Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Regulation of aversion to noxious food by Drosophila neuropeptide Y– and insulin-like systems

Nature Neuroscience volume 8, pages 1350–1355 (2005)Cite this article

Abstract

Omnivores, including humans, have an inborn tendency to avoid noxious or unfamiliar foods. Such defensive foraging behaviors are modifiable, however, in response to physiological needs. Here we describe a method for assessing risk-sensitive food acquisition in Drosophila melanogaster. Food-deprived fly larvae become more likely to feed on noxious foods (adulterated with quinine) as the duration of deprivation increases. The neuropeptide F receptor NPFR1, a mammalian neuropeptide Y (NPY) receptor homolog, centrally regulates the response to noxious food in D. melanogaster. Overexpression of NPFR1 was sufficient to cause nondeprived larvae to more readily take in noxious food, whereas loss of NPFR1 signaling led to the opposite phenotype. Moreover, NPFR1 neuronal activity may be directly regulated by the insulin-like signaling pathway. Upregulation of insulin-like receptor signaling in NPFR1 cells suppressed the feeding response to noxious food. Our results suggest that the coordinated activities of the conserved NPY- and insulin-like receptor signaling systems are essential for the dynamic regulation of noxious food intake according to the animal's energy state.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The NPF/NPFR1 neuronal pathway acutely suppresses aversion to noxious food in deprived larvae.
Figure 2: NPFR1 mediates hunger regulation of feeding response to noxious food.
Figure 3: Upregulation of dInR signaling in NPFR1 cells attenuates hunger-driven feeding of noxious food.
Figure 4: Simultaneous modulation of npfr1 and dS6K activities in NPFR1 cells suggests that dS6K negatively regulates NPFR1 signaling.

Similar content being viewed by others

References

  1. Charnov, E.L. Optimal foraging, the marginal value theorem. Theor. Popul. Biol. 9, 129–136 (1976).

    Article  CAS  Google Scholar 

  2. Stricker, E.M. Neurobiology of Food and Fluid Intake (Plenum, New York, 1990).

    Book  Google Scholar 

  3. Bateson, M. Recent advances in our understanding of risk-sensitive foraging preferences. Proc. Nutr. Soc. 61, 509–516 (2002).

    Article  Google Scholar 

  4. Hewes, R.S. & Taghert, P.H. Neuropeptides and neuropeptide receptors in the Drosophila melanogaster genome. Genome Res. 11, 1126–1142 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Brown, M.R. et al. Identification of a Drosophila brain-gut peptide related to the neuropeptide Y family. Peptides 20, 1035–1042 (1999).

    Article  CAS  Google Scholar 

  6. Wu, Q. et al. Developmental control of foraging and social behavior by the Drosophila neuropeptide Y-like system. Neuron 39, 147–161 (2003).

    Article  CAS  Google Scholar 

  7. Bannon, A.W. et al. Behavioral characterization of neuropeptide Y knockout mice. Brain Res. 868, 79–87 (2000).

    Article  CAS  Google Scholar 

  8. Segal-Lieberman, G., Trombly, D.J., Juthani, V., Wang, X. & Maratos-Flier, E. NPY ablation in C57BL/6 mice leads to mild obesity and to an impaired refeeding response to fasting. Am. J. Physiol. Endocrinol. Metab. 284, E1131–E1139 (2003).

    Article  CAS  Google Scholar 

  9. Brogiolo, W. et al. An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr. Biol. 11, 213–221 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Rulifson, E.J., Kim, S.K. & Nusse, R. Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science 296, 1118–1120 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Ikeya, T., Galic, M., Belawat, P., Nairz, K. & Hafen, E. Nutrient-dependent expression of insulin-like peptides from neuroendocrine cells in the CNS contributes to growth regulation in Drosophila. Curr. Biol. 12, 1293–1300 (2002).

    Article  CAS  Google Scholar 

  12. Oldham, S. & Hafen, E. Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control. Trends Cell Biol. 13, 79–85 (2003).

