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The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function
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The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (1 December 2020) | Viewed by 41044

Special Issue Editor

Dr. Vincenzo Di Marzo

E-Mail Website1 Website2
Guest Editor
1. Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Université Laval, Québec City, QC G1V 0A6, Canada
2. National Research Council (CNR), Institute of Biomolecular Chemistry, Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Naples, Italy
Interests: endocannabinoids; cannabinoids; gut microbiome; obesity; neurological and neuropsychiatric disorders; inflammation; lipid mediators

Special Issue Information

Dear Colleagues,

This Special Issue entitled “The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function” will include both reviews and experimental studies on the expanded endocannabinoid system, including endocannabinoids as well as their many biochemically, and often functionally, related mediators, and their several molecular targets, encompassing G protein-coupled receptors, ligand-activated membrane channels, and nuclear receptors. Previously established concepts, as well as emerging ideas, on the molecular and cellular biology of this complex “endocannabinoidome”, which are emblematic of its pleiotropic involvement in most physiological and pathological aspects of mammalian cell life, will be described by the authors. Special emphasis will be laid on endocannabinoid and endocannabinoidome function and dysfunction in: energy metabolism, the communication between the host cell and the gut microbiota, inflammation, and cancer. I am confident that this Special Issue will receive great attention from all those researchers who are interested in the understanding of the multifaceted aspects of endocannabinoid regulation of cells.

Dr. Vincenzo Di Marzo
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Endocannabinoids
  • Obesity
  • Microbiota
  • Cancer
  • Inflammation

Published Papers (10 papers)

