Fatty Acid Amide Hydrolase Gene Research Articles

Association between the FAAH C385A variant (rs324420) and obesity-related traits: a systematic review.

Overweight and obesity are the consequence of a sustained positive energy balance. Twin studies show high heritability rates pointing to genetics as one of the principal risk factors. By 2022, genomic studies led to the identification of almost 300 obesity-associated variants that could help to fill the gap of the high heritability rates. The endocannabinoid system is a critical regulator of metabolism for its effects on the central nervous system and peripheral tissues. Fatty acid amide hydrolase (FAAH) is a key enzyme in the inactivation of one of the two endocannabinoids, anandamide, and of its congeners. The rs324420 variant within the FAAH gene is a nucleotide missense change at position 385 from cytosine to adenine, resulting in a non-synonymous amino acid substitution from proline to threonine in the FAAH enzyme. This change increases sensitivity to proteolytic degradation, leading to reduced FAAH levels and increased levels of anandamide, associated with obesity-related traits. However, association studies of this variant with metabolic parameters have found conflicting results. This work aims to perform a systematic review of the existing literature on the association of the rs324420 variant in the FAAH gene with obesity and its related traits. A literature search was conducted in PubMed, Web of Science, and Scopus. A total of 645 eligible studies were identified for the review. After the identification, duplicate elimination, title and abstract screening, and full-text evaluation, 28 studies were included, involving 28 183 individuals. We show some evidence of associations between the presence of the variant allele and higher body mass index, waist circumference, fat mass, and waist-to-hip ratio levels and alterations in glucose and lipid homeostasis. However, this evidence should be taken with caution, as many included studies did not report a significant difference between genotypes. These discordant results could be explained mainly by the pleiotropy of the endocannabinoid system, the increase of other anandamide-like mediators metabolized by FAAH, and the influence of gene-environment interactions. More research is necessary to study the endocannabinoidomic profiles and their association with metabolic diseases.

Multimodal covarying brain patterns mediate genetic and psychological contributions to individual differences in pain sensitivity.

Individuals vary significantly in their pain sensitivity, with contributions from the brain, genes, and psychological factors. However, a multidimensional model integrating these factors is lacking due to their complex interactions. To address this, we measured pain sensitivity (ie, pain threshold and pain tolerance) using the cold pressor test, collected magnetic resonance imaging (MRI) data and genetic data, and evaluated psychological factors (ie, pain catastrophizing, pain-related fear, and pain-related anxiety) from 450 healthy participants with both sexes (160 male, 290 female). Using multimodal MRI fusion methods, we identified 2 pairs of covarying structural and functional brain patterns associated with pain threshold and tolerance, respectively. These patterns primarily involved regions related to self-awareness, sensory-discriminative, cognitive-evaluative, motion preparation and execution, and emotional aspects of pain. Notably, pain catastrophizing was negatively correlated with pain tolerance, and this relationship was mediated by the multimodal covarying brain patterns in male participants only. Furthermore, we identified an association between the single-nucleotide polymorphism rs4141964 within the fatty acid amide hydrolase gene and pain threshold, mediated by the identified multimodal covarying brain patterns across all participants. In summary, we suggested a model that integrates the brain, genes, and psychological factors to elucidate their role in shaping interindividual variations in pain sensitivity, highlighting the important contribution of the multimodal covarying brain patterns as important biological mediators in the associations between genes/psychological factors and pain sensitivity.

Functional Variation in the FAAH Gene Is Directly Associated with Subjective Well-Being and Indirectly Associated with Problematic Alcohol Use.