    Article  CAS  Google Scholar 

  13. Bruning, J.C. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 (2000).

    Article  CAS  Google Scholar 

  14. Gerozissis, K. Brain insulin: regulation, mechanisms of action and functions. Cell. Mol. Neurobiol. 23, 1–25 (2003).

    Article  Google Scholar 

  15. Moore, P. Controlling how many cells make a fly. J. Biol. 2, 16–16.5 (2003).

    Article  PubMed  Google Scholar 

  16. Song, J., Wu, L., Chen, Z., Kohanski, R.A. & Pick, L. Axons guided by insulin receptor in Drosophila visual system. Science 300, 502–505 (2003).

    Article  CAS  Google Scholar 

  17. Osborne, K.A. et al. Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila. Science 277, 834–836 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Shen, P. & Cai, H.N. Drosophila neuropeptide F mediates integration of chemosensory stimulation and conditioning of the nervous system by food. J. Neurobiol. 47, 16–25 (2001).

    Article  CAS  Google Scholar 

  19. Kitamoto, T. Targeted expression of temperature-sensitive dynamin to study neural mechanisms of complex behavior in Drosophila. J. Neurogenet. 16, 205–228 (2002).

    Article  CAS  Google Scholar 

  20. Cao, H., Thompson, H.M., Krueger, E.W. & McNiven, M.A. Disruption of Golgi structure and function in mammalian cells expressing a mutant dynamin. J. Cell Sci. 113, 1993–2002 (2000).

    CAS  Google Scholar 

  21. Jones, S.M., Howell, K.E., Henley, J.R., Cao, H. & McNiven, M.A. Role of dynamin in the formation of transport vesicles from the trans-Golgi network. Science 279, 573–577 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Kreitzer, G., Marmorstein, A., Okamoto, P., Vallee, R. & Rodriguez-Boulan, E. Kinesin and dynamin are required for post-Golgi transport of a plasma-membrane protein. Nat. Cell Biol. 2, 125–127 (2000).

    Article  CAS  Google Scholar 

  23. Haass, M., Hock, M., Richardt, G. & Schomig, A. Neuropeptide Y differentiates between exocytotic and nonexocytotic noradrenaline release in guinea-pig heart. Naunyn Schmiedebergs Arch. Pharmacol. 340, 509–515 (1989).

    Article  CAS  Google Scholar 

  24. Wen, T., Parrish, C.A., Xu, D., Wu, Q. & Shen, P. Drosophila neuropeptide F and its receptor NPFR1 define a signaling pathway that acutely modulates alcohol sensitivity. Proc. Natl. Acad. Sci. USA 102, 2141–2146 (2005).

    Article  CAS  Google Scholar 

  25. Colombani, J. et al. A nutrient sensor mechanism controls Drosophila growth. Cell 114, 739–749 (2003).

    Article  CAS  Google Scholar 

  26. Kimball, S.R. & Jefferson, L.S. Regulation of protein synthesis by branched-chain amino acids. Curr. Opin. Clin. Nutr. Metab. Care 4, 39–43 (2001).

    Article  CAS  Google Scholar 

  27. Thomas, G. The S6 kinase signaling pathway in the control of development and growth. Biol. Res. 35, 305–313 (2002).

    Article  CAS  Google Scholar 

  28. Barcelo, H. & Stewart, M.J. Altering Drosophila S6 kinase activity is consistent with a role for S6 kinase in growth. Genesis 34, 83–85 (2002).

    Article  CAS  Google Scholar 

  29. Thorsell, A. & Heilig, M. Diverse functions of neuropeptide Y revealed using genetically modified animals. Neuropeptides 36, 182–193 (2002).

    Article  CAS  Google Scholar 

  30. Thorsell, A. et al. Behavioral insensitivity to restraint stress, absent fear suppression of behavior and impaired spatial learning in transgenic rats with hippocampal neuropeptide Y overexpression. Proc. Natl. Acad. Sci. USA 97, 12852–12857 (2000).