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Research

Jump to: Review

20 pages, 3568 KiB  
Article
Biosynthesis of the Novel Endogenous 15-Lipoxygenase Metabolites N-13-Hydroxy-octodecadienoyl-ethanolamine and 13-Hydroxy-octodecadienoyl-glycerol by Human Neutrophils and Eosinophils
by Anne-Sophie Archambault, Francesco Tinto, Élizabeth Dumais, Volatiana Rakotoarivelo, Magdalena Kostrzewa, Pier-Luc Plante, Cyril Martin, Mélissa Simard, Cristoforo Silvestri, Roxane Pouliot, Michel Laviolette, Louis-Philippe Boulet, Rosa Maria Vitale, Alessia Ligresti, Vincenzo Di Marzo and Nicolas Flamand
Cells 2021, 10(9), 2322; https://doi.org/10.3390/cells10092322 - 05 Sep 2021
Cited by 11 | Viewed by 3806
Abstract
The endocannabinoids 2-arachidonoyl-glycerol and N-arachidonoyl-ethanolamine are lipids regulating many physiological processes, notably inflammation. Endocannabinoid hydrolysis inhibitors are now being investigated as potential anti-inflammatory agents. In addition to 2-arachidonoyl-glycerol and N-arachidonoyl-ethanolamine, the endocannabinoidome also includes other monoacylglycerols and N-acyl-ethanolamines such as [...] Read more.
The endocannabinoids 2-arachidonoyl-glycerol and N-arachidonoyl-ethanolamine are lipids regulating many physiological processes, notably inflammation. Endocannabinoid hydrolysis inhibitors are now being investigated as potential anti-inflammatory agents. In addition to 2-arachidonoyl-glycerol and N-arachidonoyl-ethanolamine, the endocannabinoidome also includes other monoacylglycerols and N-acyl-ethanolamines such as 1-linoleoyl-glycerol (1-LG) and N-linoleoyl-ethanolamine (LEA). By increasing monoacylglycerols and/or N-acyl-ethanolamine levels, endocannabinoid hydrolysis inhibitors will likely increase the levels of their metabolites. Herein, we investigated whether 1-LG and LEA were substrates for the 15-lipoxygenase pathway, given that both possess a 1Z,4Z-pentadiene motif, near their omega end. We thus assessed how human eosinophils and neutrophils biosynthesized the 15-lipoxygenase metabolites of 1-LG and LEA. Linoleic acid (LA), a well-documented substrate of 15-lipoxygenases, was used as positive control. N-13-hydroxy-octodecadienoyl-ethanolamine (13-HODE-EA) and 13-hydroxy-octodecadienoyl-glycerol (13-HODE-G), the 15-lipoxygenase metabolites of LEA and 1-LG, were synthesized using Novozym 435 and soybean lipoxygenase. Eosinophils, which express the 15-lipoxygenase-1, metabolized LA, 1-LG, and LEA into their 13-hydroxy derivatives. This was almost complete after five minutes. Substrate preference of eosinophils was LA > LEA > 1-LG in presence of 13-HODE-G hydrolysis inhibition with methyl-arachidonoyl-fluorophosphonate. Human neutrophils also metabolized LA, 1-LG, and LEA into their 13-hydroxy derivatives. This was maximal after 15–30 s. Substrate preference was LA ≫ 1-LG > LEA. Importantly, 13-HODE-G was found in humans and mouse tissue samples. In conclusion, our data show that human eosinophils and neutrophils metabolize 1-LG and LEA into the novel endogenous 15-lipoxygenase metabolites 13-HODE-G and 13-HODE-EA. The full biological importance of 13-HODE-G and 13-HODE-EA remains to be explored. Full article
(This article belongs to the Special Issue The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function)
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17 pages, 1218 KiB  
Article
Modulation of Endocannabinoid Tone in Osteoblastic Differentiation of MC3T3-E1 Cells and in Mouse Bone Tissue over Time
by Magdalena Kostrzewa, Ali Mokhtar Mahmoud, Roberta Verde, Federica Scotto di Carlo, Fernando Gianfrancesco, Fabiana Piscitelli and Alessia Ligresti
Cells 2021, 10(5), 1199; https://doi.org/10.3390/cells10051199 - 14 May 2021
Cited by 7 | Viewed by 2336
Abstract
Bone is a highly complex and metabolically active tissue undergoing a continuous remodeling process, which endures throughout life. A complex cell-signaling system that plays role in regulating different physiological processes, including bone remodeling, is the endocannabinoid system (ECS). Bone mass expresses CB1 and [...] Read more.
Bone is a highly complex and metabolically active tissue undergoing a continuous remodeling process, which endures throughout life. A complex cell-signaling system that plays role in regulating different physiological processes, including bone remodeling, is the endocannabinoid system (ECS). Bone mass expresses CB1 and CB2 cannabinoid receptors and enzymatic machinery responsible for the metabolism of their endogenous ligands, endocannabinoids (AEA and 2-AG). Exogenous AEA is reported to increase the early phase of human osteoblast differentiation in vitro. However, regarding this cell context little is known about how endocannabinoids and endocannabinoid-related N-acylethanolamines like PEA and OEA are modulated, in vitro, during cell differentiation and, in vivo, over time up to adulthood. Here we characterized the endocannabinoid tone during the different phases of the osteoblast differentiation process in MC3T3-E1 cells, and we measured endocannabinoid levels in mouse femurs at life cycle stages characterized by highly active bone growth (i.e., of juvenile, young adult, and mature adult bone). Endocannabinoid tone was significantly altered during osteoblast differentiation, with substantial OEA increment, decline in 2-AG and AEA, and consistent modulation of their metabolic enzymes in maturing and mineralized MC3T3-E1 cells. Similarly, in femurs, we found substantial, age-related, decline in 2-AG, OEA, and PEA. These findings can expand existing knowledge underlying physiological bone cell function and contribute to therapeutic strategies for preventing bone-related metabolic changes accruing through lifespan. Full article
