Skip to main content

Thank you for visiting 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.

Genetic identification of a neural circuit that suppresses appetite



Appetite suppression occurs after a meal and in conditions when it is unfavourable to eat, such as during illness or exposure to toxins. A brain region proposed to play a role in appetite suppression is the parabrachial nucleus1,2,3, a heterogeneous population of neurons surrounding the superior cerebellar peduncle in the brainstem. The parabrachial nucleus is thought to mediate the suppression of appetite induced by the anorectic hormones amylin and cholecystokinin2, as well as by lithium chloride and lipopolysaccharide, compounds that mimic the effects of toxic foods and bacterial infections, respectively4,5,6. Hyperactivity of the parabrachial nucleus is also thought to cause starvation after ablation of orexigenic agouti-related peptide neurons in adult mice1,7. However, the identities of neurons in the parabrachial nucleus that regulate feeding are unknown, as are the functionally relevant downstream projections. Here we identify calcitonin gene-related peptide-expressing neurons in the outer external lateral subdivision of the parabrachial nucleus that project to the laterocapsular division of the central nucleus of the amygdala as forming a functionally important circuit for suppressing appetite. Using genetically encoded anatomical, optogenetic8 and pharmacogenetic9 tools, we demonstrate that activation of these neurons projecting to the central nucleus of the amygdala suppresses appetite. In contrast, inhibition of these neurons increases food intake in circumstances when mice do not normally eat and prevents starvation in adult mice whose agouti-related peptide neurons are ablated. Taken together, our data demonstrate that this neural circuit from the parabrachial nucleus to the central nucleus of the amygdala mediates appetite suppression in conditions when it is unfavourable to eat. This neural circuit may provide targets for therapeutic intervention to overcome or promote appetite.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


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

Figure 1: Co-localization of PBelo CGRP neurons with Fos following conditions that reduce food intake.
Figure 2: Stimulation of PBelo CGRP neurons reduces food intake and causes starvation.
Figure 3: Inhibition of PBelo CGRP neurons increases food intake during conditions that suppress appetite.
Figure 4: Efferent projections from PBelo CGRP neurons to the CeAlc mediate appetite suppression.


  1. Wu, Q., Clark, M. S. & Palmiter, R. D. Deciphering a neuronal circuit that mediates appetite. Nature 483, 594–597 (2012)

    Article  ADS  CAS  Google Scholar 

  2. Becskei, C., Grabler, V., Edwards, G. L., Riediger, T. & Lutz, T. A. Lesion of the lateral parabrachial nucleus attenuates the anorectic effect of peripheral amylin and CCK. Brain Res. 1162, 76–84 (2007)

    Article  CAS  Google Scholar 

  3. DiPatrizio, N. V. & Simansky, K. J. Activating parabrachial cannabinoid CB1 receptors selectively stimulates feeding of palatable foods in rats. J. Neurosci. 28, 9702–9709 (2008)

    Article  CAS  Google Scholar 

  4. Yamamoto, T. et al. C-fos expression in the rat brain after intraperitoneal injection of lithium chloride. Neuroreport 3, 1049–1052 (1992)

    Article  CAS  Google Scholar 

  5. Elmquist, J. K., Scammell, T. E., Jacobson, C. D. & Saper, C. B. Distribution of Fos-like immunoreactivity in the rat brain following intravenous lipopolysaccharide administration. J. Comp. Neurol. 371, 85–103 (1996)

    Article  CAS  Google Scholar 

  6. Paues, J., Mackerlova, L. & Blomqvist, A. Expression of melanocortin-4 receptor by rat parabrachial neurons responsive to immune and aversive stimuli. Neuroscience 141, 287–297 (2006)

    Article  CAS  Google Scholar 

  7. 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 

  8. Yizhar, O., Fenno, L. E., Davidson, T. J., Mogri, M. & Deisseroth, K. Optogenetics in neural systems. Neuron 71, 9–34 (2011)

    Article  CAS  Google Scholar 

  9. Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S. & Roth, B. L. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc. Natl Acad. Sci. USA 104, 5163–5168 (2007)

    Article  ADS  Google Scholar 

  10. Rosen, A. M., Victor, J. D. & Di Lorenzo, P. M. Temporal coding of taste in the parabrachial nucleus of the pons of the rat. J. Neurophysiol. 105, 1889–1896 (2011)

    Article  Google Scholar 

  11. Tokita, K. & Boughter, J. D., Jr Sweet-bitter and umami-bitter taste interactions in single parabrachial neurons in C57BL/6J mice. J. Neurophysiol. 108, 2179–2190 (2012)

    Article  CAS  Google Scholar 

  12. Geerling, J. C. & Loewy, A. D. Sodium deprivation and salt intake activate separate neuronal subpopulations in the nucleus of the solitary tract and the parabrachial complex. J. Comp. Neurol. 504, 379–403 (2007)

    Article  CAS  Google Scholar 

  13. Geerling, J. C. et al. FoxP2 expression defines dorsolateral pontine neurons activated by sodium deprivation. Brain Res. 1375, 19–27 (2011)

    Article  CAS  Google Scholar 

  14. Chamberlin, N. L. & Saper, C. B. Topographic organization of respiratory responses to glutamate microstimulation of the parabrachial nucleus in the rat. J. Neurosci. 14, 6500–6510 (1994)

    Article  CAS  Google Scholar 

  15. Hermanson, O. & Blomqvist, A. Subnuclear localization of FOS-like immunoreactivity in the rat parabrachial nucleus after nociceptive stimulation. J. Comp. Neurol. 368, 45–56 (1996)

