As gut microorganisms interact with host cells via several mechanisms, targeting the microbiota to treat metabolic disorders is an attractive therapeutic approach
The endocannabinoid system is involved in numerous biological processes, such as the regulation of energy homeostasis, inflammation and gut-barrier function
The endocannabinoid system is altered during the metabolic syndrome, which contributes to the onset of cardiometabolic disease
Gut microorganisms and the endocannabinoid system are intertwined
The metabolites, receptors and signalling pathways that couple the gut microbiota with the host endocannabinoid system and eventually metabolism require further investigation
Although the endocannabinoid system is currently being targeted in several pathological conditions such as obesity, diabetes mellitus and intestinal inflammation, few candidate drugs have been tested in clinical trials
Various metabolic disorders are associated with changes in inflammatory tone. Among the latest advances in the metabolism field, the discovery that gut microorganisms have a major role in host metabolism has revealed the possibility of a plethora of associations between gut bacteria and numerous diseases. However, to date, few mechanisms have been clearly established. Accumulating evidence indicates that the endocannabinoid system and related bioactive lipids strongly contribute to several physiological processes and are a characteristic of obesity, type 2 diabetes mellitus and inflammation. In this Review, we briefly define the gut microbiota as well as the endocannabinoid system and associated bioactive lipids. We discuss existing literature regarding interactions between gut microorganisms and the endocannabinoid system, focusing specifically on the triad of adipose tissue, gut bacteria and the endocannabinoid system in the context of obesity and the development of fat mass. We highlight gut-barrier function by discussing the role of specific factors considered to be putative 'gate keepers' or 'gate openers', and their role in the gut microbiota–endocannabinoid system axis. Finally, we briefly discuss data related to the different pharmacological strategies currently used to target the endocannabinoid system, in the context of cardiometabolic disorders and intestinal inflammation.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
The diet rapidly and differentially affects the gut microbiota and host lipid mediators in a healthy population
Microbiome Open Access 11 February 2023
Stable colonization of Akkermansia muciniphila educates host intestinal microecology and immunity to battle against inflammatory intestinal diseases
Experimental & Molecular Medicine Open Access 04 January 2023
Influence of diet on acute endocannabinoidome mediator levels post exercise in active women, a crossover randomized study
Scientific Reports Open Access 20 May 2022
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Lichtman, J. S., Sonnenburg, J. L. & Elias, J. E. Monitoring host responses to the gut microbiota. ISME J. 9, 1908–1915 (2015).
Cani, P. D. & Delzenne, N. M. The role of the gut microbiota in energy metabolism and metabolic disease. Curr. Pharm. Des. 15, 1546–1558 (2009).
Nicholson, J. K. et al. Host–gut microbiota metabolic interactions. Science 336, 1262–1267 (2012).
McFall-Ngai, M. et al. Animals in a bacterial world, a new imperative for the life sciences. Proc. Natl Acad. Sci. USA 110, 3229–3236 (2013).
The Human Microbiome Project. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).
Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).
Savage, D. C. Microbial ecology of the gastrointestinal tract. Annu. Rev. Microbiol. 31, 107–133 (1977).
Cani, P. D. & Delzenne, N. M. The gut microbiome as therapeutic target. Pharmacol. Ther. 130, 202–212 (2011).
Li, J. et al. An integrated catalog of reference genes in the human gut microbiome. Nat. Biotechnol. 32, 834–841 (2014).
Backhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A. & Gordon, J. I. Host–bacterial mutualism in the human intestine. Science 307, 1915–1920 (2005).
Ley, R. E., Lozupone, C. A., Hamady, M., Knight, R. & Gordon, J. I. Worlds within worlds: evolution of the vertebrate gut microbiota. Nat. Rev. Microbiol. 6, 776–788 (2008).
Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).
Rodriguez, J. M. et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb. Ecol. Health Dis. 26, 26050 (2015).
Backhed, F. et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 17, 690–703 (2015).
Goodrich, J. K. et al. Human genetics shape the gut microbiome. Cell 159, 789–799 (2014).
