A genetic variant of fatty acid amide hydrolase (FAAH) exacerbates hormone-mediated orexigenic feeding in mice
- University of Calgary, Canada
- University Hospital Bonn, Germany
- University of Pennsylvania, United States
- University of Washington, United States
- Weill Cornell Medical College, United States
- 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
Haley A Vecchiarelli
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.
Reviewing Editor
- Joel K Elmquist, University of Texas Southwestern Medical Center, United States
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.
Version history
- Received: July 15, 2022
- Preprint posted: August 11, 2022 (view preprint)
- Accepted: April 6, 2023
- Accepted Manuscript published: April 11, 2023 (version 1)
- Version of Record published: May 4, 2023 (version 2)
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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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
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