    Article  CAS  Google Scholar 

  16. Richard, S., Engblom, D., Paues, J., Mackerlova, L. & Blomqvist, A. Activation of the parabrachio-amygdaloid pathway by immune challenge or spinal nociceptive input: a quantitative study in the rat using Fos immunohistochemistry and retrograde tract tracing. J. Comp. Neurol. 481, 210–219 (2005)

    Article  Google Scholar 

  17. Nakamura, K. & Morrison, S. F. A thermosensory pathway that controls body temperature. Nature Neurosci. 11, 62–71 (2008)

    Article  CAS  Google Scholar 

  18. Nakamura, K. & Morrison, S. F. A thermosensory pathway mediating heat-defense responses. Proc. Natl Acad. Sci. USA 107, 8848–8853 (2010)

    Article  ADS  CAS  Google Scholar 

  19. 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 

  20. Ng, L. et al. An anatomic gene expression atlas of the adult mouse brain. Nature Neurosci. 12, 356–362 (2009)

    Article  CAS  Google Scholar 

  21. Jacobs, J. W. et al. Calcitonin messenger RNA encodes multiple polypeptides in a single precursor. Science 213, 457–459 (1981)

    Article  ADS  CAS  Google Scholar 

  22. Paues, J., Engblom, D., Mackerlova, L., Ericsson-Dahlstrand, A. & Blomqvist, A. Feeding-related immune responsive brain stem neurons: association with CGRP. Neuroreport 12, 2399–2403 (2001)

    Article  CAS  Google Scholar 

  23. Krashes, M. J. et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121, 1424–1428 (2011)

    Article  CAS  Google Scholar 

  24. D’Hanis, W., Linke, R. & Yilmazer-Hanke, D. M. Topography of thalamic and parabrachial calcitonin gene-related peptide (CGRP) immunoreactive neurons projecting to subnuclei of the amygdala and extended amygdala. J. Comp. Neurol. 505, 268–291 (2007)

    Article  Google Scholar 

  25. Schwaber, J. S., Sternini, C., Brecha, N. C., Rogers, W. T. & Card, J. P. Neurons containing calcitonin gene-related peptide in the parabrachial nucleus project to the central nucleus of the amygdala. J. Comp. Neurol. 270, 416–426 (1988)

    Article  CAS  Google Scholar 

  26. Elmquist, J. K., Coppari, R., Balthasar, N., Ichinose, M. & Lowell, B. B. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J. Comp. Neurol. 493, 63–71 (2005)

    Article  CAS  Google Scholar 

  27. Atasoy, D., Betley, J. N., Su, H. H. & Sternson, S. M. Deconstruction of a neural circuit for hunger. Nature 488, 172–177 (2012)

    Article  ADS  CAS  Google Scholar 

  28. Soudais, C., Laplace-Builhe, C., Kissa, K. & Kremer, E. J. Preferential transduction of neurons by canine adenovirus vectors and their efficient retrograde transport in vivo. FASEB J. 15, 2283–2285 (2001)

    Article  CAS  Google Scholar 

  29. Gao, Q. & Horvath, T. L. Neurobiology of feeding and energy expenditure. Annu. Rev. Neurosci. 30, 367–398 (2007)

    Article  CAS  Google Scholar 

  30. Neugebauer, V., Li, W., Bird, G. C. & Han, J. S. The amygdala and persistent pain. Neuroscientist 10, 221–234 (2004)

    Article  Google Scholar 

  31. 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 

  32. Paxinos, G. & Franklin, K. B. J. The Mouse Brain in Stereotaxic Coordinates 4th edn (Elsevier, 2013)

    Google Scholar 

  33. Aravanis, A. et al. An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J. Neural Eng. 4, S143–S156 (2007)

    Article  Google Scholar 

  34. Lenth, R. V. Some practical guidelines for effective sample size determination. Am. Stat. 55, 187–193 (2001)

    Article  MathSciNet  Google Scholar 

Download references


We thank B. Roth for hM3Dq–mCherry and hM4Di–mCherry constructs, and K. Deisseroth for mCherry and ChR2–mCherry constructs. E. Allen, J. Resnick, M. Soleiman and S. Padilla assisted with histology, E. Allen and A. Rainwater assisted with animal husbandry, and J. Shulkin provided suggestions and advice. We thank members of the Palmiter and Zweifel laboratories for feedback on the manuscript. M.E.C. is financed by a fellowship from the Hilda and Preston Davis Foundation. L.S.Z. is financed by a grant from the National Institutes of Health (R01MH094536). R.D.P is supported in part by grants from the National Institutes of Health (R01DA024908) and the Klarman Family Foundation.

Author information

Authors and Affiliations



M.E.C. and R.D.P. conceived and designed the study. M.E.C. performed and analysed histological and behavioural experiments, M.E.S. performed electrophysiology experiments and R.D.P. generated CalcaCre knock-in mice. L.S.Z. and R.D.P. provided equipment, reagents and expertise. M.E.C. wrote the manuscript in collaboration with the other authors.

Corresponding author

Correspondence to Richard D. Palmiter.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-17 and Supplementary Statistical Analyses. (PDF 8023 kb)

Stimulation of PBelo CGRP neurons with ChR2 during consumption of palatable food

This video is representative of data from a single trial in Figure 2b. Left (near) lickometer port contains palatable liquid diet; right (far) lickometer port contains water. Video filmed 5 minutes after start of the active period. (MOV 3696 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Carter, M., Soden, M., Zweifel, L. et al. Genetic identification of a neural circuit that suppresses appetite. Nature 503, 111–114 (2013).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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.


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