Hopkins, M. J., Sharp, R. & Macfarlane, G. T. Age and disease related changes in intestinal bacterial populations assessed by cell culture, 16S rRNA abundance, and community cellular fatty acid profiles. Gut 48, 198–205 (2001).
Ringel, Y. et al. High throughput sequencing reveals distinct microbial populations within the mucosal and luminal niches in healthy individuals. Gut Microbes 6, 173–181 (2015).
Pedron, T. et al. A crypt-specific core microbiota resides in the mouse colon. mBio 3, e00116–e00112 (2012).
Martinez, I. et al. The gut microbiota of rural Papua New Guineans: composition, diversity patterns, and ecological processes. Cell Rep. 11, 527–538 (2015).
Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).
David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).
Bindels, L. B., Delzenne, N. M., Cani, P. D. & Walter, J. Towards a more comprehensive concept for prebiotics. Nat. Rev. Gastroenterol. Hepatol. 12, 303–310 (2015).
Roberfroid, M. et al. Prebiotic effects: metabolic and health benefits. Br. J. Nutr. 104, S1–S63 (2010).
Hill, C. et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 11, 506–514 (2014).
Suez, J. et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514, 181–186 (2014).
Chassaing, B. et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519, 92–96 (2015).
Cani, P. D. & Everard, A. Keeping gut lining at bay: impact of emulsifiers. Trends Endocrinol. Metab. 26, 273–274 (2015).
Backhed, F. et al. Defining a healthy human gut microbiome: current concepts, future directions, and clinical applications. Cell Host Microbe 12, 611–622 (2012).
Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013).
Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013).
Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64 (2014).
Dao, M. C. et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut http://dx.doi.org/10.1136/gutjnl-2014-308778 (2015).
Touw, M. The religious and medicinal uses of cannabis in China, India and Tibet. J. Psychoactive Drugs 13, 23–34 (1981).
Mechoulam, R. & Gaoni, Y. Hashish. IV. The isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids. Tetrahedron 21, 1223–1229 (1965).
Devane, W. A., Dysarz, F. A. 3rd, Johnson, M. R., Melvin, L. S. & Howlett, A. C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34, 605–613 (1988).
Munro, S., Thomas, K. L. & Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65 (1993).
Pertwee, R. G. et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2 . Pharmacol. Rev. 62, 588–631 (2010).
Maccarrone, M. et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol. Sci. 36, 277–296 (2015).
Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).
Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83–90 (1995).
Brown, I. et al. Omega-3 N-acylethanolamines are endogenously synthesised from omega-3 fatty acids in different human prostate and breast cancer cell lines. Prostaglandins Leukot. Essent. Fatty Acids 85, 305–310 (2011).
Fezza, F. et al. Endocannabinoids, related compounds and their metabolic routes. Molecules 19, 17078–17106 (2014).
De Petrocellis, L. & Di Marzo, V. Non-CB1, non-CB2 receptors for endocannabinoids, plant cannabinoids, and synthetic cannabimimetics: focus on G-protein-coupled receptors and transient receptor potential channels. J. Neuroimmune Pharmacol. 5, 103–121 (2010).
Ryberg, E. et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol. 152, 1092–1101 (2007).
Ross, R. A. Anandamide and vanilloid TRPV1 receptors. Br. J. Pharmacol. 140, 790–801 (2003).
Di Marzo, V. & De Petrocellis, L. Endocannabinoids as regulators of transient receptor potential (TRP) channels: a further opportunity to develop new endocannabinoid-based therapeutic drugs. Curr. Med. Chem. 17, 1430–1449 (2010).
Ben-Shabat, S. et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur. J. Pharmacol. 353, 23–31 (1998).
Lambert, D. M. & Di Marzo, V. The palmitoylethanolamide and oleamide enigmas: are these two fatty acid amides cannabimimetic? Curr. Med. Chem. 6, 757–773 (1999).
