Since 1975, the prevalence of worldwide obesity has nearly tripled and has reached epidemic proportions (World Health Organization, 2020). An incomplete understanding surrounding the etiology of obesity has hindered the development of therapeutic interventions. Regardless, it is well known that both genetic and environmental factors contribute to its development (Goodarzi, 2018). Therefore, it is important to identify how specific genetic and environmental factors interact to contribute to the mechanisms underlying the etiology of obesity.

The endocannabinoid system (ECS), comprised of two receptors (CB1 and CB2), endogenous cannabinoids (N-arachidonoylethanolamide, [anandamide], AEA and 2-arachidonoylglycerol), and their synthetic and degradative enzymes, is recognized as a powerful regulator of energy homeostasis and body weight (Mazier et al., 2015). In general, activation of the ECS promotes energy storage, food intake, and increased weight gain. Therefore, components of the ECS are perfectly positioned to moderate individual susceptibility to obesity. In humans, there is a common genetic variant in the gene for fatty acid amide hydrolase (FAAH) (Sipe et al., 2002), the primary enzyme responsible for the inactivation of the endocannabinoid AEA. This missense mutation in FAAH (C385A; rs324420) destabilizes the FAAH protein, reduces AEA metabolism, and increases AEA signaling (Chiang et al., 2004; Sipe et al., 2002). Importantly, increased body mass index (BMI) has been associated with the low-expressing FAAH variant (A-allele carriers) (Durand et al., 2008; Monteleone et al., 2008; Sipe et al., 2005; Zhang et al., 2009). This agrees with the well-known role of AEA to stimulate feeding and enhance energy storage through the activation of CB1 receptor signaling (Mazier et al., 2015). However, the human data surrounding the C385A variant of FAAH and body weight regulation are oftentimes conflicting, with some studies showing no effect of FAAH C385A on metabolic outcomes (Jensen et al., 2007; Lieb et al., 2009). The conflicting findings may be attributed to differences in an individual’s environmental context and resulting endocrine milieu. In this regard, gene × environment interactions could govern whether the FAAH C385A genotype affects obesity susceptibility under particular environmental contexts.

Environmental conditions dictate an individual’s physiological endocrine state. For example, chronic stress and high fat diet feeding are associated with shifts in levels of circulating hormones that regulate appetite and energy homeostasis, including, but not limited to, glucocorticoids (GCs), ghrelin, and leptin (Bouassida et al., 2010; Schwarz et al., 2011; Ulrich-Lai and Ryan, 2014). Interestingly, the metabolic actions of orexigenic signals, such as GCs and ghrelin, increase endocannabinoid signaling (Balsevich et al., 2017; Edwards and Abizaid, 2016). By contrast, the anorectic peptide leptin suppresses endocannabinoid signaling to mediate its effects (Balsevich et al., 2018; Di Marzo et al., 2001). Therefore, differences in FAAH expression, due to distinct genetic FAAH variants, may influence the metabolic outcomes resulting from shifts in endocrine states. Specifically, we have previously shown that chronic exposure to GCs leads to obesity through an endocannabinoid-mediated mechanism (Bowles et al., 2015). It was likewise shown that GCs increase the activity of AMP-activated protein kinase (AMPK), through a CB1 receptor-dependent mechanism in the hypothalamus to promote weight gain (Scerif et al., 2013). Indeed hypothalamic AMPK plays an integral role in the regulation of feeding and body weight, where its activation leads to increased feeding (Andersson et al., 2004; Kim et al., 2004; Minokoshi et al., 2004). Similar to GCs, the orexigenic gastric hormone ghrelin increases the activity of hypothalamic AMPK and consequently feeding through an CB1 receptor-dependent mechanism (Kola et al., 2008). Taken together, we hypothesized that the discrepancies in the human literature for FAAH C385A and body weight outcomes are attributed to differences in their environmental context and ultimately their endocrine milieu. Therefore, we sought to characterize the behavioral, cellular, and molecular changes associated with the FAAH C385A variant in response to GC (corticosterone [CORT]) exposure using the FAAH C385A knock-in mouse model, recapitulating the common human mutation in the FAAH gene. We furthermore assessed a role for FAAH in ghrelin- and leptin-dependent feeding outcomes to determine the generalizability of these effects.

