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

  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

  • Curated by eLife

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    eLife assessment

    In this manuscript, the authors address the variable results and data regarding the role of the FAAH variant (C385A at the nucleotide level and P129T at the protein level) in the control of feeding. The authors hypothesize that the variable results might be due to the environmental context, specifically stress related conditions. They designed studies to address the role of glucocorticoids in regulating feeding and metabolism.

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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 AMP-activated protein kinase (AMPK). AMPK inhibition occluded the amplified hyperphagic response to glucocorticoids in FAAH A/A mice. FAAH knockdown exclusively in agouti-related protein (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.

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  1. Version published to 10.7554/elife.81919 on eLife
  2. eLife

    eLife assessment

    In this manuscript, the authors address the variable results and data regarding the role of the FAAH variant (C385A at the nucleotide level and P129T at the protein level) in the control of feeding. The authors hypothesize that the variable results might be due to the environmental context, specifically stress related conditions. They designed studies to address the role of glucocorticoids in regulating feeding and metabolism.

  3. eLife

    Reviewer #1 (Public Review):

    The authors note contradictory clinical data on the effects of functional FAAH mutations on body weight in clinical samples. They aim to resolve this issue via animal modes and genetic approaches combined with endocrine manipulations to vary "context". Major strengths are comprehensive evaluation of FAAH variant in several models of neuroendocrine changes in body weight (CORT, leptin, gherlin) and provide some mechanistic insight at the signal transduction level. Localization of FAAH modulation to AGRP neurons is a strength. Weaknesses include lack of cellular mechanisms, i.e. how AEA release from AGRP neurons affects ongoing cellular/synaptic activity to regulate behavioral/physiological phenotypes. The work is impactful as it potentially reconciles contradictory clinical data, is comprehensive and rigorous in many ways. These data will provide insight into how FAAH activity regulates body weight in the context of distinct hormonal signals and will likely have a major impact on the field.

  4. eLife

    Reviewer #2 (Public Review):

    Interestingly, prior analysis of the 385A allele indicated a post-translational mechanism that led to instability of the protein and an ~50% reduction in protein concentrations and FAAH activity. In addition, FAAH degrades AEA, one of several known endocannabinoids, suggesting that FAAH is a significant part of the endocannabinoid signaling although there are several other endocannabinoids that are not affected by FAAH.

    At the basal state, normal chow and home cage conditions, wild type mice were not different from homozygous mutant FAAH mice in terms of body weight and body composition. However, the FAAH mutants had reduced food intake that was compensated for by lower energy expenditure. This finding strongly suggests that compensatory mechanisms are in play during lifelong changes in strengths of AEA signaling.

    The authors go on to perform increasingly shorter durations of manipulations of glucocorticoid manipulations (down to several hours) to examine the impact of the FAAH mutation. Thus, the authors are able to conclude that the FAAH mutation leads to acute changes of feeding.

    Examination of the biochemical signaling pathway showed that AMPK activity is affected by GC/FAAH experimental manipulation although the relevance of the finding should be somewhat tempered by the later studies in hypothalamic AGRP neurons and FAAH since the measures were not neuron specific.

    Finally, the authors examine the role of FAAH expression in hypothalamic AGRP neurons since their measures of AEA concentrations showed changes only in the hypothalamus after CORT treatments. Virally mediated knockdown of FAAH, using a AAV CRISPR/Cas9 single vector system, indicated that knockdown of FAAH in AGRP neurons is sufficient to recapitulate the authors' findings on GC-modulated feeding.

    The data are convincing and settles the issue of variability in the evidence regarding the role of FAAH genetic variants in feeding.

  5. Version published to 10.1101/2022.08.09.503403v1 on bioRxiv