(This article belongs to the Special Issue The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function)
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18 pages, 2482 KiB  
Article
A Glucuronic Acid-Palmitoylethanolamide Conjugate (GLUPEA) Is an Innovative Drug Delivery System and a Potential Bioregulator
by Emiliano Manzo, Aniello Schiano Moriello, Francesco Tinto, Roberta Verde, Marco Allarà, Luciano De Petrocellis, Ester Pagano, Angelo A. Izzo, Vincenzo Di Marzo and Stefania Petrosino
Cells 2021, 10(2), 450; https://doi.org/10.3390/cells10020450 - 20 Feb 2021
Cited by 2 | Viewed by 2628
Abstract
Palmitoylethanolamide (PEA) is an endogenous anti-inflammatory lipid mediator and a widely used nutraceutical. In this study, we designed, realized, and tested a drug-carrier conjugate between PEA (the active drug) and glucuronic acid (the carrier). The conjugate, named GLUPEA, was characterized for its capability [...] Read more.
Palmitoylethanolamide (PEA) is an endogenous anti-inflammatory lipid mediator and a widely used nutraceutical. In this study, we designed, realized, and tested a drug-carrier conjugate between PEA (the active drug) and glucuronic acid (the carrier). The conjugate, named GLUPEA, was characterized for its capability of increasing PEA levels and exerting anti-inflammatory activity both in vitro and in vivo. GLUPEA treatment, compared to the same concentration of PEA, resulted in higher cellular amounts of PEA and the endocannabinoid 2-arachidonoyl glycerol (2-AG), and increased 2-AG-induced transient receptor potential vanilloid type 1 (TRPV1) channel desensitization to capsaicin. GLUPEA inhibited pro-inflammatory monocyte chemoattractant protein 2 (MCP-2) release from stimulated keratinocytes, and it was almost as efficacious as ultra-micronized PEA at reducing colitis in dinitrobenzene sulfonic acid (DNBS)-injected mice when using the same dose. GLUPEA is a novel pro-drug able to efficiently mimic the anti-inflammatory and endocannabinoid enhancing actions of PEA. Full article
(This article belongs to the Special Issue The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function)
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20 pages, 3686 KiB  
Article
Renal Proximal Tubule Cell Cannabinoid-1 Receptor Regulates Bone Remodeling and Mass via a Kidney-to-Bone Axis
by Saja Baraghithy, Yael Soae, Dekel Assaf, Liad Hinden, Shiran Udi, Adi Drori, Yankel Gabet and Joseph Tam
Cells 2021, 10(2), 414; https://doi.org/10.3390/cells10020414 - 17 Feb 2021
Cited by 3 | Viewed by 2892
Abstract
The renal proximal tubule cells (RPTCs), well-known for maintaining glucose and mineral homeostasis, play a critical role in the regulation of kidney function and bone remodeling. Deterioration in RPTC function may therefore lead to the development of diabetic kidney disease (DKD) and osteoporosis. [...] Read more.
The renal proximal tubule cells (RPTCs), well-known for maintaining glucose and mineral homeostasis, play a critical role in the regulation of kidney function and bone remodeling. Deterioration in RPTC function may therefore lead to the development of diabetic kidney disease (DKD) and osteoporosis. Previously, we have shown that the cannabinoid-1 receptor (CB1R) modulates both kidney function as well as bone remodeling and mass via its direct role in RPTCs and bone cells, respectively. Here we employed genetic and pharmacological approaches that target CB1R, and found that its specific nullification in RPTCs preserves bone mass and remodeling both under normo- and hyper-glycemic conditions, and that its chronic blockade prevents the development of diabetes-induced bone loss. These protective effects of negatively targeting CB1R specifically in RPTCs were associated with its ability to modulate erythropoietin (EPO) synthesis, a hormone known to affect bone mass and remodeling. Our findings highlight a novel molecular mechanism by which CB1R in RPTCs remotely regulates skeletal homeostasis via a kidney-to-bone axis that involves EPO. Full article
(This article belongs to the Special Issue The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function)
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22 pages, 3389 KiB  
Article
Beneficial Effects of Akkermansia muciniphila Are Not Associated with Major Changes in the Circulating Endocannabinoidome but Linked to Higher Mono-Palmitoyl-Glycerol Levels as New PPARα Agonists
