Lipid Signaling System Research Articles

Endocannabinoid System and Metabolism: The Influences of Sex

The endocannabinoid system (ECS) is a lipid signaling system involved in numerous physiological processes, such as endocrine homeostasis, appetite control, energy balance, and metabolism. The ECS comprises endocannabinoids, their cognate receptors, and the enzymatic machinery that tightly regulates their levels within tissues. This system has been identified in various organs, including the brain and liver, in multiple mammalian and non-mammalian species. However, information regarding the sex-specific regulation of the ECS remains limited, even though increasing evidence suggests that interactions between sex steroid hormones and the ECS may ultimately modulate hepatic metabolism and energy homeostasis. Within this framework, we will review the sexual dimorphism of the ECS in various animal models, providing evidence of the crosstalk between endocannabinoids and sex hormones via different metabolic pathways. Additionally, we will underscore the importance of understanding how endocrine-disrupting chemicals and exogenous cannabinoids influence ECS-dependent metabolic pathways in a sex-specific manner.

Trauma film viewing and intrusive memories: Relationship between salivary alpha amylase, endocannabinoids, and cortisol

The endogenous cannabinoid (ECB) system is a small molecule lipid signalling system that is involved in stress response activation and is associated with PTSD, but it is unclear whether salivary ECBs are part of the sympathetic nervous system response to stress. We conducted an adapted trauma film paradigm, where participants completed a cold pressor test (or control) while watching a 10-minute trauma film. We also collected saliva and hair samples and tested them for ECBs, cortisol, and salivary alpha amylase (sAA). As hypothesised, there were significant positive correlations between sAA activity and salivary ECB levels, particularly 2-arachidonoyl glycerol (2-AG), though ECBs were not correlated with sAA stress reactivity. Participants who had a significant cortisol response to the trauma film/stressor reported less intrusive memories, which were also less distressing and less vivid. This effect was moderated by arachidonoyl ethanolamide (AEA), where decreases in AEA post-stress were associated with more intrusive memories in cortisol non-responders only. This study provides new evidence for the role of ECBs in the sympathetic nervous system.

CB₂R ligands to treat inflammatory diabetes

CB₂R ligands to treat inflammatory diabetes Researchers discuss how scientific innovations might influence the discovery of future tailor-made CB2R-based anti-inflammatory treatments. The G-protein-coupled receptor (GPCR) type-2 cannabinoid receptor (CB2R) is a 2 highly promising pharmacological target for novel anti-inflammatory medicines. (1) CB2R is an essential component of a vital lipid signaling system that tremendously influences multiple human health and disease states ranging from metabolic disorders to neurodegenerative diseases and is termed endocannabinoid system (ECS). Few CB2R-activation-based drugs have been launched. (2) Several candidates are under active clinical development, aiming at treating diseases in which inflammatory processes play a significant role or are the underlying reason. Recent scientific innovations in ECS research and drug discovery in general (Figure 1) are now being incorporated into the design, synthesis and evaluation of novel ligands targeting CB2R. They will impact the generation of further improved tailor-made medicines for inflammatory diseases.

CB2R agonists in the clinics: A treasure chest for treating inflammatory diseases

CB2R agonists in the clinics: A treasure chest for treating inflammatory diseases Activation of the type-2 cannabinoid receptor (CB2R) holds great potential for treating diseases with an inflammatory component, researchers Uwe Grether and Marc Nazaré find. This G-protein-coupled receptor (GPCR) is a key element of the endocannabinoid system (ECS), an important lipid signaling system, and in these numerous small molecule activators, so-called CB2R agonists, there is a high efficacy in preclinical disease models for treating a multitude of pathological conditions such as cardiovascular, gastrointestinal, liver, kidney, lung, neurodegenerative/ neuroinflammatory, skin pathologies, rheumatoid arthritis, endometriosis, and eye diseases. Analysing the roles of CB2R agonists in science and treatment, the researchers look at using cannabis sativa for selective CB2R agonists, success from clinical trials with CB2R agonists, and their potential for treating multiple diseases.