The ECS has an important role in the regulation of body weight. In terms of anandamide, activation of anandamide signaling is known to promote a positive energy balance and weight gain (Mazier et al., 2015). Moreover, endocannabinoid signaling lies downstream of several metabolic signals. For example, it is known that GCs and ghrelin, both orexigenic signals, mobilize endocannabinoid signaling, whereas anorexigenic leptin is known to suppress endocannabinoid signaling (Balsevich et al., 2018; Bowles et al., 2015; Di Marzo et al., 2001; Kola et al., 2008; Tucci et al., 2004). Therefore, genetic factors that modify endocannabinoid signaling may affect individual responses to orexigenic and anorexigenic signals. FAAH, the primary catabolic enzyme for anandamide, regulates anandamide signaling by controlling its levels. In humans, the common missense mutation (C385A) in FAAH affects FAAH protein stability, with the A/A genotype associated with approximately half the FAAH protein expression and enzymatic activity compared with the C/C genotype (Chiang et al., 2004). More specifically, T-lymphocytes from patients homozygous for the FAAH A/A variant express less than half of the FAAH protein and activity compared to WT lymphocytes. Here, we fully characterized the effects of the functional FAAH C385A mutation on GC-dependent metabolic outcomes in a novel C385A knock-in mouse model. Importantly, this FAAH C385A knock-in mouse model recapitulates the reduction in FAAH expression and activity observed in humans expressing the FAAH A/A variant (Dincheva et al., 2015). Using this model, we established the underlying molecular and cellular mechanisms that couple FAAH-AEA signaling to GC-induced feeding responses. We furthermore demonstrated that the FAAH C385A variant is not selective for GC-mediated metabolic responses, but rather governs an individual’s sensitivity to additional orexigenic signals, namely ghrelin.

As a first step, we monitored the metabolic phenotype of FAAH C/C and A/A mice under basal conditions. In this condition, FAAH C/C and A/A mice did not present differences in body weight or body composition. Interestingly, the underlying metabolic parameters contributing to body weight regulation differed between FAAH C/C and A/A mice at baseline. Compared to FAAH C/C mice, FAAH A/A mice showed lower basal food intake and matching lower energy expenditures. This phenotype could be driven by basal elevations in AEA causing reduced basal metabolism, which in turn results in lower food intake to balance the alterations in energy expenditure. Alternately, in addition to AEA, FAAH also regulates the metabolism of fatty acid amides such as oleoylethanolamide, which is known to be a potent anorectic signal (Gaetani et al., 2003). Regardless of the exact mechanism of this subtle basal phenotype, this balance between food intake and energy expenditure offsets any differences in body weight or body composition at baseline. However, it may also predispose subjects with the FAAH A/A genotype to weight gain from overconsumption. Indeed, a low basal metabolic rate is a risk factor for weight gain in both humans and rodents (Astrup et al., 1996; Astrup et al., 1999; Buscemi et al., 2005; Kunz et al., 2000; Lazzer et al., 2010; Sadowska et al., 2017). Lower basal energy expenditure relates to lower basal maintenance costs, and consequently an energy imbalance could easily arise from overconsumption in response to specific environmental contexts (abundant access to palatable food) or endocrine states (elevated levels of orexigenic signals). In fact, this is in line with our findings that FAAH A/A mice show an amplified feeding response to GC and ghrelin orexigenic signals.

In terms of GC-endocannabinoid signaling interactions, it is recognized that the duration of GC exposure affects the interaction between them (reviewed by Balsevich et al., 2017). For example, GCs mobilize endocannabinoids through both rapid, non-genomic mechanisms and delayed, genomic mechanisms. Therefore, we examined three treatment durations to assess whether the FAAH C385A polymorphism is relevant to the chronic (4 weeks), immediate (48 hr), and/or acute (single exposure) metabolic outcomes of GCs. For chronic and immediate GC treatments, we delivered a low dose of CORT (25 μg/ml) in the drinking water, which maintains the diurnal rhythmicity of circulating GCs (Karatsoreos et al., 2010). We found that regardless of treatment duration, GC exposure increased food intake exclusively in FAAH A/A mice. Furthermore, continuous GC exposure delivered for 48 hr, increased weight gain within the first 24 hr and 4 weeks of continuous GC exposure exaggerated GC-dependent weight gain. By contrast, there was no body weight phenotype 24 hr following acute GC injections, suggesting that continuous GC treatment is required to elicit weight gain. This agrees with the body of literature demonstrating that in the short term, GC actions are adaptive, redirecting energy stores and increasing food intake without affecting body weight maintenance (Dallman et al., 2004). However, prolonged GC exposure becomes maladaptive, as seen with chronic stress, which is associated with hypercortisolism, fat accumulation, and central obesity. In this context, our findings indicate that individuals with the FAAH A/A genotype are more susceptible to weight gain when confronted with elevations in GC signaling, and therefore may be particularly vulnerable to the influence of stress (Pecoraro et al., 2004; Ulrich-Lai, 2016).