Piscitelli, F. in The Endocannabinoidome: the World of Endocannabinoids and Related Mediators (eds Di Marzo, V. & Wang, J.) 1–187 (Academic Press, 2015).
Iannotti, F. A. et al. Analysis of the 'endocannabinoidome' in peripheral tissues of obese Zucker rats. Prostaglandins Leukot. Essent. Fatty Acids 89, 127–135 (2013).
Syed, S. K. et al. Regulation of GPR119 receptor activity with endocannabinoid-like lipids. Am. J. Physiol. Endocrinol. Metab. 303, E1469–E1478 (2012).
Muccioli, G. G. Endocannabinoid biosynthesis and inactivation, from simple to complex. Drug Discov. Today 15, 474–483 (2010).
Urquhart, P., Nicolaou, A. & Woodward, D. F. Endocannabinoids and their oxygenation by cyclo-oxygenases, lipoxygenases and other oxygenases. Biochim. Biophys. Acta 1851, 366–376 (2015).
Ueda, N., Tsuboi, K. & Uyama, T. Metabolism of endocannabinoids and related N-acylethanolamines: canonical and alternative pathways. FEBS J. 280, 1874–1894 (2013).
Di Marzo, V., Stella, N. & Zimmer, A. Endocannabinoid signalling and the deteriorating brain. Nat. Rev. Neurosci. 16, 30–42 (2015).
Di Marzo, V., Bisogno, T., Sugiura, T., Melck, D. & De Petrocellis, L. The novel endogenous cannabinoid 2-arachidonoylglycerol is inactivated by neuronal- and basophil-like cells: connections with anandamide. Biochem. J. 331, 15–19 (1998).
Deutsch, D. G., Ueda, N. & Yamamoto, S. The fatty acid amide hydrolase (FAAH). Prostaglandins Leukot. Essent. Fatty Acids 66, 201–210 (2002).
Goparaju, S. K., Ueda, N., Taniguchi, K. & Yamamoto, S. Enzymes of porcine brain hydrolyzing 2-arachidonoylglycerol, an endogenous ligand of cannabinoid receptors. Biochem. Pharmacol. 57, 417–423 (1999).
Alhouayek, M. et al. N-acylethanolamine-hydrolyzing acid amidase inhibition increases colon N-palmitoylethanolamine levels and counteracts murine colitis. FASEB J. 29, 650–661 (2015).
Bandiera, T., Ponzano, S. & Piomelli, D. Advances in the discovery of N-acylethanolamine acid amidase inhibitors. Pharmacol. Res. 86, 11–17 (2014).
Dinh, T. P. et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl Acad. Sci. USA 99, 10819–10824 (2002).
Marrs, W. R. et al. The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nat. Neurosci. 13, 951–957 (2010).
Silvestri, C. & Di Marzo, V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab. 17, 475–490 (2013).
Cani, P. D., Geurts, L., Matamoros, S., Plovier, H. & Duparc, T. Glucose metabolism: focus on gut microbiota, the endocannabinoid system and beyond. Diabetes Metab. 40, 246–257 (2014).
Cota, D. et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J. Clin. Invest. 112, 423–431 (2003).
Van Gaal, L. F., Rissanen, A. M., Scheen, A. J., Ziegler, O. & Rossner, S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365, 1389–1397 (2005).
Cristino, L., Becker, T. & Di Marzo, V. Endocannabinoids and energy homeostasis: an update. Biofactors 40, 389–397 (2014).
Cristino, L. et al. Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons. Proc. Natl Acad. Sci. USA 110, E2229–E2238 (2013).
Di Marzo, V. et al. The role of endocannabinoids in the regulation of gastric emptying: alterations in mice fed a high-fat diet. Br. J. Pharmacol. 153, 1272–1280 (2008).
Izzo, A. A. et al. Peripheral endocannabinoid dysregulation in obesity: relation to intestinal motility and energy processing induced by food deprivation and re-feeding. Br. J. Pharmacol. 158, 451–461 (2009).