Fatty acid amide hydrolase (FAAH) is an enzyme that degrades anandamide, an endocannabinoid that modulates mesolimbic dopamine release and, consequently, influences states of well-being. Despite these known interactions, the specific role of FAAH in subjective well-being remains underexplored. Since well-being is a dynamic trait that can fluctuate over time, we hypothesized that we could provide deeper insights into the link between FAAH and well-being using longitudinal data. To this end, we analyzed well-being data collected three years apart using the WHO (Ten) Well-Being Index and genotyped a functional polymorphism in the FAAH gene (rs324420, Pro129Thr) in a sample of 2822 individuals. We found that the A-allele of rs324420, which results in reduced FAAH activity and elevated anandamide levels, was associated with lower well-being scores at both time points (Wave I, B: -0.52, p = 0.007; Wave II, B: -0.41, p = 0.03, adjusted for age and sex). A subsequent phenome-wide association study (PheWAS) affirmed our well-being findings in the UK Biobank (N = 126,132, alternative C-allele associated with elevated happiness, p = 0.008) and revealed an additional association with alcohol dependence. In our cohort, using lagged longitudinal mediation analyses, we uncovered evidence of an indirect association between rs324420 and problematic alcohol use (AUDIT-P) through the pathway of lower well-being (indirect effect Boot: 0.015, 95% CI [0.003, 0.030], adjusted for AUDIT in Wave I). We propose that chronically elevated anandamide levels might influence disruptions in the endocannabinoid system-a biological contributor to well-being-which could, in turn, contribute to increased alcohol intake, though multiple factors may be at play. Further genetic studies and mediation analyses are needed to validate and extend these findings.

The FAAH inhibitor URB597 reduces cocaine intake during conditioned punishment and mitigates cocaine seeking during withdrawal

The endocannabinoid system is prominently implicated in the control of cocaine reinforcement due to its relevant role in synaptic plasticity and neurotransmitter modulation in the mesocorticolimbic system. The inhibition of fatty acid amide hydrolase (FAAH), and the resulting increase in anandamide and other N-acylethanolamines, represents a promising strategy for reducing drug seeking. In the present study, we aimed to assess the effects of the FAAH inhibitor URB597 (1 mg/kg) on crucial features of cocaine addictive-like behaviour in mice. Therefore, we tested the effects of URB597 on acquisition of cocaine (0.6 mg/kg/inf) self-administration, compulsive-like cocaine intake and cue-induced drug-seeking behaviour during withdrawal. URB597 reduced cocaine intake under conditioned punishment while having no impact on acquisition. This result was associated to increased cannabinoid receptor 1 gene expression in the ventral striatum and medium spiny neurons activation in the nucleus accumbens shell. Moreover, URB597 mitigated cue-induced drug-seeking behaviour during prolonged abstinence and prevented the withdrawal-induced increase in FAAH gene expression in the ventral striatum. In this case, URB597 decreased activation of medium spiny neurons in the nucleus accumbens core. Our findings evidence the prominent role of endocannabinoids in the development of cocaine addictive-like behaviours and support the potential of FAAH inhibition as a therapeutical target for the treatment of cocaine addiction.

Assessment of the effects of CNR1, FAAH and MGLL gene variations on the synthetic cannabinoid use disorder

Abstract Objectives Given that drug addiction occurs as a result of complex gene-environment interaction, a number of studies claimed that cannabinoid receptor 1 (CNR1), fatty acid amide hydrolase (FAAH), and monoacylglycerol lipase (MGLL) single nucleotide polymorphisms (SNPs) are associated with the risk of substance use disorders such as cannabis, opioids, and, methamphetamine. However, scientific research on genetic susceptibility to synthetic cannabinoid addiction is limited. In this population-based case-control study, we aimed to evaluate the genetic susceptibility to synthetic cannabinoid use disorder in terms of these three endocannabinoid system genes in the Turkish population. Methods 100 individuals diagnosed with synthetic cannabinoid use disorder according to Diagnostics and Statistical Manual of Mental Disorders-5 criteria and 100 healthy volunteers have recruited for the study. Genotyping of the CNR1 rs1049353, FAAH rs324420, and MGLL rs604300 SNPs was performed using Real-Time Polymerase Chain Reaction hybridization probes. Results The patient and control groups consist of 98 % male, 2 % female, 80 % male, and 20 % female individuals, respectively. The genotype distributions were consistent with Hardy–Weinberg equilibrium for all SNPs (p>0.05). FAAH rs324420 and MGLL 604300 SNPs were genotyped for the first time in the Turkish population, and the variant allele frequencies were found as 0.205 and 0.085, respectively. Allele frequencies and genotype distributions CNR1 rs1049353, FAAH rs324420, and MGLL rs604300 SNPs were similar between the patient and control group (p>0.05). Conclusions These results indicate that CNR1, FAAH, and MGLL gene polymorphisms do not influence the risk of synthetic cannabinoid use disorder in the Turkish population.

