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Drosophila short neuropeptide F signalling regulates growth by ERK-mediated insulin signalling

Nature Cell Biology volume 10, pages 468–475 (2008)Cite this article

Abstract

Insulin and insulin growth factor have central roles in growth1,2, metabolism3 and ageing4,5 of animals, including Drosophila melanogaster. In Drosophila, insulin-like peptides (Dilps) are produced by specialized neurons in the brain3,6. Here we show that Drosophila short neuropeptide F (sNPF), an orthologue of mammalian neuropeptide Y (NPY), and sNPF receptor sNPFR1 regulate expression of Dilps. Body size was increased by overexpression of sNPF or sNPFR1. The fat body of sNPF mutant Drosophila had downregulated Akt, nuclear localized FOXO, upregulated translational inhibitor 4E-BP and reduced cell size. Circulating levels of glucose were elevated and lifespan was also extended in sNPF mutants. We show that these effects are mediated through activation of extracellular signal-related kinases (ERK) in insulin-producing cells of larvae and adults. Insulin expression was also increased in an ERK-dependent manner in cultured Drosophila central nervous system (CNS) cells and in rat pancreatic cells treated with sNPF or NPY peptide, respectively. Drosophila sNPF and the evolutionarily conserved mammalian NPY seem to regulate ERK-mediated insulin expression and thus to systemically modulate growth, metabolism and lifespan.

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Figure 1: Body sizes of sNPF and sNPFR1 mutants, genetic interactions between sNPFR and Dilps and localization of sNPF and sNPFR1 proteins in the larval brain.
Figure 2: sNPF and sNPFR1 regulate expression of Dilps and ERK activation.
Figure 3: sNPF and NPY peptide regulate ERK-mediated insulin expression in the Drosophila CNS BG2-c6 cells and rat insulinoma INS-1 cells respectively.
Figure 4: sNPF regulates insulin receptor/dFOXO signalling in fat body cells.
Figure 5: sNPF regulates the level of haemolymph carbohydrates and lifespan.

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Acknowledgements

We thank S.K. Ju for technical support, S.H. Hong for INS-1 cell line and E. Rulifson and O. Puig for Dilp2 and dFOXO antibodies. This work was supported by grants from Korea Research Foundation (KRF-2006-312-C00637), BioGreen 21Program of Korea Rural Development Administration (20070401034024) and KRIBB Research Initiative Program (KGM 1310811).

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Author notes

  1. Kyung-Jin Min

    Present address: Present address: Department of Biological Sciences, University of Alaska at Anchorage, Anchorage, AK 99508, USA.,

  2. Kyu-Sun Lee, O-Yu Kwon and Joon H. Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Regenerative Medicine, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-333, Korea

    Kyu-Sun Lee, Ae-Kyeong Kim & Kweon Yu

  2. Department of Anatomy, College of Medicine, Chungnam National University, Daejeon, Korea

    O-Yu Kwon & Kisang Kwon

  3. Myung-Gok Eye Research Institute, Kim's Eye Hospital, College of Medicine, Konyang University, Chungnam, Korea

    Joon H. Lee & Sun-Ah Jung

  4. Department of Ecology and Evolutionary Biology, Brown University, Providence, 02912, RI, USA

    Kyung-Jin Min & Marc Tatar

  5. School of Bioscience and Biotechnology, Chungnam National University, Daejeon, Korea

    Kwan-Hee You

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Correspondence to Kweon Yu.

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Supplementary Figures S1, S2, S3, S4, S5 and S6 (PDF 985 kb)

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Lee, KS., Kwon, OY., Lee, J. et al. Drosophila short neuropeptide F signalling regulates growth by ERK-mediated insulin signalling. Nat Cell Biol 10, 468–475 (2008). https://doi.org/10.1038/ncb1710

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