Visualizing the anti-inflammatory cannabinoid Type-2 receptor

Visualizing the anti-inflammatory cannabinoid Type-2 receptor Medicinal chemists describe how small molecule probes allow for the detection of CB2R, and thereby enable the discovery of novel anti-inflammatory treatments. The G-protein-coupled receptor (GPCR) CB2R (1) is an essential constituent of the endocannabinoid system (ECS), a central lipid signalling system in all vertebrates (2). Preclinical studies have shown that CB2R activation is a general and robust principle to attenuate inflammation and associated tissue injury in a wide variety of pathological conditions. Strong accumulating evidence suggests that diseases such as heart disorders, gastrointestinal, liver, kidney, lung, neurodegenerative or neuroinflammatory diseases, pain, skin pathologies, rheumatoid arthritis, endometriosis and eye diseases might be therapeutically addressable by CB2R (3).

Endothelial cannabinoid receptor CB1 deficiency decreases oxLDL uptake and attenuates vascular inflammation in atherosclerosis

Background and Aims : The endocannabinoid system has emerged as an important lipid signaling system in atherosclerosis. Since endothelial dysfunction plays a critical role in atherosclerosis, we aimed to study the endothelial cell-specific role of CB1 in atherosclerotic plaque development.

Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy

Diabetic complications, chiefly seen in long-term situations, are persistently deleterious to a large extent, requiring multi-factorial risk reduction strategies beyond glycemic control. Diabetic cardiomyopathy is one of the most common deleterious diabetic complications, being the leading cause of mortality among diabetic patients. The mechanisms of diabetic cardiomyopathy are multi-factorial, involving increased oxidative stress, accumulation of advanced glycation end products (AGEs), activation of various pro-inflammatory and cell death signaling pathways, and changes in the composition of extracellular matrix with enhanced cardiac fibrosis. The novel lipid signaling system, the endocannabinoid system, has been implicated in the pathogenesis of diabetes and its complications through its two main receptors: Cannabinoid receptor type 1 and cannabinoid receptor type 2, alongside other components. However, the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated. This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy. These mechanisms include oxidative/ nitrative stress, inflammation, accumulation of AGEs, cardiac remodeling, and autophagy. A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.

Lipidomics and Transcriptomics in Neurological Diseases.

Lipids serve as the primary interface to brain insults or stimuli conducive to neurological diseases and are a reservoir for the synthesis of lipids with various signaling or ligand function that can underscore the onset and progression of diseases. Often changing at the presymptomatic level, lipids are an emerging source of drug targets and biomarkers. Many neurological diseases exhibit neuroinflammation, neurodegeneration, and neuronal excitability as common hallmarks, partly modulated by specific lipid signaling systems. The interdependence and interrelation of synthesis of various lipids prompts a multilipid, multienzyme, and multireceptor analysis in order to derive the commonalities and specificities of neurological contexts and to expedite the unravelling of mechanistic aspects of disease onset and progression. Ascribing lipid roles to distinct brain regions advances the determination of lipid molecular phenotype and morphology associated with a neurological disease. Presented here is a modular protocol suitable for the analysis of membrane lipids and downstream lipid signals along with mRNA of enzymes and mediators underlying their functionality, extracted from discrete brain regions that are relevant for a particular neurological disease and/or condition. To ensure accurate comparative lipidomic profiling, the workflows and operating criteria were optimized and standardized for: i) brain sampling and dissection of regions of interest, ii) co-extraction of multiple lipid signals and membrane lipids, iii) dual lipid/mRNA extraction, iv) quantification by liquid chromatography multiple reaction monitoring (LC/MRM), and v) standard mRNA profiling. This workflow is amenable for the low tissue amounts obtained by sampling of the functionally discrete brain subregions (i.e. by brain punching), thus preventing bias in multimolecular analysis due to tissue heterogeneity and/or animal variability. To reveal peripheral consequences of neurological diseases and establish translational molecular readouts of neurological disease states, peripheral organ sampling, processing, and their subsequent lipidomic analysis, as well as plasma lipidomics, are also pursued and described. The protocol is demonstrated on an acute epilepsy mouse model.