Characterization of the biochemical and behavioral effects of cannabidiol: implications for migraine

Cannabidiol (CBD) is the main pharmacologically active phytocannabinoid. CBD exerts an analgesic effect in several pain models, does not have side effects and has low toxicity. The data about CBD mechanisms of action in pain and its therapeutic potential in this area are limited. Here, we tested CBD effects in animal models specific for migraine. We assayed CBD distribution in plasma and in cranial areas related to migraine pain in male Sprague Dawley rats treated chronically (5 days). Successively, we tested CBD activity on the behavioral and biochemical effects induced in the acute and the chronic migraine animal models by nitroglycerin (NTG) administration. In the acute migraine model, rats received CBD (15 mg or 30 mg/kg, i.p) 3 h after NTG (10 mg/kg i.p.) or vehicle injection. In the chronic migraine model, rats were treated with CBD and NTG every other day over nine days with the following doses: CBD 30 mg/kg i.p., NTG 10 mg/kg i.p. We evaluated behavioral parameters with the open field and the orofacial formalin tests. We explored the fatty acid amide hydrolase gene expression, cytokines mRNA and protein levels in selected brain areas and CGRP serum level. CBD levels in the meninges, trigeminal ganglia, cervical spinal cord, medulla pons, and plasma were higher 1 h after the last treatment than after 24 h, suggesting that CBD penetrates but does not accumulate in these tissues. In the acute model, CBD significantly reduced NTG-induced trigeminal hyperalgesia and CGRP and cytokine mRNA levels in peripheral and central sites. In the chronic model, CBD caused a significant decrease in NTG-induced IL-6 protein levels in the medulla–pons, and trigeminal ganglion. It also reduced CGRP serum levels. By contrast, CBD did not modulate TNF-alpha protein levels and fatty acid amide hydrolase (FAAH) gene expression in any of investigated areas. In both experimental conditions, there was no modulation of anxiety, motor/exploratory behavior, or grooming. These findings show that CBD reaches brain areas involved in migraine pain after systemic administration. They also show for the first time that CBD modulates migraine-related nociceptive transmission, likely via a complex signaling mechanism involving different pathways.

Endocannabinergic modulation of central serotonergic activity in healthy human volunteers

BackgroundThe serotonergic and the endocannabinoid system are involved in the etiology of depression. Depressive patients exhibit low serotonergic activity and decreased level of the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2AG). Since the cannabinoid (CB) 1 receptor is activated by endogenous ligands such as AEA and 2AG, whose concentration are controlled by the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, respectively, we investigated the effects on serotonergic utilization. In this study, we investigated the impact of the rs1049353 single-nucleotide polymorphism (SNP) of the cannabinoid receptor 1 (CNR1) gene, which codes the endocannabinoid CB1 receptor, and the rs324420 SNP of the FAAH gene on the serotonergic and endocannabinoid system in 59 healthy volunteers.MethodsSerotonergic activity was measured by loudness dependence of auditory-evoked potentials (LDAEP). Plasma concentrations of AEA, 2AG and its inactive isomer 1AG were determined by mass spectrometry. Genotyping of two SNPs (rs1049353, rs344420) was conducted by polymerase chain reaction (PCR) and differential enzymatic analysis with the PCR restriction fragment length polymorphism method.ResultsGenotype distributions by serotonergic activity or endocannabinoid concentration showed no differences. However, after detailed consideration of the CNR1-A-allele-carriers, a reduced AEA (A-allele-carrier M = 0.66, SD = 0.24; GG genotype M = 0.72, SD = 0.24) and 2AG (A-allele-carriers M = 0.70, SD = 0.33; GG genotype M = 1.03, SD = 0.83) plasma concentration and an association between the serotonergic activity and the concentrations of AEA and 2AG has been observed.ConclusionsOur results suggest that carriers of the CNR1-A allele may be more susceptible to developing depression.