Capasso, R. et al. Palmitoylethanolamide normalizes intestinal motility in a model of post-inflammatory accelerated transit: involvement of CB1 receptors and TRPV1 channels. Br. J. Pharmacol. 171, 4026–4037 (2014).
Di Patrizio, N. V. & Piomelli, D. Intestinal lipid-derived signals that sense dietary fat. J. Clin. Invest. 125, 891–898 (2015).
Piomelli, D. A fatty gut feeling. Trends Endocrinol. Metab. 24, 332–341 (2013).
Troy-Fioramonti, S. et al. Acute activation of cannabinoid receptors by anandamide reduces gastrointestinal motility and improves postprandial glycemia in mice. Diabetes 64, 808–818 (2015).
Hoareau, L. et al. Anti-inflammatory effect of palmitoylethanolamide on human adipocytes. Obesity (Silver Spring) 17, 431–438 (2009).
Muccioli, G. G. et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol. Syst. Biol. 6, 392 (2010).
Backhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).
Rousseaux, C. et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat. Med. 13, 35–37 (2007).
Cani, P. D. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1481 (2008).
Cani, P. D. et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58, 1091–1103 (2009).
Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).
Liu, J. et al. Lipopolysaccharide induces anandamide synthesis in macrophages via CD14/MAPK/phosphoinositide 3-kinase/NF-κB independently of platelet-activating factor. J. Biol. Chem. 278, 45034–45039 (2003).
Maccarrone, M. et al. Lipopolysaccharide downregulates fatty acid amide hydrolase expression and increases anandamide levels in human peripheral lymphocytes. Arch. Biochem. Biophys. 393, 321–328 (2001).
Zhu, C. et al. Proinflammatory stimuli control N-acylphosphatidylethanolamine-specific phospholipase D expression in macrophages. Mol. Pharmacol. 79, 786–792 (2011).
Geurts, L., Muccioli, G. G., Delzenne, N. M. & Cani, P. D. Chronic endocannabinoid system stimulation induces muscle macrophage and lipid accumulation in type 2 diabetic mice independently of metabolic endotoxaemia. PLoS ONE 8, 5 (2013).
Matias, I. et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and β-pancreatic cells and in obesity and hyperglycemia. J. Clin. Endocrinol. Metab. 91, 3171–3180 (2006).
Pagano, C. et al. The endogenous cannabinoid system stimulates glucose uptake in human fat cells via phosphatidylinositol 3-kinase and calcium-dependent mechanisms. J. Clin. Endocrinol. Metab. 92, 4810–4819 (2007).
Everard, A. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl Acad. Sci. USA 110, 9066–9071 (2013).
Alhouayek, M., Lambert, D. M., Delzenne, N. M., Cani, P. D. & Muccioli, G. G. Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation. FASEB J. 25, 2711–2721 (2011).
Alhamoruni, A., Lee, A. C., Wright, K. L., Larvin, M. & O'Sullivan, S. E. Pharmacological effects of cannabinoids on the Caco-2 cell culture model of intestinal permeability. J. Pharmacol. Exp. Ther. 335, 92–102 (2010).
Drucker, D. J. Glucagon-like peptides. Diabetes 47, 159–169 (1998).
Lauffer, L. M., Iakoubov, R. & Brubaker, P. L. GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell. Diabetes 58, 1058–1066 (2009).
Cheng, Y. H., Ho, M. S., Huang, W. T., Chou, Y. T. & King, K. Modulation of glucagon-like peptide-1 (GLP-1) potency by endocannabinoid-like lipids represents a novel mode of regulating GLP-1 receptor signaling. J. Biol. Chem. 290, 14302–14313 (2015).
Everard, A. & Cani, P. D. Gut microbiota and GLP-1. Rev. Endocr. Metab. Disord. 15, 189–196 (2014).
Everard, A. et al. Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status. Nat. Commun. 5, 5648 (2014).
Geurts, L. et al. Adipose tissue NAPE-PLD controls fat mass development by altering the browning process and gut microbiota. Nat. Commun. 6, 6495 (2015).