Facile and Sustainable Synthesis of Commendamide and its Analogues.

Commendamide, or N-(3-hydroxypalmitoyl)-glycine 1a, is a gut microbiota-derived bioactive metabolite, structurally similar to long-chain N-acyl-amino acids which belong to the complex lipid signaling system known as endocannabinoidome and play important roles in mammals through activation of, inter alia, G-protein-coupled receptors (GPCRs). In this work, we describe a simple, green and economic method for the preparation of commendamide 1a, a GPCR G2A/132 agonist. The developed protocol is general and could also be applied to the synthesis of deuterated commendamide 1b, as well as to other minor microbiota-derived metabolites, such as the analog 2.

Activation of the endocannabinoid system mediates cardiac hypertrophy induced by rosiglitazone.

Rosiglitazone (RSG) is a synthetic agonist of peroxisome proliferator-activated receptor-γ (PPARγ), which plays a central role in the regulation of metabolism. Meta-analyses have suggested that RSG is associated with increased cardiovascular risk. However, the mechanisms underlying such adverse cardiac effects are still poorly understood. Here, we found that activation of PPARγ by RSG stimulated the endocannabinoid system (ECS), a membrane lipid signaling system, which induced cardiac hypertrophy. In neonatal rat cardiomyocytes, RSG increased the level of anandamide (AEA); upregulated the expression of N-acyl phosphatidylethanolamine phospholipase D (NapePLD), a key enzyme for AEA synthesis; and downregulated the expression of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of AEA. Importantly, PPARγ activation increased the expression of cannabinoid receptor type 1 (CB1) through an identified binding site for PPARγ in the CB1 promoter region. Moreover, both the in vitro and in vivo results showed that inhibition of the ECS by rimonabant, an antagonist of CB1, attenuated RSG-induced cardiac hypertrophy, as indicated by decreased expression of cardiac hypertrophy markers (ANP and BNP), deactivation of the mTOR pathway, and decreased cardiomyocyte size. Thus, these results demonstrated that the ECS functions as a novel target of PPARγ and that the AEA/CB1/mTOR axis mediates RSG-induced cardiac remodeling.

Mutual Links between the Endocannabinoidome and the Gut Microbiome, with Special Reference to Companion Animals: A Nutritional Viewpoint.

Simple SummaryDysbiosis, which is an imbalance of gut microbial composition and function, can be caused by several external as well as internal factors, contributing to the onset of human and animal disorders, not limited to the gastrointestinal tract. Accordingly, the mechanisms leading to disease development involve a crucial interaction between the gut microbiota, their metabolic products, and the host. The expanded endocannabinoid system, also known as the “endocannabinoidome”, includes endocannabinoids (e.g., anandamide) and endocannabinoid-like mediators (e.g., palmitoylethanolamide), their receptors and metabolic enzymes. Dysregulation of this newly recognized endogenous system is also involved in several diseases. It is becoming increasingly apparent that a link between the endocannabinoidome and the gut microbiome exists. Here, we review some of the latest discoveries related to the functional link between these two complex systems and the disorders emerging from the malfunctioning of such a mutual interaction: for example, idiopathic inflammation, chronic enteropathies, metabolic disease and certain neuroinflammatory disorders. It is expected that in the near future new nutritional tools will emerge based on the expanding knowledge in this cutting-edge field.There is growing evidence that perturbation of the gut microbiome, known as “dysbiosis”, is associated with the pathogenesis of human and veterinary diseases that are not restricted to the gastrointestinal tract. In this regard, recent studies have demonstrated that dysbiosis is linked to the pathogenesis of central neuroinflammatory disorders, supporting the existence of the so-called microbiome-gut-brain axis. The endocannabinoid system is a recently recognized lipid signaling system and termed endocannabinoidome monitoring a variety of body responses. Accumulating evidence demonstrates that a profound link exists between the gut microbiome and the endocannabinoidome, with mutual interactions controlling intestinal homeostasis, energy metabolism and neuroinflammatory responses during physiological conditions. In the present review, we summarize the latest data on the microbiome-endocannabinoidome mutual link in health and disease, focalizing the attention on gut dysbiosis and/or altered endocannabinoidome tone that may distort the bidirectional crosstalk between these two complex systems, thus leading to gastrointestinal and metabolic diseases (e.g., idiopathic inflammation, chronic enteropathies and obesity) as well as neuroinflammatory disorders (e.g., neuropathic pain and depression). We also briefly discuss the novel possible dietary interventions based not only on probiotics and/or prebiotics, but also, and most importantly, on endocannabinoid-like modulators (e.g., palmitoylethanolamide) for intestinal health and beyond.