The study of rs324420 (C385A) polymorphism of the FAAH gene of the endocannabinoid system in patients with epilepsy and ADHD

The endocannabinoid (eCB) system regulates many physiological functions in the central nervous system. Fatty acid amide hydrolase (FAAH) is an essential enzyme in the eCB system, degrading anandamide. Single nucleotide polymorphism (SNP) rs324420 is a common genetic polymorphism of the FAAH gene and has been associated with susceptibility to neurological conditions. This study examined whether the SNP rs324420 (C385A) is associated with epilepsy and attention deficit hyperactivity disorder (ADHD). This study consists of two case-control parts. The first part comprises 250 epilepsy subjects and 250 healthy individuals as controls. The second one comprises 157 cases with ADHD and 136 healthy individuals as controls. Genotyping was carried out using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) technique. Interestingly, the FAAH C384A genotype (OR 1.755, 95 % CI 1.124–2.742, p = 0.013) and allele (OR 1.462, 95 % CI 1.006–2.124, p = 0.046) distribution showed an association with generalized epilepsy. On the other hand, this SNP was not associated with the risk of ADHD. To our knowledge, there was no study on the association between rs324420 (C385A) polymorphism and the risks of ADHD or epilepsy. This study provided the first evidence of an association between generalized epilepsy and rs324420 (C385A) of FAAH. Larger sample sizes and functional studies are warranted to explore the clinical utility of FAAH genotyping as a possible marker for increased generalized epilepsy risk.

Fatty acid amide hydrolase and 9-lipoxygenase modulate cotton seedling growth by ethanolamide oxylipin levels.

Polyunsaturated N-acylethanolamines (NAEs) can be hydrolyzed by fatty acid amide hydrolase (FAAH) or oxidized by lipoxygenase (LOX). In Arabidopsis (Arabidopsis thaliana), the 9-LOX product of linoleoylethanolamide, namely, 9-hydroxy linoleoylethanolamide (9-NAE-HOD), is reported to negatively regulate seedling development during secondary dormancy. In upland cotton (Gossypium hirsutum L.), six putative FAAH genes (from two diverged groups) and six potential 9-LOX genes are present; however, their involvement in 9-NAE-HOD metabolism and its regulation of seedling development remain unexplored. Here, we report that in cotton plants, two specific FAAH isoforms (GhFAAH Ib and GhFAAH IIb) are needed for hydrolysis of certain endogenous NAEs. Virus-induced gene silencing (VIGS) of either or both FAAHs led to reduced seedling growth and this coincided with reduced amidohydrolase activities and elevated quantities of endogenous 9-NAE-HOD. Transcripts of GhLOX21 were consistently elevated in FAAH-silenced tissues, and co-silencing of GhLOX21 and GhFAAH (Ib and/or IIb) led to reversal of seedling growth to normal levels (comparable with no silencing). This was concomitant with reductions in the levels of 9-NAE-HOD, but not of 13-NAE-HOD. Pharmacological experiments corroborated the genetic and biochemical evidence, demonstrating that direct application of 9-NAE-HOD, but not 13-NAE-HOD or their corresponding free fatty acid oxylipins, inhibited the growth of cotton seedlings. Additionally, VIGS of GhLOX21 in cotton lines overexpressing AtFAAH exhibited enhanced growth and no detectable 9-NAE-HOD. Altogether, we conclude that the growth of cotton seedlings involves fine-tuning of 9-NAE-HOD levels via FAAH-mediated hydrolysis and LOX-mediated production, expanding the mechanistic understanding of plant growth modulation by NAE oxylipins to a perennial crop species.

Enhanced seedling growth by 3-n-pentadecylphenolethanolamide is mediated by fatty acid amide hydrolases in upland cotton (Gossypium hirsutum L.).