Geurts, L. et al. Altered gut microbiota and endocannabinoid system tone in obese and diabetic leptin-resistant mice: impact on apelin regulation in adipose tissue. Front. Microbiol. 2, 149 (2011).
Bajzer, M. et al. Cannabinoid receptor 1 (CB1) antagonism enhances glucose utilisation and activates brown adipose tissue in diet-induced obese mice. Diabetologia 54, 3121–3131 (2011).
Gibellini, L. et al. Silencing of mitochondrial Lon protease deeply impairs mitochondrial proteome and function in colon cancer cells. FASEB J. 28, 5122–5135 (2014).
Quarta, C. et al. CB1 signaling in forebrain and sympathetic neurons is a key determinant of endocannabinoid actions on energy balance. Cell Metab. 11, 273–285 (2010).
Izzo, A. A. & Sharkey, K. A. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol. Ther. 126, 21–38 (2010).
Igarashi, M., Di Patrizio, N. V., Narayanaswami, V. & Piomelli, D. Feeding-induced oleoylethanolamide mobilization is disrupted in the gut of diet-induced obese rodents. Biochim. Biophys. Acta 1851, 1218–1226 (2015).
Suarez, J. et al. Oleoylethanolamide enhances β-adrenergic-mediated thermogenesis and white-to-brown adipocyte phenotype in epididymal white adipose tissue in rat. Dis. Model Mech. 7, 129–141 (2014).
Alhouayek, M. & Muccioli, G. G. Harnessing the anti-inflammatory potential of palmitoylethanolamide. Drug Discov. Today 19, 1632–1639 (2014).
Borrelli, F. et al. Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti-inflammatory agent. Br. J. Pharmacol. 172, 142–158 (2015).
Esposito, G. et al. Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation. Gut 63, 1300–1312 (2014).
Mattace Raso, G. et al. Palmitoylethanolamide prevents metabolic alterations and restores leptin sensitivity in ovariectomized rats. Endocrinology 155, 1291–1301 (2014).
Turcotte, C., Chouinard, F., Lefebvre, J. S. & Flamand, N. Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites. J. Leukoc. Biol. 97, 1049–1070 (2015).
Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).
Alhamoruni, A., Wright, K. L., Larvin, M. & O'Sullivan, S. E. Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability. Br. J. Pharmacol. 165, 2598–2610 (2012).
Ligresti, A. et al. Possible endocannabinoid control of colorectal cancer growth. Gastroenterology 125, 677–687 (2003).
Wright, K. et al. Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Gastroenterology 129, 437–453 (2005).
D'Argenio, G. et al. Overactivity of the intestinal endocannabinoid system in celiac disease and in methotrexate-treated rats. J. Mol. Med. 85, 523–530 (2007).
Guagnini, F. et al. Neural contractions in colonic strips from patients with diverticular disease: role of endocannabinoids and substance P. Gut 55, 946–953 (2006).
Di Marzo, V. & Izzo, A. A. Endocannabinoid overactivity and intestinal inflammation. Gut 55, 1373–1376 (2006).
Smid, S. D. Gastrointestinal endocannabinoid system: multifaceted roles in the healthy and inflamed intestine. Clin. Exp. Pharmacol. Physiol. 35, 1383–1387 (2008).
Osei-Hyiaman, D. et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J. Clin. Invest. 115, 1298–1305 (2005).
Osei-Hyiaman, D. et al. Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J. Clin. Invest. 118, 3160–3169 (2008).
Bartelt, A. et al. Altered endocannabinoid signalling after a high-fat diet in Apoe−/− mice: relevance to adipose tissue inflammation, hepatic steatosis and insulin resistance. Diabetologia 54, 2900–2910 (2011).
Tam, J. et al. Endocannabinoids in liver disease. Hepatology 53, 346–355 (2011).
Bowles, N. P. et al. A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome. Proc. Natl Acad. Sci. USA 112, 285–290 (2015).
Christensen, R., Kristensen, P. K., Bartels, E. M., Bliddal, H. & Astrup, A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 370, 1706–1713 (2007).
Tam, J. et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J. Clin. Invest. 120, 2953–2966 (2010).
Tam, J. et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab. 16, 167–179 (2012).
Chorvat, R. J. Peripherally restricted CB1 receptor blockers. Bioorg. Med. Chem. Lett. 23, 4751–4760 (2013).
Sharma, M. K., Murumkar, P. R., Kanhed, A. M., Giridhar, R. & Yadav, M. R. Prospective therapeutic agents for obesity: molecular modification approaches of centrally and peripherally acting selective cannabinoid 1 receptor antagonists. Eur. J. Med. Chem. 79, 298–339 (2014).
Sharma, M. K., Murumkar, P. R., Barmade, M. A., Giridhar, R. & Yadav, M. R. A comprehensive patents review on cannabinoid 1 receptor antagonists as antiobesity agents. Expert Opin. Ther. Pat. 25, 1093–1116 (2015).
Klumpers, L. E. et al. Peripheral selectivity of the novel cannabinoid receptor antagonist TM38837 in healthy subjects. Br. J. Clin. Pharmacol. 76, 846–857 (2013).
LoVerme, J. et al. Synthesis and characterization of a peripherally restricted CB1 cannabinoid antagonist, URB447, that reduces feeding and body-weight gain in mice. Bioorg. Med. Chem. Lett. 19, 639–643 (2009).
Bermudez-Silva, F. J., Viveros, M. P., McPartland, J. M. & Rodriguez de Fonseca, F. The endocannabinoid system, eating behavior and energy homeostasis: the end or a new beginning? Pharmacol. Biochem. Behav. 95, 375–382 (2010).
Ohishi, T. & Yoshida, S. The therapeutic potential of GPR119 agonists for type 2 diabetes. Expert Opin. Investig. Drugs 21, 321–328 (2012).
Bisogno, T. et al. Development of the first potent and specific inhibitors of endocannabinoid biosynthesis. Biochim. Biophys. Acta 1761, 205–212 (2006).
Powell, D. R. et al. Diacylglycerol lipase α knockout mice demonstrate metabolic and behavioral phenotypes similar to those of cannabinoid receptor 1 knockout mice. Front. Endocrinol. (Lausanne) 6, 86 (2015).
Bisogno, T. et al. A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects. Br. J. Pharmacol. 169, 784–793 (2013).
Alhouayek, M., Masquelier, J., Cani, P. D., Lambert, D. M. & Muccioli, G. G. Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6. Proc. Natl Acad. Sci. USA 110, 17558–17563 (2013).
Thomas, G. et al. The serine hydrolase ABHD6 is a critical regulator of the metabolic syndrome. Cell Rep. 5, 508–520 (2013).
Zhao, S. et al. α/β-hydrolase domain-6-accessible monoacylglycerol controls glucose-stimulated insulin secretion. Cell. Metab. 19, 993–1007 (2014).
Patel, J. Z. et al. Optimization of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors. Chem. Med. Chem. 10, 253–265 (2015).
Janssen, F. J. et al. Discovery of glycine sulfonamides as dual inhibitors of sn-1-diacylglycerol lipase α and α/β-hydrolase domain 6. J. Med. Chem. 57, 6610–6622 (2014).
Chang, J. W., Cognetta, A. B. 3rd, Niphakis, M. J. & Cravatt, B. F. Proteome-wide reactivity profiling identifies diverse carbamate chemotypes tuned for serine hydrolase inhibition. ACS Chem. Biol. 8, 1590–1599 (2013).
Wangensteen, T., Akselsen, H., Holmen, J., Undlien, D. & Retterstøl, L. A common haplotype in NAPEPLD is associated with severe obesity in a Norwegian population-based cohort (the HUNT study). Obesity (Silver Spring) 19, 612–617 (2011).
Salaga, M., Sobczak, M. & Fichna, J. Inhibition of fatty acid amide hydrolase (FAAH) as a novel therapeutic strategy in the treatment of pain and inflammatory diseases in the gastrointestinal tract. Eur. J. Pharm. Sci. 52, 173–179 (2014).
Tourino, C., Oveisi, F., Lockney, J., Piomelli, D. & Maldonado, R. FAAH deficiency promotes energy storage and enhances the motivation for food. Int. J. Obes. (Lond.) 34, 557–268 (2009).
Gillum, M. P. et al. N-acylphosphatidylethanolamine, a gut-derived circulating factor induced by fat ingestion, inhibits food intake. Cell 135, 813–824 (2008).
Cani, P. D., Montoya, M. L., Neyrinck, A. M., Delzenne, N. M. & Lambert, D. M. Potential modulation of plasma ghrelin and glucagon-like peptide-1 by anorexigenic cannabinoid compounds, SR141716A (rimonabant) and oleoylethanolamide. Br. J. Nutr. 92, 757–761 (2004).
Rodriguez de Fonseca, F. et al. An anorexic lipid mediator regulated by feeding. Nature 414, 209–212 (2001).
Terrazzino, S. et al. Stearoylethanolamide exerts anorexic effects in mice via down-regulation of liver stearoyl-coenzyme A desaturase-1 mRNA expression. FASEB J. 18, 1580–1582 (2004).
Kim, J., Li, Y. & Watkins, B. A. Fat to treat fat: emerging relationship between dietary PUFA, endocannabinoids, and obesity. Prostaglandins Other Lipid Mediat. 104–105, 32–41 (2013).
Kim, J., Carlson, M. E., Kuchel, G. A., Newman, J. W. & Watkins, B. A. Dietary DHA reduces downstream endocannabinoid and inflammatory gene expression and epididymal fat mass while improving aspects of glucose use in muscle in C57BL/6J mice. Int. J. Obes. (Lond.) http://dx.doi.org/10.1038/ijo.2015.135 (2015).
Banni, S. et al. Krill oil significantly decreases 2-arachidonoylglycerol plasma levels in obese subjects. Nutr. Metab. (Lond.) 8, 7 (2011).
Brown, I. et al. Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines. Carcinogenesis 31, 1584–1591 (2010).
Chen, Z. et al. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. J. Clin. Invest. 124, 3391–3406 (2014).
Bisogno, T. et al. Synthesis and pharmacological activity of a potent inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol. ChemMedChem 4, 946–950 (2009).
P.D.C. is the recipient of grants from Fonds de la Recherche Scientifique (FNRS) (convention J.0084.15 and convention 3.4579.11), Projet de Recherche (convention: T.0138.14) and Action de Recherche Concertée (Communauté française de Belgique convention 12/17-047). The authors work is also supported by the FNRS for the Fund For Strategic Fundamental Research (FRFS)-WELBIO under grant WELBIO-CR-2012S-02R and in part by the Funds InBev-Baillet Latour (Grant for Medical Research 2015). P.D.C. is also a recipient of a European Research Council Starting Grant 2013 (Starting grant 336452-ENIGMO).
The authors declare no competing financial interests.
About this article
Cite this article
Cani, P., Plovier, H., Van Hul, M. et al. Endocannabinoids — at the crossroads between the gut microbiota and host metabolism. Nat Rev Endocrinol 12, 133–143 (2016). https://doi.org/10.1038/nrendo.2015.211
This article is cited by
The diet rapidly and differentially affects the gut microbiota and host lipid mediators in a healthy population
Targeting the endocannabinoid system for the treatment of abdominal pain in irritable bowel syndrome
Nature Reviews Gastroenterology & Hepatology (2023)
Stable colonization of Akkermansia muciniphila educates host intestinal microecology and immunity to battle against inflammatory intestinal diseases
Experimental & Molecular Medicine (2023)
Nature Reviews Endocrinology (2023)
A Critical Review on Akkermansia muciniphila: Functional Mechanisms, Technological Challenges, and Safety Issues
Probiotics and Antimicrobial Proteins (2023)