Lipid Signaling Modulates the Response to Fumonisin Contamination and Its Source, Fusarium verticillioides, in Maize

Fumonisin-contaminated maize (Zea mays L.) products are a major health concern because of their toxic effects in humans and animals. Breeding maize for increased mycotoxin resistance is one of the key sustainable strategies for mitigating the effects of fumonisin contamination. Recent studies suggest a link between fumonisin accumulation and plant lipid and oxylipin profiles. However, the data collected so far do not reveal a cause-and-effect relationship. In this study, to decipher the multifactorial nature of mycotoxin resistance and plant–pathogen interaction mechanisms, we examined the oxylipin and complex lipid profiles of two maize hybrids (H21 and H22, the latter showing significantly lower FBs content) grown in the open field in two locations over 3years. Untargeted ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight (UHPLC-Q-TOF), together with chemometrics analysis, successfully distinguished between the two hybrids as having low- and high-level fumonisin contamination. Considering that H21 and H22 were exposed to the same environmental factors, the higher activation of lipid signaling systems in H22 suggests that other routes are enabled in the less susceptible hybrids to limit fumonisin B (FB) accumulation. Our results highlighted the crucial role played by oxylipin and sphingolipid signaling in modulating the complex maize response to F. verticillioides infection. Overall, our results returned a global view on the changes in lipid metabolites related to fumonisin accumulation under open field conditions, and revealed a strong activation of the lipid signaling cascade in maize in the presence of FB1.

Diacylglycerol Lipase-β Knockout Mice Display a Sex-Dependent Attenuation of Traumatic Brain Injury-Induced Mortality with No Impact on Memory or Other Functional Consequences.

Background: The endogenous cannabinoid system modulates inflammatory signaling in a variety of pathological states, including traumatic brain injury (TBI). The selective expression of diacylglycerol lipase-β (DAGL-β), the 2-arachidonylglycerol biosynthetic enzyme, on resident immune cells of the brain (microglia) and the role of this pathway in neuroinflammation, suggest that this enzyme may contribute to TBI-induced neuroinflammation. Accordingly, we tested whether DAGL-β-/- mice would show a protective phenotype from the deleterious consequences of TBI on cognitive and neurological motor functions. Materials and Methods: DAGL-β-/- and -β+/+ mice were subjected to the lateral fluid percussion model of TBI and assessed for learning and memory in the Morris water maze (MWM) Fixed Platform (reference memory) and Reversal (cognitive flexibility) tasks, as well as in a cued MWM task to infer potential sensorimotor/motivational deficits. In addition, subjects were assessed for motor behavior (Rotarod and the Neurological Severity Score assays) and in the light/dark box and the elevated plus maze to infer whether these manipulations affected anxiety-like behavior. Finally, we also examined whether brain injury disrupts the ceramide/sphingolipid lipid signaling system and if DAGL-β deletion offers protection. Results: TBI disrupted all measures of neurological motor function and reduced body weight, but did not affect body temperature or performance in common assays used to infer anxiety. TBI also impaired performance in MWM Fixed Platform and Reversal tasks, but did not affect cued MWM performance. Although no differences were found between DAGL-β-/- and -β+/+ mice in any of these measures, male DAGL-β-/- mice displayed an unexpected survival-protective phenotype, which persisted at increased injury severities. In contrast, TBI did not elicit mortality in female mice regardless of genotype. TBI also produced significant changes in sphingolipid profiles (a family of lipids, members of which have been linked to both apoptotic and antiapoptotic pathways), in which DAGL-β deletion modestly altered levels of select species. Conclusions: These findings indicate that although DAGL-β does not play a necessary role in TBI-induced cognitive and neurological function, it appears to contribute to the increased vulnerability of male mice to TBI-induced mortality, whereas female mice show high survival rates irrespective of DAGL-β expression.