Fatty acid amide hydrolase (FAAH) is a conserved amidase that is known to modulate the levels of endogenous N‐acylethanolamines (NAEs) in both plants and animals. The activity of FAAH is enhanced in vitro by synthetic phenoxyacylethanolamides resulting in greater hydrolysis of NAEs. Previously, 3‐n‐pentadecylphenolethanolamide (PDP‐EA) was shown to exert positive effects on the development of Arabidopsis seedlings by enhancing Arabidopsis FAAH (AtFAAH) activity. However, there is little information regarding FAAH activity and the impact of PDP‐EA in the development of seedlings of other plant species. Here, we examined the effects of PDP‐EA on growth of upland cotton ( Gossypium hirsutum L. cv Coker 312) seedlings including two lines of transgenic seedlings overexpressing AtFAAH. Independent transgenic events showed accelerated true‐leaf emergence compared with non‐transgenic controls. Exogenous applications of PDP‐EA led to increases in overall seedling growth in AtFAAH transgenic lines. These enhanced‐growth phenotypes coincided with elevated FAAH activities toward NAEs and NAE oxylipins. Conversely, the endogenous contents of NAEs and NAE‐oxylipin species, especially linoleoylethanolamide and 9‐hydroxy linoleoylethanolamide, were lower in PDP‐EA treated seedlings than in controls. Further, transcripts for endogenous cotton FAAH genes were increased following PDP‐EA exposure. Collectively, our data corroborate that the enhancement of FAAH enzyme activity by PDP‐EA stimulates NAE‐hydrolysis and that this results in enhanced growth in seedlings of a perennial crop species, extending the role of NAE metabolism in seedling development beyond the model annual plant species, Arabidopsis thaliana .

Effects of active, inactive, and derivatives of Akkermansia muciniphila on the expression of the endocannabinoid system and PPARs genes

This study aimed to investigate the effects of active and heat-inactivated forms of Akkermansia muciniphila, bacterium-derived outer membrane vesicles (OMVs), and cell-free supernatant on the transcription of endocannabinoid system (ECS) members, including cannabinoid receptors 1 and 2 (CB1 and CB2), fatty acid amide hydrolase (FAAH), and peroxisome proliferator-activated receptors (PPARs) genes (i.e., α, β/δ, and δ) in Caco-2 and HepG-2 cell lines. After the inoculation of A. muciniphila in brain heart infusion enriched medium, OMVs and cell-free supernatant were extracted. For the investigation of the effects of bacteria and its derivatives on the expression of ECS and PPARs genes, the aforementioned cells were treated by active and heat-inactivated bacteria, OMVs, and cell-free supernatant. Quantitative real-time polymerase chain reaction analysis revealed that both forms of the bacterium, bacterial-derived OMVs, and cell-free supernatant could affect the expression of CB1, CB2, FAAH, and PPARs genes (i.e., α, β/δ, and δ) significantly (P < 0.05). Considering the engagement of the aforementioned genes in metabolic pathways, it might be suggested that both forms of the bacterium, OMVs, and cell-free supernatant might have the potential to serve as a probiotic, paraprobiotic, and postbiotic candidate to prevent obesity, metabolic disorders, and liver diseases.

Comparative Transcriptome Analysis Reveals Regulatory Mechanism of Long Non-Coding RNAs during Abdominal Preadipocyte Adipogenic Differentiation in Chickens.