by Clara Depommier, Rosa Maria Vitale, Fabio Arturo Iannotti, Cristoforo Silvestri, Nicolas Flamand, Céline Druart, Amandine Everard, Rudy Pelicaen, Dominique Maiter, Jean-Paul Thissen, Audrey Loumaye, Michel P. Hermans, Nathalie M. Delzenne, Willem M. de Vos, Vincenzo Di Marzo and Patrice D. Cani
Cells 2021, 10(1), 185; https://doi.org/10.3390/cells10010185 - 19 Jan 2021
Cited by 43 | Viewed by 6809
Abstract
Akkermansia muciniphila is considered as one of the next-generation beneficial bacteria in the context of obesity and associated metabolic disorders. Although a first proof-of-concept of its beneficial effects has been established in the context of metabolic syndrome in humans, mechanisms are not yet [...] Read more.
Akkermansia muciniphila is considered as one of the next-generation beneficial bacteria in the context of obesity and associated metabolic disorders. Although a first proof-of-concept of its beneficial effects has been established in the context of metabolic syndrome in humans, mechanisms are not yet fully understood. This study aimed at deciphering whether the bacterium exerts its beneficial properties through the modulation of the endocannabinoidome (eCBome). Circulating levels of 25 endogenous endocannabinoid-related lipids were quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in the plasma of overweight or obese individuals before and after a 3 months intervention consisting of the daily ingestion of either alive or pasteurized A. muciniphila. Results from multivariate analyses suggested that the beneficial effects of A. muciniphila were not linked to an overall modification of the eCBome. However, subsequent univariate analysis showed that the decrease in 1-Palmitoyl-glycerol (1-PG) and 2-Palmitoyl-glycerol (2-PG), two eCBome lipids, observed in the placebo group was significantly counteracted by the alive bacterium, and to a lower extent by the pasteurized form. We also discovered that 1- and 2-PG are endogenous activators of peroxisome proliferator-activated receptor alpha (PPARα). We hypothesize that PPARα activation by mono-palmitoyl-glycerols may underlie part of the beneficial metabolic effects induced by A. muciniphila in human metabolic syndrome. Full article
(This article belongs to the Special Issue The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function)
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19 pages, 2183 KiB  
Article
Linking the Endocannabinoidome with Specific Metabolic Parameters in an Overweight and Insulin-Resistant Population: From Multivariate Exploratory Analysis to Univariate Analysis and Construction of Predictive Models
by Clara Depommier, Nicolas Flamand, Rudy Pelicaen, Dominique Maiter, Jean-Paul Thissen, Audrey Loumaye, Michel P. Hermans, Amandine Everard, Nathalie M. Delzenne, Vincenzo Di Marzo and Patrice D. Cani
Cells 2021, 10(1), 71; https://doi.org/10.3390/cells10010071 - 05 Jan 2021
Cited by 6 | Viewed by 3021
Abstract
The global obesity epidemic continues to rise worldwide. In this context, unraveling new interconnections between biological systems involved in obesity etiology is highly relevant. Dysregulation of the endocannabinoidome (eCBome) is associated with metabolic complications in obesity. This study aims at deciphering new associations [...] Read more.
The global obesity epidemic continues to rise worldwide. In this context, unraveling new interconnections between biological systems involved in obesity etiology is highly relevant. Dysregulation of the endocannabinoidome (eCBome) is associated with metabolic complications in obesity. This study aims at deciphering new associations between circulating endogenous bioactive lipids belonging to the eCBome and metabolic parameters in a population of overweight or obese individuals with metabolic syndrome. To this aim, we combined different multivariate exploratory analysis methods: canonical correlation analysis and principal component analysis, revealed associations between eCBome subsets, and metabolic parameters such as leptin, lipopolysaccharide-binding protein, and non-esterified fatty acids (NEFA). Subsequent construction of predictive regression models according to the linear combination of selected endocannabinoids demonstrates good prediction performance for NEFA. Descriptive approaches reveal the importance of specific circulating endocannabinoids and key related congeners to explain variance in the metabolic parameters in our cohort. Analysis of quartiles confirmed that these bioactive lipids were significantly higher in individuals characterized by important levels for aforementioned metabolic variables. In conclusion, by proposing a methodology for the exploration of large-scale data, our study offers additional evidence of the existence of an interplay between eCBome related-entities and metabolic parameters known to be altered in obesity. Full article
(This article belongs to the Special Issue The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function)
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19 pages, 2152 KiB  
Article