The effects of the FAAH C385A variant on GC-mediated metabolic outcomes were specific to feeding responses. In particular, whereas the FAAH A/A genotype amplified the hyperphagic effects of GCs, there was no genotype effect on GC-dependent changes to energy expenditure or substrate utilization. Specifically, GC exposure decreased energy expenditure and increased carbohydrate utilization in both FAAH C/C and A/A mice. This agrees with the known role of GCs to suppress energy expenditure and promote carbohydrate utilization (Dulloo et al., 1990; Flatt, 1993; Poggioli et al., 2013). Therefore, our data suggest that while GCs mobilize AEA signaling to mediate feeding responses, it is unclear whether AEA signaling lies downstream of GC actions to regulate energy expenditure or substrate utilization. Regardless, the data herein delineate how the FAAH C385A variant affects energy balance by demonstrating that the FAAH C385A polymorphism modifies GC-induced weight gain through its effect on feeding rather than energy expenditure.

The exaggerated hyperphagic response to GC exposure was associated with increased hypothalamic anandamide levels exclusively in FAAH A/A mice. The hypothalamus is certainly recognized as one of the major brain regions responsible for endocannabinoid-mediated effects on feeding. Therefore, it is likely that elevated hypothalamic anandamide in the FAAH A/A genotype drives the heightened feeding response to orexigenic signals. Interestingly, one human study found that the C385A SNP did not associate with increased BMI per se, but rather higher levels of anandamide were positively associated with both the FAAH A/A genotype and a higher BMI (Martins et al., 2015). In agreement with this, we show that under basal conditions there is neither an effect of the A/A genotype on body weight nor anandamide content in brain regions central to endocannabinoid-mediated feeding. However, under the influence of specific endocrine drivers, such as GCs, anandamide levels increased exclusively in FAAH A/A mice within the hypothalamus, which likewise associated with a hyperphagic response selectively in the FAAH A/A mice. Taken together, GCs elevate hypothalamic anandamide levels selectively in the FAAH A/A genotype to sensitize the FAAH A/A genotype to hyperphagic feeding outcomes.

We next sought to characterize the cellular population within the hypothalamus driving the AEA-dependent exaggerated feeding response to GC exposure. Within the arcuate nucleus of the hypothalamus, POMC- and AgRP-expressing neurons are considered the prototypic regulators of homeostatic food intake (Gautron et al., 2015). Whereas POMC neuronal activity promotes satiety, AgRP neuronal activity promotes feeding. Interestingly, GCs increase AgRP neuronal firing rates to induce hyperphagia (Perry et al., 2019). Therefore, we examined whether FAAH knockdown exclusively in AgRP neurons is sufficient to recapitulate the exaggerated feeding response to GC exposure seen in FAAH A/A mice. For this purpose, we employed a recently described conditional single vector CRISPR/SaCas9 virus system (Hunker et al., 2020) for efficient cre-dependent mutagenesis of Faah (or control) into AgRP-Ires-cre mice. Considering there is low FAAH activity in the sparsely distributed hypothalamic AgRP neurons, it was unfeasible to functionally measure changes in AgRP FAAH activity, driven by the saCas9-FAAH construct, using an enzymatic FAAH activity assay. Therefore, to confirm cre-dependent reductions of FAAH activity on account of our SaCas9-FAAH construct, we assessed FAAH enzymatic activity in the hippocampus where FAAH expression is high (Egertová et al., 1998; Gulyas et al., 2004; Tsou et al., 1998). Following targeted intra-hippocampal delivery of the SaCas9-FAAH construct in CaMKIIα-cre mice to drive cre expression in hippocampal CA1 pyramidal cells (Tsien et al., 1996), we measured a dramatic, significant reduction in FAAH activity compared to the SaCas9-Control vector, validating the construct. Remarkably decreasing FAAH expression selectively in AgRP neurons paralleled the feeding phenotype of FAAH A/A mice in response to acute CORT injections. Specifically, under vehicle conditions AgRP^FAAH mice displayed reduced cumulative food intake despite no difference in basal body weights compared to AgRP^Control mice. However, following a single injection of CORT, AgRP^FAAH mice increased their light phase feeding, a period when feeding is typically low. By contrast, this hyperphagic response to acute CORT was absent in Agrp^Control mice.