Simple SummaryExcessive fat deposition, particularly abdominal fat, negatively affects meat quality, feed utilization, and reproduction performance in chickens. Adipogenesis is a well-orchestrated process that involves a network of regulatory molecules. Emerging evidence has shown that long non-coding RNAs (lncRNAs) participate in mammalian adipogenesis. However, limited information is available about their role in adipogenesis in chickens. Therefore, we investigated the genome-wide identification, expression profiles, and regulatory networks of lncRNAs during adipogenic differentiation of chicken abdominal preadipocytes. We found that lncRNAs were expressed in chicken abdominal adipocytes, characterized by their differentiation stage-specific expression pattern and were involved in multiple lipid metabolism-related pathways. Several lncRNAs were identified as key lncRNAs responsible for adipogenic differentiation. These key lncRNAs could regulate lipid-related protein-encoding genes in cis- and trans-regulation manners, and/or competitively sponge miRNA to sequester it away from lipid-related genes, thereby functioning as regulators of chicken adipogenesis. These findings provide valuable information that improves our understanding of functional mechanisms of lncRNAs underlying adipogenesis and contributes to the genetic improvement of excessive abdominal fat in chickens.Long non-coding RNAs (lncRNAs) are implicated in mammalian adipogenesis and obesity. However, their genome-wide distribution, expression profiles, and regulatory mechanisms during chicken adipogenesis remain rarely understood. In the present study, lncRNAs associated with adipogenesis were identified from chicken abdominal adipocytes at multiple differentiation stages using Ribo-Zero RNA-seq. A total of 15,179 lncRNAs were identified and characterized by stage-specific expression patterns. Of these, 840 differentially expressed lncRNAs were detected, and their cis- and trans-target genes were significantly enriched in multiple lipid-related pathways. Through weighted gene co-expression network analysis (WGCNA) and time-series expression profile clustering analysis, 14 key lncRNAs were identified as candidate regulatory lncRNAs in chicken adipogenic differentiation. The cis- and trans-regulatory interactions of key lncRNAs were constructed based on their differentially expressed cis- and trans-target genes, respectively. We also constructed a competing endogenous RNA (ceRNA) network based on the key lncRNAs, differentially expressed miRNAs, and differentially expressed mRNAs. MSTRG.25116.1 was identified as a potential regulator of chicken abdominal preadipocyte adipogenic differentiation by acting as a transcriptional trans-regulator of fatty acid amide hydrolase (FAAH) gene expression and/or a ceRNA that post-transcriptionally mediates FAAH gene expression by sponging gga-miR-1635.

Genetic Variants of Fatty Acid Amide Hydrolase Modulate Acute Inflammatory Responses to Colitis in Adult Male Mice

Cannabinoids, including cannabis derived phytocannabinoids and endogenous cannabinoids (endocannabinoids), are typically considered anti-inflammatory. One such endocannabinoid is N-arachidonoylethanolamine (anandamide, AEA), which is metabolized by fatty acid amide hydrolase (FAAH). In humans, there is a loss of function single nucleotide polymorphism (SNP) in the FAAH gene (C385A, rs324420), that leads to increases in the levels of AEA. Using a mouse model with this SNP, we investigated how this SNP affects inflammation in a model of inflammatory bowel disease. We administered 2,4,6-trinitrobenzene sulfonic acid (TNBS) intracolonically, to adult male FAAH SNP mice and examined colonic macroscopic tissue damage and myeloperoxidase activity, as well as levels of plasma and amygdalar cytokines and chemokines 3 days after administration, at the peak of colitis. We found that mice possessing the loss of function alleles (AC and AA), displayed no differences in colonic damage or myeloperoxidase activity compared to mice with wild type alleles (CC). In contrast, in plasma, colitis-induced increases in interleukin (IL)-2, leukemia inhibitory factor (LIF), monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF) were reduced in animals with an A allele. A similar pattern was observed in the amygdala for granulocyte colony stimulating factor (G-CSF) and MCP-1. In the amygdala, the mutant A allele led to lower levels of IL-1α, IL-9, macrophage inflammatory protein (MIP)-1β, and MIP-2 independent of colitis—providing additional understanding of how FAAH may serve as a regulator of inflammatory responses in the brain. Together, these data provide insights into how FAAH regulates inflammatory processes in disease.

Cannabinoid receptor type 2 gene is associated with comorbidity of schizophrenia and cannabis dependence and fatty acid amide hydrolase gene is associated with cannabis dependence in the Spanish population.

