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.

  • Letter
  • Published:

Deciphering a neuronal circuit that mediates appetite

Abstract

Hypothalamic neurons that co-express agouti-related protein (AgRP), neuropeptide Y and γ-aminobutyric acid (GABA) are known to promote feeding and weight gain by integration of various nutritional, hormonal, and neuronal signals1,2. Ablation of these neurons in mice leads to cessation of feeding that is accompanied by activation of Fos in most regions where they project3,4,5,6. Previous experiments have indicated that the ensuing starvation is due to aberrant activation of the parabrachial nucleus (PBN) and it could be prevented by facilitating GABAA receptor signalling in the PBN within a critical adaptation period5. We speculated that loss of GABA signalling from AgRP-expressing neurons (AgRP neurons) within the PBN results in unopposed excitation of the PBN, which in turn inhibits feeding. However, the source of the excitatory inputs to the PBN was unknown. Here we show that glutamatergic neurons in the nucleus tractus solitarius (NTS) and caudal serotonergic neurons control the excitability of PBN neurons and inhibit feeding. Blockade of serotonin (5-HT3) receptor signalling in the NTS by either the chronic administration of ondansetron or the genetic inactivation of Tph2 in caudal serotonergic neurons that project to the NTS protects against starvation when AgRP neurons are ablated. Likewise, genetic inactivation of glutamatergic signalling by the NTS onto N-methyl d-aspartate-type glutamate receptors in the PBN prevents starvation. We also show that suppressing glutamatergic output of the PBN reinstates normal appetite after AgRP neuron ablation, whereas it promotes weight gain without AgRP neuron ablation. Thus we identify the PBN as a hub that integrates signals from several brain regions to bidirectionally modulate feeding and body weight.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Chronic administration of ondansetron into the NTS, or genetic inactivation of serotonergic input to the NTS prevents starvation in AgRP neuron-ablated mice.
Figure 2: Serotonergic projections from the ROb and RMg to the NTS mediate starvation after ablation of AgRP neurons.
Figure 3: Viral-mediated disruption of glutamatergic circuitry between the NTS and PBN, or glutamatergic output of the PBN, rescues feeding after ablation of AgRP neurons.
Figure 4: Diagram illustrating circuitry that mediates loss of appetite after acute ablation of hypothalamic AgRP neurons.

Similar content being viewed by others

References

  1. Wu, Q. & Palmiter, R. D. GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism. Eur. J. Pharmacol. 660, 21–27 (2011)

    Article  CAS  Google Scholar 

  2. Morton, G. J., Cummings, D. E., Baskin, D. G., Barsh, G. S. & Schwartz, M. W. Central nervous system control of food intake and body weight. Nature 443, 289–295 (2006)

    Article  ADS  CAS  Google Scholar 

  3. Gropp, E. et al. Agouti-related peptide-expressing neurons are mandatory for feeding. Nature Neurosci. 8, 1289–1291 (2005)

    Article  CAS  Google Scholar 

  4. Luquet, S., Perez, F. A., Hnasko, T. S. & Palmiter, R. D. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310, 683–685 (2005)

    Article  ADS  CAS  Google Scholar 

  5. Wu, Q., Boyle, M. P. & Palmiter, R. D. Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137, 1225–1234 (2009)

    Article  Google Scholar 

  6. Wu, Q., Howell, M. P. & Palmiter, R. D. Ablation of neurons expressing agouti-related protein activates Fos and gliosis in postsynaptic target regions. J. Neurosci. 28, 9218–9226 (2008)

    Article  CAS  Google Scholar 

  7. Wu, Q., Howell, M. P., Cowley, M. A. & Palmiter, R. D. Starvation after AgRP neuron ablation is independent of melanocortin signaling. Proc. Natl Acad. Sci. USA 105, 2687–2692 (2008)

    Article  ADS  CAS  Google Scholar 

  8. Swank, M. W. & Bernstein, I. L. c-Fos induction in response to a conditioned stimulus after single trial taste aversion learning. Brain Res. 636, 202–208 (1994)

    Article  CAS  Google Scholar 

  9. Yamamoto, T. Neural substrates for the processing of cognitive and affective aspects of taste in the brain. Arch. Histol. Cytol. 69, 243–255 (2006)

    Article  CAS  Google Scholar 

  10. Berridge, K. C. & Pecina, S. Benzodiazepines, appetite, and taste palatability. Neurosci. Biobehav. Rev. 19, 121–131 (1995)

    Article  CAS  Google Scholar 

  11. Gershon, M. D. & Tack, J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132, 397–414 (2007)

    Article  CAS  Google Scholar 

  12. Barnes, N. M., Hales, T. G., Lummis, S. C. & Peters, J. A. The 5-HT3 receptor—the relationship between structure and function. Neuropharmacology 56, 273–284 (2009)