Sex Differences in a Rat Model of Peripheral Neuropathic Pain and Associated Levels of Endogenous Cannabinoid Ligands

Chronic neuropathic pain is a major unmet clinical need affecting 10% of the world population, the majority of whom suffer from co-morbid mood disorders. Sex differences have been reported in pain prevalence, perception and response to analgesics. However, sexual dimorphism in chronic neuropathic pain and the associated neurobiology, are still poorly understood. The lack of efficacy and the adverse effects associated with current pharmacological treatments, further underline the need for new therapeutic targets. The endocannabinoid system (ECS) is a lipid signalling system which regulates a large number of physiological processes, including pain. The aim of this study was to investigate sexual dimorphism in pain-, anxiety- and depression-related behaviours, and concomitant alterations in supraspinal and spinal endocannabinoid levels in the spared nerve injury (SNI) animal model of peripheral neuropathic pain. Sham or SNI surgery was performed in adult male and female Sprague-Dawley rats. Mechanical and cold allodynia was tested weekly using von Frey and acetone drop tests, respectively. Development of depression-related behaviours was analysed using sucrose splash and sucrose preference tests. Locomotor activity and anxiety-related behaviours were assessed with open field and elevated plus maze tests. Levels of endocannabinoid ligands and related N-acylethanolamines in supraspinal regions of the descending inhibitory pain pathway, and spinal cord, were analysed 42 days post-surgery. SNI surgery induced allodynia in rats of both sexes. Female-SNI rats exhibited earlier onset and greater sensitivity to cold and mechanical allodynia than their male counterparts. In male rats, SNI induced a significant reduction of rearing, compared to sham controls. Trends for depressive-like behaviours in females and for anxiety-like behaviours in males were observed after SNI surgery but did not reach statistical significance. No concomitant alterations in levels of endogenous cannabinoid ligands and related N-acylethanolamines were observed in the regions analysed. Our results demonstrate differential development of SNI-induced nociceptive behaviour between male and female rats suggesting important sexually dimorphic modifications in pain pathways. SNI had no effect on depression- or anxiety-related behaviours in animals of either sex, or on levels of endocannabinoid ligands and related N-acylethanolamines across the regions involved in the descending modulation of nociception at the time points investigated.

Modulatory Potential of Cannabidiol on the Opioid-Induced Inflammatory Response.

Opioids are effective analgesics; however, there are many negative consequences of chronic use. One important side effect of chronic opioid use is the continuous engagement of the immune response that can exacerbate chronic pain. The opioid, morphine, initiates a Toll-like receptor 4 (TLR4) signaling cascade that drives the activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome proteins, resulting in cytokine production and effectively creating a positive feedback loop for continuous TLR4 activation. In addition to driving cytokine production, morphine drives changes in proinflammatory lipid signaling. The alteration of both cytokine and lipid signaling systems by morphine suggests that its chronic use leads to a pathological immune response that would benefit from targeted therapy. Engaging the endogenous cannabinoid system has shown therapeutic benefit, particularly regarding its anti-inflammatory and immunosuppressive effects. Promising preclinical and clinical investigations suggest that cannabidiol (CBD) is an effective adjuvant for treatment of symptoms of opioid use disorders; however, the mechanism through which CBD drives this outcome is unclear. One potential source of insight into this mechanism is in how CBD regulates immune regulators such as cytokines and lipid signaling systems, including endocannabinoids and related immune-responsive lipids. In this review, we outline the immune response to chronic opioid use as well as CBD in the context of a lipopolysaccharide-induced immune response and speculate on the mechanism of CBD as a modulator of chronic opioid-induced immune system dysregulation.