Mgll Knockout Mouse Resistance to Diet-Induced Dysmetabolism Is Associated with Altered Gut Microbiota
by Niokhor Dione, Sébastien Lacroix, Ulrike Taschler, Thomas Deschênes, Armita Abolghasemi, Nadine Leblanc, Vincenzo Di Marzo and Cristoforo Silvestri
Cells 2020, 9(12), 2705; https://doi.org/10.3390/cells9122705 - 17 Dec 2020
Cited by 24 | Viewed by 3173
Abstract
Monoglyceride lipase (MGLL) regulates metabolism by catabolizing monoacylglycerols (MAGs), including the endocannabinoid 2-arachidonoyl glycerol (2-AG) and some of its bioactive congeners, to the corresponding free fatty acids. Mgll knockout mice (Mgll−/−) exhibit elevated tissue levels of MAGs in association with [...] Read more.
Monoglyceride lipase (MGLL) regulates metabolism by catabolizing monoacylglycerols (MAGs), including the endocannabinoid 2-arachidonoyl glycerol (2-AG) and some of its bioactive congeners, to the corresponding free fatty acids. Mgll knockout mice (Mgll−/−) exhibit elevated tissue levels of MAGs in association with resistance to the metabolic and cardiovascular perturbations induced by a high fat diet (HFD). The gut microbiome and its metabolic function are disrupted in obesity in a manner modulated by 2-arachidonoyl glycerol (2-AG’s) main receptors, the cannabinoid CB1 receptors. We therefore hypothesized that Mgll−/− mice have an altered microbiome, that responds differently to diet-induced obesity from that of wild-type (WT) mice. We subjected mice to HFD and assessed changes in the microbiomes after 8 and 22 weeks. As expected, Mgll−/− mice showed decreased adiposity, improved insulin sensitivity, and altered circulating incretin/adipokine levels in response to HFD. Mgll−/− mice on a chow diet exhibited significantly higher levels of Hydrogenoanaerobacterium, Roseburia, and Ruminococcus than WT mice. The relative abundance of the Lactobacillaceae and Coriobacteriaceae and of the Lactobacillus, Enterorhabdus, Clostridium_XlVa, and Falsiporphyromonas genera was significantly altered by HFD in WT but not Mgll−/− mice. Differently abundant families were also associated with changes in circulating adipokine and incretin levels in HFD-fed mice. Some gut microbiota family alterations could be reproduced by supplementing 2-AG or MAGs in culturomics experiments carried out with WT mouse fecal samples. We suggest that the altered microbiome of Mgll−/− mice contributes to their obesity resistant phenotype, and results in part from increased levels of 2-AG and MAGs. Full article
(This article belongs to the Special Issue The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function)
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16 pages, 2347 KiB  
Article
Role of 2-Arachidonoyl-Glycerol and CB1 Receptors in Orexin-A-Mediated Prevention of Oxygen–Glucose Deprivation-Induced Neuronal Injury
by Letizia Palomba, Andrea Motta, Roberta Imperatore, Fabiana Piscitelli, Raffaele Capasso, Federica Mastroiacovo, Giuseppe Battaglia, Valeria Bruno, Luigia Cristino and Vincenzo Di Marzo
Cells 2020, 9(6), 1507; https://doi.org/10.3390/cells9061507 - 20 Jun 2020
Cited by 10 | Viewed by 2749
Abstract
Orexin-A (OX-A) protects the brain against oxidative stress-mediated ischemic injury. Since the endocannabinoid 2-arachidonoylglycerol (2-AG) and cannabinoid type-1 (CB1) receptors were previously shown to mediate some of the effects of OX-A exerted through the orexin-1 receptor (OX-1R), we investigated the involvement of 2-AG [...] Read more.
Orexin-A (OX-A) protects the brain against oxidative stress-mediated ischemic injury. Since the endocannabinoid 2-arachidonoylglycerol (2-AG) and cannabinoid type-1 (CB1) receptors were previously shown to mediate some of the effects of OX-A exerted through the orexin-1 receptor (OX-1R), we investigated the involvement of 2-AG in OX-A-induced neuroprotection following oxygen and glucose deprivation (OGD) in mouse cortical neurons. OGD-induced reactive oxygen species (ROS) accumulation and neuronal death were prevented by both OX-A and arachidonyl-2′-chloroethylamide (ACEA), a synthetic CB1 receptor agonist, in a manner sensitive to OX-1R and CB1 receptor antagonists, SB334867 and AM251. OX-A stimulated 2-AG biosynthesis in cortical neurons. In neurons isolated from monoacylglycerol lipase (MAGL, a 2-AG hydrolyzing enzyme) null mice, 10-fold higher 2-AG concentrations were found and OGD failed to induce ROS production and cell death, whereas AM251 restored these noxious effects. OX-A-induced neuroprotection was mediated by the phosphoinositide-3-kinase/Akt (PI3K/Akt) survival pathway since both OX-A and ACEA induced phosphorylation of Akt and prevented OGD-induced cytochrome c release from the mitochondria, in a manner counteracted by SB334867 or AM251. Administration of OX-A reduced infarct volume and elevated brain 2-AG levels in a mouse model of transient ischemia. These results suggest that 2-AG and CB1 receptor mediate OX-A prevention of ischemia-induced neuronal apoptosis. Full article
(This article belongs to the Special Issue The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function)
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Review