The endocannabinoid system has been associated with various psychiatric disorders, such as schizophrenia or addictive disorders. Recent studies have found that some polymorphisms in the cannabinoid receptor type 2 (CNR2), cannabinoid receptor type 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes could play an important role as risk factors in the etiology of these diseases. We analysed different cannabinoid gene polimorphisms from non-substance using patients diagnosed with schizophrenia (n = 379), schizophrenic patients with cannabis use disorders (n = 124), cannabis users who did not have psychoses (n = 71), and 316 controls from various Spanish hospitals and health centres. We found a statistical association between polymorphisms rs35761398 and rs12744386 in the CNR2 gene and comorbidity of schizophrenia and cannabis dependence, as well as an association between loss of heterozygosity (overdominance) for polymorphism rs324420 in the FAAH gene and cannabis dependence in a Spanish population sample. The rs35761398 and rs12744386 polymorphisms in the CNR2 gene are genetic risk factors for schizophrenia in cannabis-dependent subjects. Loss of heterozygosity for polymorphism rs324420 in the FAAH gene is a genetic risk factor for cannabis dependence in this population.

Augmentation in NF-κB, NRF2 and FAAH Gene Expression in Bipolar Depression

Bipolar Disorder (BD) is associated with increased inflammatory and oxidative stress markers. Nuclear factor erythroid 2-related factor-2 (NRF2) is a transcription factor implicated in the antioxidant response while the nuclear factor kappa B (NF-κB) participates in the transcription of genes related to the inflammatory response. The enzymes monoacylglycerol lipase (MGLL) and fatty-acid-amide hydrolase (FAAH) are endocannabinoid-degrading enzymes whose inhibition leads to a reduction in neuroinflammation. If implicated in BD, these factors might become novel treatment targets.

Peripheral changes of endocannabinoid system components in episodic and chronic migraine patients: A pilot study.

Preclinical and clinical evidence suggests a role for the dysregulation of the endocannabinoid system in migraine pain, particularly in subjects with chronic migraine. The gene expression of endocannabinoid system components was assayed in peripheral blood mononuclear cells of 25 subjects with episodic migraine, 26 subjects with chronic migraine with medication overuse (CM-MO) and 24 age-matched healthy controls. We also evaluated the protein expression of cannabinoid receptors 1 and 2 as well as DNA methylation changes in genes involved in endocannabinoid system components. Both episodic migraine and CM-MO subjects showed higher cannabinoid receptor 1 and cannabinoid receptor 2 gene and protein expression compared to controls. Fatty acid amide hydrolase gene expression, involved in anandamide degradation, was lower in migraine groups compared to healthy control subjects. N-arachidonoyl phosphatidylethanolamine phospholipase D gene expression was significantly higher in all migraineurs, as were monoacylglycerol lipase and diacylglycerol lipase gene expressions. The above markers significantly correlated with the number of migraine days and with the days of acute drug intake. The findings point to transcriptional changes in endocannabinoid system components occurring in migraineurs. These changes were detected peripherally, which make them amenable for a wider adoption to further investigate their role and applicability in the clinical field.clinicaltrials.gov NTC04324710.

Association of cannabinoid receptor genes (CNR1 and CNR2) polymorphisms and panic disorder

ABSTRACTBackground and objectives: Panic disorder (PD) is an anxiety disorder characterized by recurrent and unexpected panic attacks along with sudden onset of apprehension, fear or terror. The endocannabinoid system (ECS) has a role in stress recovery, regulating anxiety. The aim of this study was to analyze potential genetic alterations in key ECS targets in patients suffering from panic disorders.Design and methods: We analyzed single nucleotide polymorphisms (SNPs) of the cannabinoid receptors (CNR1; CNR2) and the endocannabinoid hydrolytic enzyme fatty acid amide hydrolase (FAAH) genes in 164 Spanish PD patients and 320 matched controls.Results: No significant differences were observed in the SNPs of the CNR2 and FAAH genes tested. However, when analyzing genotype-by-sex interaction at A592G (rs2501431) and C315T (rs2501432) in the CNR2 gene, the presence of the G-allele in males was associated with a protective haplotype. Genotyping analysis revealed that variants in CNR1 confer vulnerability to PD, with a significantly increased risk associated with the G-allele (rs12720071) and C-allele (rs806368). This finding was consistent when analyzing genotype-by-sex interaction, where females presented a greater PD risk.Conclusions: Polymorphisms at the CNR1 gene may be a risk factor for PD contributing to sex-specific dysfunction in females.

