Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit

  1. Giuseppe D'Agostino
  2. David Joseph Lyons
  3. Claudia Cristiano
  4. Luke Kennedy Burke
  5. Joseph C Madara
  6. John N Campbell
  7. Ana Paula Garcia
  8. Benjamin Bruce Land
  9. Bradford B Lowell
  10. Ralph Joseph Dileone
  11. Lora K Heisler  Is a corresponding author
  1. University of Aberdeen, United Kingdom
  2. University of Cambridge, United Kingdom
  3. Harvard Medical School, United States
  4. Yale University School of Medicine, United States

Abstract

The nucleus of the solitary tract (NTS) is a key gateway for meal-related signals entering the brain from the periphery. However, the chemical mediators crucial to this process have not been fully elucidated. We reveal that a subset of NTS neurons containing cholecystokinin (CCKNTS) is responsive to nutritional state and that their activation reduces appetite and body weight in mice. Cell-specific anterograde tracing revealed that CCKNTS neurons provide a distinctive innervation of the paraventricular nucleus of the hypothalamus (PVH), with fibers and varicosities in close apposition to a subset of melanocortin-4 receptor (MC4RPVH) cells, which are also responsive to CCK. Optogenetic activation of CCKNTS axon terminals within the PVH reveal the satiating function of CCKNTS neurons to be mediated by a CCKNTS→PVH pathway that also encodes positive valence. These data identify the functional significance of CCKNTS neurons and reveal a sufficient and discrete NTS to hypothalamic circuit controlling appetite.

Article and author information

Author details

  1. Giuseppe D'Agostino

    Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. David Joseph Lyons

    Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Claudia Cristiano

    Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Luke Kennedy Burke

    Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Joseph C Madara

    Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. John N Campbell

    Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ana Paula Garcia

    Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Benjamin Bruce Land

    Department of Psychiatry, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Bradford B Lowell

    Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Ralph Joseph Dileone

    Department of Psychiatry, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Lora K Heisler

    Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom
    For correspondence
    lora.heisler@abdn.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All experimental procedures were performed in accordance with the UK Animals (Scientific Procedures) Act 1986 (Project License No. 60/4565).

Copyright

© 2016, D'Agostino et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Giuseppe D'Agostino
  2. David Joseph Lyons
  3. Claudia Cristiano
  4. Luke Kennedy Burke
  5. Joseph C Madara
  6. John N Campbell
  7. Ana Paula Garcia
  8. Benjamin Bruce Land
  9. Bradford B Lowell
  10. Ralph Joseph Dileone
  11. Lora K Heisler
(2016)
Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit
eLife 5:e12225.
https://doi.org/10.7554/eLife.12225

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https://doi.org/10.7554/eLife.12225