Jump to: Research

19 pages, 1757 KiB  
Review
Neurobiological Processes Induced by Aerobic Exercise through the Endocannabinoidome
by Fabiola Forteza, Giada Giorgini and Frédéric Raymond
Cells 2021, 10(4), 938; https://doi.org/10.3390/cells10040938 - 17 Apr 2021
Cited by 12 | Viewed by 4118
Abstract
Evidence suggesting the triangulation of the endocannabinoid system, exercise, and neurological health is emerging. In addition to the endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), the expanded endocannabinoid system, known as the endocannabinoidome (eCBome), appears to be an important player in this [...] Read more.
Evidence suggesting the triangulation of the endocannabinoid system, exercise, and neurological health is emerging. In addition to the endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), the expanded endocannabinoid system, known as the endocannabinoidome (eCBome), appears to be an important player in this relationship. The eCBome includes several endocannabinoid-like mediators such as N-acylethanolamines and 2-monoacylglycerols, the enzymes involved in their biosynthesis and degradation, and the receptors they affect. This review aims to relate the functional interactions between aerobic exercise, and the molecular and cellular pathways related to endocannabinoids, in the hypothalamus, hippocampus, and the periphery, with special attention given to associations with emotional state, cognition, and mental health. Given the well-documented roles of many eCBome members in regulating stress and neurological processes, we posit that the eCBome is an important effector of exercise-induced central and peripheral adaptive mechanisms that benefit mental health. Gut microbiota imbalance, affecting the gut-brain axis and metabolism, also influences certain eCBome-modulated inflammation pathways. The integrity of the gut microbiota could thus be crucial in the onset of neuroinflammation and mental conditions. Further studies on how the modulation by exercise of the peripheral eCBome affects brain functions could reveal to be key elements in the prevention and treatment of neuropsychological disorders. Full article
(This article belongs to the Special Issue The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function)
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22 pages, 3470 KiB  
Review
The Endocannabinoid System and PPARs: Focus on Their Signalling Crosstalk, Action and Transcriptional Regulation
by Fabio Arturo Iannotti and Rosa Maria Vitale
Cells 2021, 10(3), 586; https://doi.org/10.3390/cells10030586 - 07 Mar 2021
Cited by 58 | Viewed by 7613
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors including PPARα, PPARγ, and PPARβ/δ, acting as transcription factors to regulate the expression of a plethora of target genes involved in metabolism, immune reaction, cell differentiation, and a variety of other cellular changes [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors including PPARα, PPARγ, and PPARβ/δ, acting as transcription factors to regulate the expression of a plethora of target genes involved in metabolism, immune reaction, cell differentiation, and a variety of other cellular changes and adaptive responses. PPARs are activated by a large number of both endogenous and exogenous lipid molecules, including phyto- and endo-cannabinoids, as well as endocannabinoid-like compounds. In this view, they can be considered an extension of the endocannabinoid system. Besides being directly activated by cannabinoids, PPARs are also indirectly modulated by receptors and enzymes regulating the activity and metabolism of endocannabinoids, and, vice versa, the expression of these receptors and enzymes may be regulated by PPARs. In this review, we provide an overview of the crosstalk between cannabinoids and PPARs, and the importance of their reciprocal regulation and modulation by common ligands, including those belonging to the extended endocannabinoid system (or “endocannabinoidome”) in the control of major physiological and pathophysiological functions. Full article
(This article belongs to the Special Issue The Endocannabinoidome: A Pleiotropic Expanded Endocannabinoid System Controlling Cell Function)
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