Since there are no reliable FAAH antibodies to detect FAAH expression nor is there a fluorophore in the AgRP-Ires-cre mice, we could not quantify the percent of AgRP neurons targeted by our viral delivery system. Therefore, it is possible that only a subset of AgRP neurons were targeted and lacked FAAH. In fact, our HA-tagged SaCas9 protein expression profile, used to confirm cre-mediated DNA recombination, supports the notion that a discrete subset of AgRP neurons was targeted. Specifically, the HA-tagged SaCas9 protein expression spread into the dorsal aspects of the arcuate nuclei whereas AgRP neurons are largely concentrated in the ventral aspects of the arcuate nuclei. This suggests that indeed only a subset of AgRP neurons were targeted. It is possible that we targeted more dorsally positioned AgRP neurons based on our injection strategy wherein we positioned the tip of the cannula toward the dorsal aspects of the arcuate nuclei to avoid penetrating the base of the brain and cerebrospinal fluid. Nevertheless, this study demonstrates that lowering FAAH expression exclusively in AgRP neurons (targeted or widespread) is sufficient to recapitulate the hyperphagic feeding response of FAAH A/A mice to acute GC treatment. Of course, both GCs and AEA act broadly across several cell types and brain regions to regulate feeding. Our findings that reducing FAAH expression in AgRP neurons heightens GC-mediated feeding does not preclude the involvement of other brain regions. Whether other neuronal populations are likewise involved will require further work.

Given the effects of FAAH knockdown in AgRP neurons on GC-dependent feeding responses, we investigated whether AgRP neurons are likewise important cellular mediators of FAAH’s effects on leptin-dependent feeding outcomes. It is known that leptin suppresses hypothalamic endocannabinoid signaling to decrease feeding (Balsevich et al., 2018; Cardinal et al., 2012; Di Marzo et al., 2001; Jo et al., 2005). Furthermore, we have specifically shown that elevated AEA signaling in FAAH A/A mice prevents the anorectic effects of leptin following 16 hr food deprivation (Balsevich et al., 2018). Therefore, we hypothesized that FAAH deletion specifically in AgRP neurons would dampen the hypophagic responses to leptin, similar to what was seen in FAAH A/A mice. In agreement with this, AgRP^Control mice exhibited weight loss and reduced feeding in response to acute leptin exposure. However, AgRP^FAAH mice were unresponsive to acute leptin. Our results indicate that AgRP neurons are an important cellular population mediating the effects of FAAH-AEA signaling events of multiple upstream endocrine signals regulating feeding behavior.

We next explored whether the FAAH C385A variant modulates the metabolic outcomes of additional orexigenic signals. Specifically, we examined the metabolic phenotypes of FAAH C/C and A/A mice in response to ghrelin exposure based on the known interactions between ghrelin and endocannabinoid signaling pathways (Edwards and Abizaid, 2016). A single, subthreshold dose of ghrelin paralleled the outcomes arising from acute GC exposure, wherein ghrelin increased light phase food intake exclusively in FAAH A/A mice. Again, the effects were specific to feeding as ghrelin had no effect on energy expenditure across genotypes. Considering chronic stress elevates circulating GC and ghrelin levels (Abizaid, 2019), it is reasonable to suspect that individuals presenting the FAAH A/A genotype are more susceptible to stress-associated weight gain on account of amplified responses to these orexigenic signals. Follow-up studies should address the feeding response of FAAH C/C and A/A mice to acute and chronic stress exposures.

An important question raised by this study is how does the FAAH C385A variant coordinate the feeding responses to multiple orexigenic signals? For instance, is there a common pathway downstream of FAAH-AEA signaling driving the orexigenic feeding responses? Along these lines, it has previously been shown that GCs and ghrelin activate hypothalamic AMPK through a CB1R-dependent mechanism (Kola et al., 2008; Scerif et al., 2013). Indeed, hypothalamic AMPK activity elicits powerful feeding responses (Minokoshi et al., 2004). In agreement with this, we found that AMPK signaling is heightened in the hypothalamus following acute exposure to either GCs or ghrelin exclusively in FAAH A/A mice. Moreover, pretreatment with an AMPK inhibitor blocked the orexigenic response to acute GC treatment in FAAH A/A mice. The data herein provide unequivocal evidence that AMPK lies downstream of FAAH-AEA signaling to coordinate ghrelin and GC signaling.