N-acylethanolamine-hydrolysing acid amidase: A new potential target to treat paclitaxel-induced neuropathy.

Although paclitaxel is an effective chemotherapeutic agent used to treat multiple types of cancer (e.g. breast, ovarian, neck and lung), it also elicits paclitaxel-induced peripheral neuropathy (PIPN), which represents a major dose-limiting side effect of this drug. As the endogenously produced N-acylethanolamine, palmitoylethanolamide (PEA), reverses paclitaxel-induced mechanical hypersensitivity in mice, the main goals of this study were to examine if paclitaxel affects levels of endogenous PEA in the spinal cord of mice and whether exogenous administration of PEA provides protection from the occurrence of paclitaxel-induced mechanical hypersensitivity. We further examined whether inhibition of N-acylethanolamine-hydrolysing acid amidase (NAAA), a hydrolytic PEA enzyme, would offer protection in mouse model of PIPN. Paclitaxel reduced PEA levels in the spinal cord, suggesting that dysregulation of this lipid signalling system may contribute to PIPN. Consistent with this idea, repeated administration of PEA partially prevented the paclitaxel-induced mechanical hypersensitivity. We next evaluated whether the selective NAAA inhibitor, AM9053, would prevent paclitaxel-induced mechanical hypersensitivity in mice. Acute administration of AM9053 dose-dependently reversed mechanical hypersensitivity through a PPAR-α mechanism, whereas repeated administration of AM9053 fully prevented the development of PIPN, without any evidence of tolerance. Moreover, AM9053 produced a conditioned place preference in paclitaxel-treated mice, but not in control mice. This pattern of findings suggests a lack of intrinsic rewarding effects, but a reduction in the pain aversiveness induced by paclitaxel. Finally, AM9053 did not alter paclitaxel-induced cytotoxicity in lung tumour cells. Collectively, these studies suggest that NAAA represents a promising target to treat and prevent PIPN. The present study demonstrates that the chemotherapeutic paclitaxel alters PEA levels in the spinal cord, whereas repeated exogenous PEA administration moderately alleviates PIPN in mice. Additionally, targeting NAAA, PEA's hydrolysing enzyme with a selective compound AM9053 reverses and prevents the PIPN via the PPAR-α mechanism. Overall, the data suggest that selective NAAA inhibitors denote promising future therapeutics to mitigate and prevent PIPN.

Endocannabinoid-Like Lipid Neuromodulators in the Regulation of Dopamine Signaling: Relevance for Drug Addiction.

The family of lipid neuromodulators has been rapidly growing, as the use of different -omics techniques led to the discovery of a large number of naturally occurring N-acylethanolamines (NAEs) and N-acyl amino acids belonging to the complex lipid signaling system termed endocannabinoidome. These molecules exert a variety of biological activities in the central nervous system, as they modulate physiological processes in neurons and glial cells and are involved in the pathophysiology of neurological and psychiatric disorders. Their effects on dopamine cells have attracted attention, as dysfunctions of dopamine systems characterize a range of psychiatric disorders, i.e., schizophrenia and substance use disorders (SUD). While canonical endocannabinoids are known to regulate excitatory and inhibitory synaptic inputs impinging on dopamine cells and modulate several dopamine-mediated behaviors, such as reward and addiction, the effects of other lipid neuromodulators are far less clear. Here, we review the emerging role of endocannabinoid-like neuromodulators in dopamine signaling, with a focus on non-cannabinoid N-acylethanolamines and their receptors. Mounting evidence suggests that these neuromodulators contribute to modulate synaptic transmission in dopamine regions and might represent a target for novel medications in alcohol and nicotine use disorder.