    Article  CAS  Google Scholar 

  31. Levine, A.S., Kotz, C.M. & Gosnell, B.A. Sugars and fats: the neurobiology of preference. J. Nutr. 133, 831S–834S (2003).

    Article  CAS  Google Scholar 

  32. Levine, A.S., Jewett, D.C., Cleary, J.P., Kotz, C.M. & Billington, C.J. Our journey with neuropeptide Y: effects on ingestive behaviors and energy expenditure. Peptides 25, 505–510 (2004).

    Article  CAS  Google Scholar 

  33. Larhammar, D. Evolution of neuropeptide Y, peptide YY and pancreatic polypeptide. Regul. Pept. 62, 1–11 (1996).

    Article  CAS  Google Scholar 

  34. Davis, G.W., DiAntonio, A., Petersen, S.A. & Goodman, C.S. Postsynaptic PKA controls quantal size and reveals a retrograde signal that regulates presynaptic transmitter release in Drosophila. Neuron 20, 305–315 (1998).

    Article  CAS  Google Scholar 

  35. Gao, X., Neufeld, T.P. & Pan, D. Drosophila PTEN regulates cell growth and proliferation through PI3K-dependent and -independent pathways. Dev. Biol. 221, 404–418 (2000).

    Article  CAS  Google Scholar 

  36. Leevers, S.J., Weinkove, D., MacDougall, L.K., Hafen, E. & Waterfield, M.D. The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J. 15, 6584–6594 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Lin, D.M. & Goodman, C.S. Ectopic and increased expression of Fasciclin II alters motoneuron growth cone guidance. Neuron 13, 507–523 (1994).

    Article  CAS  PubMed  Google Scholar 

  38. Torroja, L., Chu, H., Kotovsky, I. & White, K. Neuronal overexpression of APPL, the Drosophila homologue of the amyloid precursor protein (APP), disrupts axonal transport. Curr. Biol. 9, 489–492 (1999).

    Article  CAS  Google Scholar 

  39. Rao, S., Lang, C., Levitan, E.S. & Deitcher, D.L. Visualization of neuropeptide expression, transport, and exocytosis in Drosophila melanogaster. J. Neurobiol. 49, 159–172 (2001).

    Article  CAS  Google Scholar 

  40. Piccin, A. et al. Efficient and heritable functional knock-out of an adult phenotype in Drosophila using a GAL4-driven hairpin RNA incorporating a heterologous spacer. Nucleic Acids Res. 29, E55 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Garczynski, S.F., Brown, M.R., Shen, P., Murray, T.F. & Crim, J.W. Characterization of a functional neuropeptide F receptor from Drosophila melanogaster. Peptides 23, 773–780 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D.L. Deitcher, E. Hafen, T. Kitamoto, D. Pan, J.H. Park, Exelixis Inc. and the Bloomington Fly Stock Center for fly lines, and J.S. Willis for the critical reading of the manuscript. This work was funded by a National Institutes of Health grant DK-58348 to P.S.

Author information

Authors and Affiliations

  1. Department of Cellular Biology and Biomedical and Health Sciences Institute, University of Georgia, 724 Biological Sciences Building, Athens, 30602, Georgia, USA

    Qi Wu, Zhangwu Zhao & Ping Shen

Authors
  1. Qi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhangwu Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ping Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ping Shen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Representative images of feeding and nonfeeding larvae in quinine assays. (PDF 117 kb)

Supplementary Fig. 2

Dissection of the midgut of feeding and nonfeeding larvae. (PDF 587 kb)

Supplementary Fig. 3

Comparison of the size of adult eyes. (PDF 407 kb)

Supplementary Fig. 4

Model of the central regulation of risk-sensitive feeding response to noxious food. (PDF 94 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, Q., Zhao, Z. & Shen, P. Regulation of aversion to noxious food by Drosophila neuropeptide Y– and insulin-like systems. Nat Neurosci 8, 1350–1355 (2005). https://doi.org/10.1038/nn1540

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1540

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing