The endocannabinoid system and its relevance for nutrition.

Endocannabinoids bind to cannabinoid, vanilloid, and peroxisome proliferator-activated receptors. The biological actions of these polyunsaturated lipids are controlled by key agents responsible for their synthesis, transport and degradation, which together form an endocannabinoid system (ECS). In the past few years, evidence has been accumulated for a role of the ECS in regulating food intake and energy balance, both centrally and peripherally. In addition, up-regulation of the ECS in the gastrointestinal tract has a potential impact on inflammatory bowel diseases. In this review, the main features of the ECS are summarized in order to put in better focus our current knowledge of the nutritional relevance of endocannabinoid signaling and of its role in obesity, cardiovascular pathologies, and gastrointestinal diseases. The central and peripheral pathways that underlie these effects are discussed, as well as the possible exploitation of ECS components as novel drug targets for therapeutic intervention in eating disorders.

[1]  M. Maccarrone Endocannabinoids: friends and foes of reproduction. , 2009, Progress in lipid research.

[2]  H. Hansen,et al.  N-acylethanolamines, anandamide and food intake. , 2009, Biochemical pharmacology.

[3]  N. Stella,et al.  The therapeutic potential of novel cannabinoid receptors. , 2009, Pharmacology & therapeutics.

[4]  D. Kendall,et al.  Time-Dependent Vascular Effects of Endocannabinoids Mediated by Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) , 2009, PPAR research.

[5]  M. Kwiatkowska,et al.  The FAAH inhibitor URB-597 interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus (house musk shrew) , 2009, Physiology & Behavior.

[6]  J. M. Mancilla-Díaz,et al.  Role of cannabinoid CB1 receptors on macronutrient selection and satiety in rats , 2009, Physiology & Behavior.

[7]  R. Ross The enigmatic pharmacology of GPR55. , 2009, Trends in pharmacological sciences.

[8]  U. Kristiansen,et al.  Ketogenic diet is antiepileptogenic in pentylenetetrazole kindled mice and decrease levels of N-acylethanolamines in hippocampus , 2009, Neurochemistry International.

[9]  B. Oldfield,et al.  The Effects of Rimonabant on Brown Adipose Tissue in Rat: Implications for Energy Expenditure , 2009, Obesity.

[10]  V. Di Marzo,et al.  An introduction to the endocannabinoid system: from the early to the latest concepts. , 2009, Best practice & research. Clinical endocrinology & metabolism.

[11]  P. Pacher,et al.  Cannabinoid CB1 receptor inhibition decreases vascular smooth muscle migration and proliferation , 2008, Biochemical and biophysical research communications.

[12]  J. McCarron,et al.  IP(3)R-mediated Ca(2+) release is modulated by anandamide in isolated cardiac nuclei. , 2008, Journal of molecular and cellular cardiology.

[13]  Benjamin F. Cravatt,et al.  Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects , 2008, Nature chemical biology.

[14]  N. DiPatrizio,et al.  Inhibiting parabrachial fatty acid amide hydrolase activity selectively increases the intake of palatable food via cannabinoid CB1 receptors. , 2008, American journal of physiology. Regulatory, integrative and comparative physiology.

[15]  S. Gaetani,et al.  The lipid messenger OEA links dietary fat intake to satiety. , 2008, Cell metabolism.

[16]  G. Godlewski,et al.  Modulation of the endocannabinoid system in cardiovascular disease: therapeutic potential and limitations. , 2008, Hypertension.

[17]  E. Herradón,et al.  Vasorelaxation caused by cannabinoids: mechanisms in different vascular beds. , 2008, Current vascular pharmacology.

[18]  N. DiPatrizio,et al.  Activating Parabrachial Cannabinoid CB1 Receptors Selectively Stimulates Feeding of Palatable Foods in Rats , 2008, The Journal of Neuroscience.

[19]  R. Krauss,et al.  Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins , 2008, Proceedings of the National Academy of Sciences.

[20]  M. Thevis,et al.  Δ6‐Desaturase (FADS2) deficiency unveils the role of ω3‐ and ω6‐polyunsaturated fatty acids , 2008, The EMBO journal.

[21]  S. Yazulla Endocannabinoids in the retina: From marijuana to neuroprotection , 2008, Progress in Retinal and Eye Research.

[22]  N. Volkow,et al.  Leptin receptor deficiency is associated with upregulation of cannabinoid 1 receptors in limbic brain regions , 2008, Synapse.

[23]  S. Stefano,et al.  Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. , 2008, European journal of cancer care.

[24]  István Katona,et al.  Endocannabinoid signaling as a synaptic circuit breaker in neurological disease , 2008, Nature Medicine.

[25]  R. Pratley,et al.  The cannabinoid CB1 receptor is expressed in pancreatic delta-cells. , 2008, Biochemical and biophysical research communications.

[26]  D. Piomelli,et al.  Targeted enhancement of oleoylethanolamide production in proximal small intestine induces across-meal satiety in rats. , 2008, American journal of physiology. Regulatory, integrative and comparative physiology.

[27]  Peter Tontonoz,et al.  Integration of metabolism and inflammation by lipid-activated nuclear receptors , 2008, Nature.

[28]  K. Mackie,et al.  Cannabinoid CB2 receptors in the enteric nervous system modulate gastrointestinal contractility in lipopolysaccharide-treated rats. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

[29]  J. Jelsing,et al.  Identification of cannabinoid type 1 receptor expressing cocaine amphetamine-regulated transcript neurons in the rat hypothalamus and brainstem using in situ hybridization and immunohistochemistry , 2008, Neuroscience.

[30]  V. Marzo The endocannabinoid system in obesity and type 2 diabetes , 2008, Diabetologia.

[31]  U. Pagotto,et al.  The Endocannabinoid System and Energy Metabolism , 2008, Journal of neuroendocrinology.

[32]  R. Vettor,et al.  Endocannabinoids, Adipose Tissue and Lipid Metabolism , 2008, Journal of neuroendocrinology.

[33]  D. Diz,et al.  Cytochrome P-450 metabolites of 2-arachidonoylglycerol play a role in Ca2+-induced relaxation of rat mesenteric arteries. , 2008, American journal of physiology. Heart and circulatory physiology.

[34]  H. Hansen,et al.  Endocannabinoids and Nutrition , 2008, Journal of neuroendocrinology.

[35]  Ethan B. Russo Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? , 2008, Neuro endocrinology letters.

[36]  Christian Skonberg,et al.  Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine. , 2008, Biochimica et biophysica acta.

[37]  F. Mach,et al.  CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways. , 2008, American journal of physiology. Heart and circulatory physiology.

[38]  F. Bermúdez-Silva,et al.  Presence of functional cannabinoid receptors in human endocrine pancreas , 2008, Diabetologia.

[39]  D. Centonze,et al.  Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum , 2008, Nature Neuroscience.

[40]  H. Wyatt,et al.  Dietary Fat Increases Energy Intake Across the Range of Typical Consumption in the United States , 2008, Obesity.

[41]  K. Mackie,et al.  CB2 cannabinoid receptor agonists attenuate TNF‐α‐induced human vascular smooth muscle cell proliferation and migration , 2008, British journal of pharmacology.

[42]  P. Bernante,et al.  The endogenous cannabinoid system stimulates glucose uptake in human fat cells via phosphatidylinositol 3-kinase and calcium-dependent mechanisms. , 2007, The Journal of clinical endocrinology and metabolism.

[43]  C. Paraskeva,et al.  The cannabinoid δ9‐tetrahydrocannabinol inhibits RAS‐MAPK and PI3K‐AKT survival signalling and induces BAD‐mediated apoptosis in colorectal cancer cells , 2007 .

[44]  V. Ralevic,et al.  Cannabinoids inhibit noradrenergic and purinergic sympathetic cotransmission in the rat isolated mesenteric arterial bed , 2007, British journal of pharmacology.

[45]  M. Randall Endocannabinoids and the haematological system , 2007, British journal of pharmacology.

[46]  Z. Song,et al.  Molecular and cellular changes induced by the activation of CB2 cannabinoid receptors in trabecular meshwork cells. , 2007, Molecular vision.

[47]  L. Parsons,et al.  Specific Alterations of Extracellular Endocannabinoid Levels in the Nucleus Accumbens by Ethanol, Heroin, and Cocaine Self-Administration , 2007, The Journal of Neuroscience.

[48]  G. Wittert,et al.  Effects of cannabinoid receptors on skeletal muscle oxidative pathways , 2007, Molecular and Cellular Endocrinology.

[49]  E. Kossoff,et al.  The Ketogenic Diet: One Decade Later , 2007, Pediatrics.

[50]  V. Marzo,et al.  Endocannabinoids and the control of energy balance , 2007, Trends in Endocrinology & Metabolism.

[51]  A. Zinsmeister,et al.  Effect of a cannabinoid agonist on gastrointestinal transit and postprandial satiation in healthy human subjects: a randomized, placebo‐controlled study , 2006, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[52]  M. Maj,et al.  Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. , 2006, The Journal of clinical endocrinology and metabolism.

[53]  S. Di,et al.  Opposing Crosstalk between Leptin and Glucocorticoids Rapidly Modulates Synaptic Excitation via Endocannabinoid Release , 2006, The Journal of Neuroscience.

[54]  S. Dey,et al.  Jekyll and Hyde : Two Faces of Cannabinoid Signaling in Male and Female Fertility , 2006 .

[55]  E. Berry,et al.  Endocannabinoids, feeding and suckling – from our perspective , 2006, International Journal of Obesity.

[56]  C. Reynet,et al.  Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. , 2006, Cell metabolism.

[57]  F. Bermúdez-Silva,et al.  Cannabinoid receptors regulate Ca2+ signals and insulin secretion in pancreatic β-cell , 2006 .

[58]  A. Finazzi-Agro’,et al.  Regulation by cannabinoid receptors of anandamide transport across the blood-brain barrier and through other endothelial cells , 2005, Thrombosis and Haemostasis.

[59]  Arya M. Sharma,et al.  Activation of the peripheral endocannabinoid system in human obesity. , 2005, Diabetes.

[60]  M. Palkovits,et al.  Cocaine- and Amphetamine-Related Transcript Is Involved in the Orexigenic Effect of Endogenous Anandamide , 2005, Neuroendocrinology.

[61]  P. Casellas,et al.  Anandamide induced PPARgamma transcriptional activation and 3T3-L1 preadipocyte differentiation. , 2005, European journal of pharmacology.

[62]  D. Hardie,et al.  Cannabinoids and Ghrelin Have Both Central and Peripheral Metabolic and Cardiac Effects via AMP-activated Protein Kinase* , 2005, Journal of Biological Chemistry.

[63]  A. Gerber,et al.  Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH) , 2005, International Journal of Obesity.

[64]  K. Mackie,et al.  Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. , 2005, The Journal of clinical investigation.

[65]  T. Klein Cannabinoid-based drugs as anti-inflammatory therapeutics , 2005, Nature Reviews Immunology.

[66]  M. Korbonits,et al.  The cannabinoid CB1 receptor antagonist SR141716 blocks the orexigenic effects of intrahypothalamic ghrelin , 2004, British journal of pharmacology.

[67]  K. Chapman Occurrence, metabolism, and prospective functions of N-acylethanolamines in plants. , 2004, Progress in lipid research.

[68]  B. Cravatt,et al.  The endogenous cannabinoid system protects against colonic inflammation. , 2004, The Journal of clinical investigation.

[69]  P. Soubrié,et al.  CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity , 2004, International Journal of Obesity.

[70]  N. Ueda,et al.  Molecular Characterization of a Phospholipase D Generating Anandamide and Its Congeners* , 2004, Journal of Biological Chemistry.

[71]  Gareth Williams,et al.  Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain , 2003, The Journal of cell biology.

[72]  E. Berry,et al.  Short-term fasting and prolonged semistarvation have opposite effects on 2-AG levels in mouse brain , 2003, Brain Research.

[73]  P. Hornby,et al.  Cannabinoid1 Receptor in the Dorsal Vagal Complex Modulates Lower Oesophageal Sphincter Relaxation in Ferrets , 2003, The Journal of physiology.

[74]  T. Hamazaki,et al.  n-3 Polyunsaturated fatty acid (PUFA) deficiency elevates and n-3 PUFA enrichment reduces brain 2-arachidonoylglycerol level in mice. , 2003, Prostaglandins, leukotrienes, and essential fatty acids.

[75]  A. Finazzi-Agro’,et al.  Leptin Activates the Anandamide Hydrolase Promoter in Human T Lymphocytes through STAT3* , 2003, The Journal of Biological Chemistry.

[76]  T. Freund,et al.  A role for monoglyceride lipase in 2-arachidonoylglycerol inactivation. , 2002, Chemistry and physics of lipids.

[77]  A. Finazzi-Agro’,et al.  Binding, degradation and apoptotic activity of stearoylethanolamide in rat C6 glioma cells. , 2002, The Biochemical journal.

[78]  K. Mackie,et al.  Localisation of cannabinoid CB1 receptor immunoreactivity in the guinea pig and rat myenteric plexus , 2002, The Journal of comparative neurology.

[79]  N. Jamshidi,et al.  Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats , 2001, British journal of pharmacology.

[80]  A. Nilsson,et al.  Sources of eicosanoid precursor fatty acid pools in tissues. , 2001, Journal of lipid research.