N-acyl taurines are endogenous lipid messengers that improve glucose homeostasis

Fatty acid amide hydrolase (FAAH) degrades 2 major classes of bioactive fatty acid amides, the N-acylethanolamines (NAEs) and N-acyl taurines (NATs), in central and peripheral tissues. A functional polymorphism in the human FAAH gene is linked to obesity and mice lacking FAAH show altered metabolic states, but whether these phenotypes are caused by elevations in NAEs or NATs is unknown. To overcome the problem of concurrent elevation of NAEs and NATs caused by genetic or pharmacological disruption of FAAH in vivo, we developed an engineered mouse model harboring a single-amino acid substitution in FAAH (S268D) that selectively disrupts NAT, but not NAE, hydrolytic activity. The FAAH-S268D mice accordingly show substantial elevations in NATs without alterations in NAE content, a unique metabolic profile that correlates with heightened insulin sensitivity and GLP-1 secretion. We also show that N-oleoyl taurine (C18:1 NAT), the most abundant NAT in human plasma, decreases food intake, improves glucose tolerance, and stimulates GPR119-dependent GLP-1 and glucagon secretion in mice. Together, these data suggest that NATs act as a class of lipid messengers that improve postprandial glucose regulation and may have potential as investigational metabolites to modify metabolic disease.

Transcriptional regulation of the endocannabinoid system in a rat model of binge-eating behavior reveals a selective modulation of the hypothalamic fatty acid amide hydrolase gene.

Binge-eating episodes are recurrent and are defining features of several eating disorders. Thus binge-eating episodes might influence eating disorder development of which exact underlying mechanisms are still largely unknown. Here we focused on the transcriptional regulation of the endocannabinoid system, a potent regulator of feeding behavior, in relevant rat brain regions, using a rat model in which a history of intermittent food restriction and a frustration stress induce binge-like palatable food consumption. We observed a selective down-regulation of fatty acid amide hydrolase (faah) gene expression in the hypothalamus of rats showing the binge-eating behavior with a consistent reduction in histone 3 acetylation at lysine 4 of the gene promoter. No relevant changes were detected for any other endocannabinoid system components in any brain regions under study, as well as for the other epigenetic mechanisms investigated (DNA methylation and histone 3 lysine 27 methylation) at the faah gene promoter. Our findings suggest that faah transcriptional regulation is a potential biomarker of binge-eating episodes, with a relevant role in the homeostatic regulation of food intake.

FAAH variant Pro129Thr modulates subjective effects produced by cocaine administration.

The endogenous cannabinoid anandamide (AEA), an agonist at type-1 cannabinoid (CB1) receptors, is metabolized by fatty acid amide hydrolase (FAAH). The common variant rs324420 C->A within the FAAH gene on chromosome 1 codes for a missense substitution (Pro129Thr), resulting in decreased FAAH activity and increased endocannabinoid potentiation. This FAAH variant has been linked to alterations in mood and stress reactivity, as well as being independently linked to increased risk for addiction. We hypothesized that cocaine use disordered (CUD) participants with the FAAH Pro129 Thr variant would exhibit a distinct profile of cocaine-induced subjective effects in the laboratory. A total of 70 CUD participants received intravenous doses of saline (placebo, 0 mg) and cocaine (20, 40 mg) in a lab-controlled setting and rated 10 subjective effect measures prior to and following saline and cocaine administration, using a Visual Analog Scale (VAS). The variant allele was associated with increased cocaine-induced subjective ratings for "Drug Effect," "High," and "Depressed." The prevalence of the variant allele A and the AA genotypes were greater in our CUD group than in the general population (A allele: 47% vs. 34%; AA genotype: 30% vs. 13%; p < .05). Finally, the reported amount and frequency of tobacco and cocaine use was higher in subjects with the AC/AA allele. These results add to existing evidence that this variant of the FAAH genotype may be over-represented among those who have CUD, and this over-representation may result from greater subjective responses to cocaine administration. (Am J Addict 2018;27:567-573).