Influence of the endocannabinoid system on memory processes

The endocannabinoid system (ECS) is a lipid signaling system, which consists of the endocannabinoids (EC) anandamide (AEA) and 2-arachidonylglycerol (2-AG), the cannabinoid receptors (CB1 and CB2), and the enzymes that regulate their production and degradation. AEA and 2-AG are lipid compounds derived presynaptically from the degradation of membrane phospholipids and act as key modulators on synaptic transmission. This article presents accumulated data on the mechanisms by which ECS affects learning and memory. Substances that modulate the activity of ECS have impact on different phases of memory formation through direct and indirect influences. Studies show contradictory results on the role of the ECS in learning and memory processes.

Endocannabinoids and endocannabinoid-like molecules are present in foods, blood and ileal fluids from ileostomy subjects: insight into possible metabolic implications

AbstractThe endocannabinoid system is a lipid signalling system with several regulatory functions throughout the body including regulation of appetite, food intake, macronutrient metabolism, pain sensation, blood pressure, mood, cognition and immunity. It consists of endocannabinoids (ECs), their receptors and enzymes involved in their synthesis and degradation. The two best-characterized endocannabinoids are N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). They are ligands of cannabinoid receptors CB1 and CB2 which are located in the central nervous system (CNS) but also in in the enteric nervous system, in the liver and in the adipose tissue.Several structural congeners of ECs including N-acylethanolamines (NAEs) such as oleoylethanolamine (OEA), linoleyethanolamine (LEA), and palmitoyletahanolamine (PEA), show similar mechanisms of action, tissue distribution as well as pathways of formation and breakdown. They are considered “endocannabinoid-like” molecules acting through receptors that are located both in CNS and in the gastro-intestinal tract mucosa such as the G-protein coupled receptor 119 (GPR119) and peroxisome proliferator-activated receptors (PPARs). NAEs display EC50 values for human GPR119 and PPAR-α between 65 ng/mL and 1000 ng/mL. Some evidence indicated that NAEs, their phosphorylated precursors N-acylphosphatidylethanolamines (NAPEs) and ECs are also present in food. Thus, we developed a food database of these molecules and we calculated the daily dietary intake in a healthy population.This study aimed to evaluate whether the concentrations of NAPEs, NAEs and ECs in the human intestinal lumen may support their activity through the receptors lining in the gastro-intestinal tract and if they correlated with those in plasma.The observational study (16/NI/0267, Ulster University) involved 35 ileostomists (18F/17M, aged 18–70 y, BMI 17–40 kg/m2) who collected overnight fasting samples of ileal fluid and plasma. The concentrations of NAEs, NAPEs and ECs in biological samples were determined by LC-HRMS.Data showed that NAEs and NAPEs were present in ileal fluids and plasma from all subjects ranging between 46851.0–104742.8 ng/mL and 0.3–59.6 ng/mL in ileal samples and 1159.4–3985.7 ng/mL and 0.19–1.24 ng/mL in plasma, respectively. Contrarily, no ECs in ileal fluids were found except 2-AG in two ileal samples whereas they ranged between 1.6–22.3 ng/mL in plasma. Differences between genders and associations of plasma levels with individual energy intakes were found.Altogether, the data demonstrated that NAEs in the intestinal lumen are sufficient to elicit metabolic responses through the gastro-intestinal receptors.

N-Acyl Amino Acids: Metabolism, Molecular Targets, and Role in Biological Processes.

The lipid signal is becoming increasingly crowded as increasingly fatty acid amide derivatives are being identified and considered relevant therapeutic targets. The identification of N-arachidonoyl-ethanolamine as endogenous ligand of cannabinoid type-1 and type-2 receptors as well as the development of different–omics technologies have the merit to have led to the discovery of a huge number of naturally occurring N-acyl-amines. Among those mediators, N-acyl amino acids, chemically related to the endocannabinoids and belonging to the complex lipid signaling system now known as endocannabinoidome, have been rapidly growing for their therapeutic potential. Here, we review the current knowledge of the mechanisms for the biosynthesis and inactivation of the N-acyl amino acids, as well as the various molecular targets for some of the N-acyl amino acids described so far.