[81]  H. Kilbinger,et al.  Differential effects of anandamide on acetylcholine release in the guinea‐pig ileum mediated via vanilloid and non‐CB1 cannabinoid receptors , 2001, British journal of pharmacology.

[82]  R. Pertwee Cannabinoids and the gastrointestinal tract , 2001, Gut.

[83]  T. Bisogno,et al.  Anandamide and diet: Inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[84]  R. Palmiter,et al.  Leptin-regulated endocannabinoids are involved in maintaining food intake , 2001, Nature.

[85]  S. Vandevoorde,et al.  Anticonvulsant Activity of N‐Palmitoylethanolamide, a Putative Endocannabinoid, in Mice , 2001, Epilepsia.

[86]  K. Michaelsen,et al.  The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina. , 2001, Progress in lipid research.

[87]  J. Koch Δ9-THC stimulates food intake in Lewis rats: effects on chow, high-fat and sweet high-fat diets , 2001, Pharmacology Biochemistry and Behavior.

[88]  A. Finazzi-Agro’,et al.  Human platelets bind and degrade 2-arachidonoylglycerol, which activates these cells through a cannabinoid receptor. , 2001, European journal of biochemistry.

[89]  G. Melino,et al.  Anandamide Induces Apoptosis in Human Cells via Vanilloid Receptors , 2000, The Journal of Biological Chemistry.

[90]  L. Petrocellis,et al.  Trick or treat from food endocannabinoids? , 1998, Nature.

[91]  G. Kunos,et al.  Cardiovascular actions of cannabinoids and their generation during shock , 1998, Journal of Molecular Medicine.

[92]  H. Hansen The essential nature of linoleic acid in mammals , 1986 .

[93]  R. García,et al.  Inhibition of histamine-stimulated gastric acid secretion by Δ9-tetrahydrocannabinol in rat isolated stomach , 1980 .

[94]  Masahiko Watanabe,et al.  Endocannabinoid-mediated control of synaptic transmission. , 2009, Physiological reviews.

[95]  A. Makriyannis,et al.  Should peripheral CB(1) cannabinoid receptors be selectively targeted for therapeutic gain? , 2009, Trends in pharmacological sciences.

[96]  M. Maccarrone 16 The Endocannabinoid System and its Manifold Central Actions , 2009 .

[97]  F. Fezza,et al.  Fatty acid amide hydrolase: a gate-keeper of the endocannabinoid system. , 2008, Sub-cellular biochemistry.

[98]  I. Matias,et al.  Effect of polyunsaturated fatty acids on endocannabinoid and N-acyl-ethanolamine levels in mouse adipocytes. , 2008, Biochimica et biophysica acta.

[99]  D. Diz,et al.  Cytochrome P-450 metabolites of 2-arachidonoylglycerol play a role in Ca 2-induced relaxation of rat mesenteric arteries , 2008 .

[100]  A. C. Williams,et al.  The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells. , 2007, International journal of cancer.

[101]  F. Fezza,et al.  Endocannabinoids in adipocytes during differentiation and their role in glucose uptake , 2006, Cellular and Molecular Life Sciences.

[102]  F. Massa,et al.  Endocannabinoids and the gastrointestinal tract. , 2006, Journal of endocrinological investigation.

[103]  T. Bisogno,et al.  Up-regulation of the endocannabinoid system in the uterus of leptin knockout (ob/ob) mice and implications for fertility. , 2005, Molecular human reproduction.

[104]  P. Pacher,et al.  Cardiovascular pharmacology of cannabinoids. , 2005, Handbook of experimental pharmacology.

[105]  G. Cabral,et al.  Effects on the immune system. , 2005, Handbook of experimental pharmacology.

[106]  A. Sanyal,et al.  Systemic and portal hemodynamic effects of anandamide. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[107]  J. Koch Delta(9)-THC stimulates food intake in Lewis rats: effects on chow, high-fat and sweet high-fat diets. , 2001, Pharmacology, biochemistry, and behavior.

[108]  R. García,et al.  Inhibition of histamine-stimulated gastric acid secretion by delta 9-tetrahydrocannabinol in rat isolated stomach. , 1980, European journal of pharmacology.

[109]  K. Mackie,et al.  Identification functional characterization of brainstem cannabinoid CB2 receptors. , 2022 .

[110]  A. Izzo,et al.  Introduction Cannabinoids and Gastrointestinal Motility: Animal and Human Studies Cannabinoid Receptors in the Digestive Tract: Focus on the Myenteric Pplexus Animal Studies on Gastrointestinal Motility , 2022 .