHDA- 2016/12/07 06:00
CRDT- 2016/12/07 06:00
PHST- 2016/07/06 [received]
PHST- 2016/11/14 [accepted]
AID - 10.7554/eLife.19430 [doi]
PST - epublish
SO  - Elife. 2016 Dec 6;5. pii: e19430. doi: 10.7554/eLife.19430.

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