    Article  CAS  Google Scholar 

  13. Herbert, H., Moga, M. M. & Saper, C. B. Connections of the parabrachial nucleus with the nucleus of the solitary tract and the medullary reticular formation in the rat. J. Comp. Neurol. 293, 540–580 (1990)

    Article  CAS  Google Scholar 

  14. Jhamandas, J. H. & Harris, K. H. Excitatory amino acids may mediate nucleus tractus solitarius input to rat parabrachial neurons. Am. J. Physiol. 263, R324–R330 (1992)

    CAS  PubMed  Google Scholar 

  15. Walther, D. J. & Bader, M. A unique central tryptophan hydroxylase isoform. Biochem. Pharmacol. 66, 1673–1680 (2003)

    Article  CAS  Google Scholar 

  16. Thor, K. B. & Helke, C. J. Serotonin- and substance P-containing projections to the nucleus tractus solitarii of the rat. J. Comp. Neurol. 265, 275–293 (1987)

    Article  CAS  Google Scholar 

  17. Abizaid, A. & Horvath, T. L. Brain circuits regulating energy homeostasis. Regul. Pept. 149, 3–10 (2008)

    Article  CAS  Google Scholar 

  18. Grill, H. J. Distributed neural control of energy balance: contributions from hindbrain and hypothalamus. Obesity (Silver Spring) 14 (Suppl 5). 216S–221S (2006)

    Article  Google Scholar 

  19. Berthoud, H. R. & Morrison, C. The brain, appetite, and obesity. Annu. Rev. Psychol. 59, 55–92 (2008)

    Article  Google Scholar 

  20. Heisler, L. K. et al. Serotonin reciprocally regulates melanocortin neurons to modulate food intake. Neuron 51, 239–249 (2006)

    Article  CAS  Google Scholar 

  21. Xu, Y. et al. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron 60, 582–589 (2008)

    Article  CAS  Google Scholar 

  22. Xu, Y. et al. A serotonin and melanocortin circuit mediates d-fenfluramine anorexia. J. Neurosci. 30, 14630–14634 (2010)

    Article  CAS  Google Scholar 

  23. Takase, L. F. & Nogueira, M. I. Patterns of fos activation in rat raphe nuclei during feeding behavior. Brain Res. 1200, 10–18 (2008)

    Article  CAS  Google Scholar 

  24. Fulwiler, C. E. & Saper, C. B. Subnuclear organization of the efferent connections of the parabrachial nucleus in the rat. Brain Res. 319, 229–259 (1984)

    Article  CAS  Google Scholar 

  25. Rask-Andersen, M., Olszewski, P. K., Levine, A. S. & Schioth, H. B. Molecular mechanisms underlying anorexia nervosa: focus on human gene association studies and systems controlling food intake. Brain Res. Brain Res. Rev. 62, 147–164 (2010)

    Article  CAS  Google Scholar 

  26. Kaye, W. Neurobiology of anorexia and bulimia nervosa. Physiol. Behav. 94, 121–135 (2008)

    Article  CAS  Google Scholar 

  27. Tsien, J. Z., Huerta, P. T. & Tonegawa, S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87, 1327–1338 (1996)

    Article  CAS  Google Scholar 

  28. Hnasko, T. S. et al. Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. Neuron 65, 643–656 (2010)

    Article  CAS  Google Scholar 

  29. Kremer, E. J., Boutin, S., Chillon, M. & Danos, O. Canine adenovirus vectors: an alternative for adenovirus-mediated gene transfer. J. Virol. 74, 505–512 (2000)

    Article  CAS  Google Scholar 

  30. Kaplitt, M. G. et al. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nature Genet. 8, 148–154 (1994)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank G. Froelick, J. Wang and K. Battani for help with histology; A. Rainwater for help with mouse breeding; A. Quintana for propagating CAV2-Cre virus and preparing AAV1-CreGFP virus; and A. Guler and M. Carter for helpful comments on the manuscript. This work was supported in part by National Institutes of Health grant DA024908 to R.D.P.

Author information

Authors and Affiliations

Authors

Contributions

Q.W. and R.D.P. designed the research. Q.W. performed experiments and analysed the data. M.C. provided the conditional Tph2 mouse line. R.D.P. and Q.W. wrote the paper.

Corresponding author

Correspondence to Richard D. Palmiter.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-9. (PDF 735 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, Q., Clark, M. & Palmiter, R. Deciphering a neuronal circuit that mediates appetite. Nature 483, 594–597 (2012). https://doi.org/10.1038/nature10899

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10899

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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