The current study clearly demonstrates that the FAAH A/A genotype predisposes individuals to the feeding responses of orexigenic signals, CORT and ghrelin. Specifically, our working model is that orexigenic signals mobilize AEA in AgRP neurons of the hypothalamus. This effect is amplified in the A/A genotype (with low FAAH expression) because there is reduced enzymatic degradation of AEA. The exaggerated AEA levels lead to heightened CB1R activation and downstream AMPK activation to ultimately sensitize A/A individuals to orexigenic signaling outcomes. By contrast, our previous work determined that FAAH A/A mice are less responsive to the anorexigenic signal leptin (Balsevich et al., 2018). Furthermore, the current study established that FAAH knockdown exclusively in AgRP neurons is sufficient to blunt feeding and body weight responses to leptin. Thus, based on the current study and our previous findings, we demonstrate that the FAAH C385A variant shifts an individual’s sensitivity to metabolic feeding signals, where individuals with the FAAH A/A genotype are more responsive to orexigenic signals at the expense of being less responsive to anorexigenic signals (Figure 7). Given orexigenic signals favor weight gain and anorexigenic signals favor weight loss, individuals with the minor A/A genotype may show exaggerated weight gain in response to environmental conditions that increase orexigenic signals (such as GCs and ghrelin) and decrease anorexigenic signals (such as leptin). Chronic stress, for example, is known to increase levels of both GCs and ghrelin while also producing decreased levels of leptin (Bouillon-Minois et al., 2021; Lu et al., 2006). Collectively, our data indicate that human studies be conducted for the FAAH C385A polymorphism in a manner that considers external environmental contexts.

Figure 7

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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.

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Author details

1. Georgia Balsevich

   Hotchkiss Brain Institute, University of Calgary, Calgary, Canada

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review and editing

   For correspondence

   georgia.balsevich@ucalgary.ca

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7839-018X

2. Gavin N Petrie

   Hotchkiss Brain Institute, University of Calgary, Calgary, Canada

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

3. Daniel E Heinz

   Neurohomeostasis Research Group, Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7103-9621

4. Arashdeep Singh

   Monell Chemical Senses Center and Department of Neuroscience, University of Pennsylvania, Philadelphia, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

   "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

   Contribution

   Investigation

   Competing interests

   No competing interests declared

   "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

   Contribution

   Methodology

   Competing interests

   No competing interests declared

7. Haley A Vecchiarelli

   Hotchkiss Brain Institute, University of Calgary, Calgary, Canada

   Contribution

   Validation, Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6331-6107

8. Hiulan Yau

   Hotchkiss Brain Institute, University of Calgary, Calgary, Canada

   Contribution

   Investigation

   Competing interests

   No competing interests declared

9. Martin Sticht

   Hotchkiss Brain Institute, University of Calgary, Calgary, Canada

   Contribution

   Investigation

   Competing interests

   No competing interests declared

10. Roger J Thompson

    Hotchkiss Brain Institute, University of Calgary, Calgary, Canada

    Contribution

    Resources

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-7019-7246

11. Francis S Lee

    Weill Cornell Medical College, Cornell University, New York, United States

    Contribution

    Resources

    Competing interests

    No competing interests declared

    "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

    Contribution

    Resources, Methodology, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-3465-5331

13. Prasanth K Chelikani

    Texas Tech University, School of Veterinary Medicine, Amarillo, United States

    Contribution

    Resources, Methodology, Writing – review and editing

    Competing interests

    No competing interests declared

14. Nils C Gassen

    Neurohomeostasis Research Group, Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany

    Contribution

    Investigation, Methodology, Writing – review and editing

    Competing interests

    No competing interests declared

15. Matthew N Hill

    Hotchkiss Brain Institute, University of Calgary, Calgary, Canada

    Contribution

    Conceptualization, Supervision, Funding acquisition, Methodology, Project administration, Writing – review and editing

    For correspondence

    mnhill@ucalgary.ca

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-7144-9209

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