1. Neuroscience

Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat

  1. Lisa R Beutler
  2. Timothy V Corpuz
  3. Jamie S Ahn
  4. Seher Kosar
  5. Weimin Song
  6. Yiming Chen
  7. Zachary A Knight  Is a corresponding author
  1. University of California, San Francisco, United States
  2. Northwestern University, United States
https://doi.org/10.7554/eLife.55909
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Cite this article
  1. Lisa R Beutler
  2. Timothy V Corpuz
  3. Jamie S Ahn
  4. Seher Kosar
  5. Weimin Song
  6. Yiming Chen
  7. Zachary A Knight
(2020)
Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat
eLife 9:e55909.
https://doi.org/10.7554/eLife.55909
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Abstract

Body weight is regulated by interoceptive neural circuits that track energy need, but how the activity of these circuits is altered in obesity remains poorly understood. Here we describe the in vivo dynamics of hunger-promoting AgRP neurons during the development of diet-induced obesity in mice. We show that high-fat diet attenuates the response of AgRP neurons to an array of nutritionally-relevant stimuli including food cues, intragastric nutrients, cholecystokinin and ghrelin. These alterations are are specific to dietary fat but not carbohydrate or protein. Subsequent weight loss restores the responsiveness of AgRP neurons to exterosensory cues but fails to rescue their sensitivity to gastrointestinal hormones or nutrients. These findings reveal that obesity triggers broad dysregulation of hypothalamic hunger neurons that is incompletely reversed by weight loss and may contribute to the difficulty of maintaining a reduced weight.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file

Article and author information

Author details

  1. Lisa R Beutler

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Timothy V Corpuz

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Jamie S Ahn

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Seher Kosar

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Weimin Song

    Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Yiming Chen

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Zachary A Knight

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    For correspondence
    zachary.knight@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7621-1478

Funding

National Institutes of Health (R01DK106399)

  • Zachary A Knight

National Institutes of Health (R01NS094781)

  • Zachary A Knight

National Institutes of Health (DP2DK021153)

  • Zachary A Knight

Howard Hughes Medical Institute (Investigator)

  • Zachary A Knight

American Diabetes Association (Pathway Award)

  • Zachary A Knight

New York Stem Cell Foundation (Robertson Investigator Award)

  • Zachary A Knight

Rita Allen Foundation (Scholar Award)

  • Zachary A Knight

National Institutes of Health (K08DK118188)

  • Lisa R Beutler

National Institutes of Health (P30 DK063720)

  • Lisa R Beutler

The funders played no role in the design or interpretation of the work.

Ethics

Animal experimentation: Experimental protocols were approved by the University of California, San Francisco IACUC following the National Institutes of Health guidelines for the Care and Use of Laboratory Animals. (protocol# AN179674)

Reviewing Editor

  1. Joel K Elmquist, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: February 10, 2020
  2. Accepted: July 20, 2020
  3. Accepted Manuscript published: July 28, 2020 (version 1)
  4. Version of Record published: August 3, 2020 (version 2)
  5. Version of Record updated: September 10, 2020 (version 3)

Copyright

© 2020, Beutler 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. Lisa R Beutler
  2. Timothy V Corpuz
  3. Jamie S Ahn
  4. Seher Kosar
  5. Weimin Song
  6. Yiming Chen
  7. Zachary A Knight
(2020)
Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat
eLife 9:e55909.
https://doi.org/10.7554/eLife.55909

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