A genetic variant of fatty acid amide hydrolase (FAAH) exacerbates hormone-mediated orexigenic feeding in mice

  1. Georgia Balsevich  Is a corresponding author
  2. Gavin N Petrie
  3. Daniel E Heinz
  4. Arashdeep Singh
  5. Robert J Aukema
  6. Avery C Hunker
  7. Haley A Vecchiarelli
  8. Hiulan Yau
  9. Martin Sticht
  10. Roger J Thompson
  11. Francis S Lee
  12. Larry S Zweifel
  13. Prasanth K Chelikani
  14. Nils C Gassen
  15. Matthew N Hill  Is a corresponding author
  1. University of Calgary, Canada
  2. University Hospital Bonn, Germany
  3. University of Pennsylvania, United States
  4. University of Washington, United States
  5. Weill Cornell Medical College, United States
  6. Texas Tech University, United States

Abstract

Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide. A polymorphism in FAAH (FAAH C385A) reduces FAAH expression, increases anandamide levels, and increases the risk of obesity. Nevertheless, some studies have found no association between FAAH C385A and obesity. We investigated whether the environmental context governs the impact of FAAH C385A on metabolic outcomes. Using a C385A knock-in mouse model, we found that FAAH A/A mice are more susceptible to glucocorticoid-induced hyperphagia, weight gain, and activation of hypothalamic AMPK. AMPK inhibition occluded the amplified hyperphagic response to glucocorticoids in FAAH A/A mice. FAAH knockdown exclusively in AgRP neurons mimicked the exaggerated feeding response of FAAH A/A mice to glucocorticoids. FAAH A/A mice likewise presented exaggerated orexigenic responses to ghrelin, while FAAH knockdown in AgRP neurons blunted leptin anorectic responses. Together, the FAAH A/A genotype amplifies orexigenic responses and decreases anorexigenic responses, providing a putative mechanism explaining the diverging human findings.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures and supplemental figures.

Article and author information

Author details

  1. Georgia Balsevich

    Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
    For correspondence
    georgia.balsevich@ucalgary.ca
    Competing interests
    The authors declare that no competing interests exist.
  2. Gavin N Petrie

    Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Daniel E Heinz

    Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7103-9621
  4. Arashdeep Singh

    Department of Neuroscience, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2477-1438
  5. Robert J Aukema

    Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3490-3390
  6. Avery C Hunker

    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Haley A Vecchiarelli

    Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6331-6107
  8. Hiulan Yau

    Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Martin Sticht

    Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Roger J Thompson

    Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7019-7246
  11. Francis S Lee

    Psychiatry, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7108-9650
  12. Larry S Zweifel

    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3465-5331
  13. Prasanth K Chelikani

    Texas Tech University, Amarillo, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Nils C Gassen

    Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Matthew N Hill

    Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
    For correspondence
    mnhill@ucalgary.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7144-9209

Funding

Natural Sciences and Engineering Research Council of Canada

  • Matthew N Hill

American Heart Association (953881)

  • Prasanth K Chelikani

Canadian Institutes of Health Research

  • Georgia Balsevich

Alberta Innovates

  • Georgia Balsevich

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All studies were carried out in compliance with the ARRIVE guidelines. All protocols had been approved by the University of Calgary Animal Care Committee and were carried out in accordance with Canadian Council on Animal Care (under protocols AC16-0171, AC16-0053, AC20-0003, and AC20-0090). All surgery was performed under Isofluorane anesthesia and Metacam was given as a post-operative analgesic.

Copyright

© 2023, Balsevich 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. Georgia Balsevich
  2. Gavin N Petrie
  3. Daniel E Heinz
  4. Arashdeep Singh
  5. Robert J Aukema
  6. Avery C Hunker
  7. Haley A Vecchiarelli
  8. Hiulan Yau
  9. Martin Sticht
  10. Roger J Thompson
  11. Francis S Lee
  12. Larry S Zweifel
  13. Prasanth K Chelikani
  14. Nils C Gassen
  15. Matthew N Hill
(2023)
A genetic variant of fatty acid amide hydrolase (FAAH) exacerbates hormone-mediated orexigenic feeding in mice
eLife 12:e81919.
https://doi.org/10.7554/eLife.81919

Share this article

https://doi.org/10.7554/eLife.81919

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