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.
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.
Metrics
-
- 1,091
- views
-
- 136
- downloads
-
- 2
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
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
Further reading
-
- Neuroscience
Evidence accumulation models (EAMs) are the dominant framework for modeling response time (RT) data from speeded decision-making tasks. While providing a good quantitative description of RT data in terms of abstract perceptual representations, EAMs do not explain how the visual system extracts these representations in the first place. To address this limitation, we introduce the visual accumulator model (VAM), in which convolutional neural network models of visual processing and traditional EAMs are jointly fitted to trial-level RTs and raw (pixel-space) visual stimuli from individual subjects in a unified Bayesian framework. Models fitted to large-scale cognitive training data from a stylized flanker task captured individual differences in congruency effects, RTs, and accuracy. We find evidence that the selection of task-relevant information occurs through the orthogonalization of relevant and irrelevant representations, demonstrating how our framework can be used to relate visual representations to behavioral outputs. Together, our work provides a probabilistic framework for both constraining neural network models of vision with behavioral data and studying how the visual system extracts representations that guide decisions.
-
- Neuroscience
How and why is working memory (WM) capacity limited? Traditional cognitive accounts focus either on limitations on the number or items that can be stored (slots models), or loss of precision with increasing load (resource models). Here, we show that a neural network model of prefrontal cortex and basal ganglia can learn to reuse the same prefrontal populations to store multiple items, leading to resource-like constraints within a slot-like system, and inducing a trade-off between quantity and precision of information. Such ‘chunking’ strategies are adapted as a function of reinforcement learning and WM task demands, mimicking human performance and normative models. Moreover, adaptive performance requires a dynamic range of dopaminergic signals to adjust striatal gating policies, providing a new interpretation of WM difficulties in patient populations such as Parkinson’s disease, ADHD, and schizophrenia. These simulations also suggest a computational rather than anatomical limit to WM capacity.
