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

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

Version 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.

Metrics

  • 7,073
    Page views
  • 951
    Downloads
  • 54
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.55909

Further reading

    1. Neuroscience
    Maureen van der Grinten, Jaap de Ruyter van Steveninck ... Yağmur Güçlütürk
    Tools and Resources

    Blindness affects millions of people around the world. A promising solution to restoring a form of vision for some individuals are cortical visual prostheses, which bypass part of the impaired visual pathway by converting camera input to electrical stimulation of the visual system. The artificially induced visual percept (a pattern of localized light flashes, or ‘phosphenes’) has limited resolution, and a great portion of the field’s research is devoted to optimizing the efficacy, efficiency, and practical usefulness of the encoding of visual information. A commonly exploited method is non-invasive functional evaluation in sighted subjects or with computational models by using simulated prosthetic vision (SPV) pipelines. An important challenge in this approach is to balance enhanced perceptual realism, biologically plausibility, and real-time performance in the simulation of cortical prosthetic vision. We present a biologically plausible, PyTorch-based phosphene simulator that can run in real-time and uses differentiable operations to allow for gradient-based computational optimization of phosphene encoding models. The simulator integrates a wide range of clinical results with neurophysiological evidence in humans and non-human primates. The pipeline includes a model of the retinotopic organization and cortical magnification of the visual cortex. Moreover, the quantitative effects of stimulation parameters and temporal dynamics on phosphene characteristics are incorporated. Our results demonstrate the simulator’s suitability for both computational applications such as end-to-end deep learning-based prosthetic vision optimization as well as behavioral experiments. The modular and open-source software provides a flexible simulation framework for computational, clinical, and behavioral neuroscientists working on visual neuroprosthetics.

    1. Neuroscience
    Simon Lui, Ashleigh K Brink, Laura H Corbit
    Research Article

    Extinction is a specific example of learning where a previously reinforced stimulus or response is no longer reinforced, and the previously learned behaviour is no longer necessary and must be modified. Current theories suggest extinction is not the erasure of the original learning but involves new learning that acts to suppress the original behaviour. Evidence for this can be found when the original behaviour recovers following the passage of time (spontaneous recovery) or reintroduction of the reinforcement (i.e. reinstatement). Recent studies have shown that pharmacological manipulation of noradrenaline (NA) or its receptors can influence appetitive extinction; however, the role and source of endogenous NA in these effects are unknown. Here, we examined the role of the locus coeruleus (LC) in appetitive extinction. Specifically, we tested whether optogenetic stimulation of LC neurons during extinction of a food-seeking behaviour would enhance extinction evidenced by reduced spontaneous recovery in future tests. LC stimulation during extinction trials did not change the rate of extinction but did serve to reduce subsequent spontaneous recovery, suggesting that stimulation of the LC can augment reward-related extinction. Optogenetic inhibition of the LC during extinction trials reduced responding during the trials where it was applied, but no long-lasting changes in the retention of extinction were observed. Since not all LC cells expressed halorhodopsin, it is possible that more complete LC inhibition or pathway-specific targeting would be more effective at suppressing extinction learning. These results provide further insight into the neural basis of appetitive extinction, and in particular the role of the LC. A deeper understanding of the physiological bases of extinction can aid development of more effective extinction-based therapies.