Endocannabinoids-at the crossroads between the gut microbiota and host metabolism

Nature Reviews Endocrinology

Volumn 12, Issue 3, 2016, Pages 133-143

  Cani, Patrice D ^a   Plovier, Hubert ^a   Van Hul, Matthias ^a   Geurts, Lucie ^a   Delzenne, Nathalie M ^a   Druart, Céline ^a   Everard, Amandine ^a  

^a UNIVERSITÉ CATHOLIQUE DE LOUVAIN   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

ENDOCANNABINOID; IBIPINABANT; LIPID; OTENABANT; TARANABANT; CANNABINOID RECEPTOR;

ADIPOSE TISSUE; ENERGY METABOLISM; ENTERITIS; FAT MASS; GLUCOSE HOMEOSTASIS; GLUCOSE METABOLISM; HEALTH STATUS; HOST; HUMAN; INNATE IMMUNITY; INSULIN RESISTANCE; INTESTINE FLORA; LACTOBACILLUS ACIDOPHILUS; METABOLISM; MICROBIAL DIVERSITY; NONHUMAN; OBESITY; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; ANIMAL; DRUG EFFECTS; GASTROINTESTINAL TRACT; MICROBIOLOGY; PHYSIOLOGY;

ANIMALS; ENDOCANNABINOIDS; GASTROINTESTINAL MICROBIOME; GASTROINTESTINAL TRACT; HUMANS; RECEPTORS, CANNABINOID;

EID: 84958116472     PISSN: 17595029     EISSN: 17595037     Source Type: Journal    
DOI: 10.1038/nrendo.2015.211     Document Type: Review

References (153)

1. Lichtman, J. S., Sonnenburg, J. L., & Elias, J. E. Monitoring host responses to the gut microbiota. ISME J. 9, 1908-1915 (2015
2. 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
3. Nicholson, J. K., et al. Host-gut microbiota metabolic interactions. Science 336, 1262-1267 (2012
4. 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
5. The Human Microbiome Project. Structure, function and diversity of the healthy human microbiome. Nature 486, 207-214 (2012
6. Qin, J., et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59-65 (2010
7. Savage, D. C. Microbial ecology of the gastrointestinal tract. Annu. Rev. Microbiol. 31, 107-133 (1977
8. Cani, P. D., & Delzenne, N. M. The gut microbiome as therapeutic target. Pharmacol. Ther. 130, 202-212 (2011
9. Li, J., et al. An integrated catalog of reference genes in the human gut microbiome. Nat. Biotechnol. 32, 834-841 (2014
10. 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
11. 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
12. Turnbaugh, P. J., et al. A core gut microbiome in obese and lean twins. Nature 457, 480-484 (2009
13. 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
14. 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
15. Goodrich, J. K., et al. Human genetics shape the gut microbiome. Cell 159, 789-799 (2014
16. 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
17. 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
18. Pedron, T., et al. A crypt-specific core microbiota resides in the mouse colon. mBio 3, e00116-e00112 (2012
19. Martinez, I., et al. The gut microbiota of rural Papua New Guineans: composition, diversity patterns, and ecological processes. Cell Rep. 11, 527-538 (2015
20. Wu, G. D., et al. Linking long-Term dietary patterns with gut microbial enterotypes. Science 334, 105-108 (2011
21. David, L. A., et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559-563 (2014
22. 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
23. Roberfroid, M., et al. Prebiotic effects: metabolic and health benefits. Br. J. Nutr. 104, S1-S63 (2010
24. 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
25. Suez, J., et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514, 181-186 (2014
26. Chassaing, B., et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519, 92-96 (2015
27. Cani, P. D., & Everard, A. Keeping gut lining at bay: impact of emulsifiers. Trends Endocrinol. Metab. 26, 273-274 (2015
28. Backhed, F., et al. Defining a healthy human gut microbiome: current concepts, future directions, and clinical applications. Cell Host Microbe 12, 611-622 (2012
29. Le Chatelier, E., et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541-546 (2013
30. Karlsson, F. H., et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99-103 (2013
31. Qin, N., et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59-64 (2014
32. 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
33. Touw, M. The religious and medicinal uses of cannabis in China, India and Tibet. J. Psychoactive Drugs 13, 23-34 (1981
34. Mechoulam, R., & Gaoni, Y. Hashish. IV. The isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids. Tetrahedron 21, 1223-1229 (1965
35. 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
36. Munro, S., Thomas, K. L., & Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61-65 (1993
37. 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
38. Maccarrone, M., et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol. Sci. 36, 277-296 (2015
39. Devane, W. A., et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946-1949 (1992
40. 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
41. 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
42. Fezza, F., et al. Endocannabinoids, related compounds and their metabolic routes. Molecules 19, 17078-17106 (2014
43. 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
44. Ryberg, E., et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol. 152, 1092-1101 (2007
45. Ross, R. A. Anandamide and vanilloid TRPV1 receptors. Br. J. Pharmacol. 140, 790-801 (2003
46. 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
47. 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
48. 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
49. Piscitelli, F. in The Endocannabinoidome: the World of Endocannabinoids and Related Mediators (eds Di Marzo, V., & Wang, J) 1-187 (Academic Press, 2015
50. 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
51. Syed, S. K., et al. Regulation of GPR119 receptor activity with endocannabinoid-like lipids. Am. J. Physiol. Endocrinol. Metab. 303, E1469-E1478 (2012
52. Muccioli, G. G. Endocannabinoid biosynthesis and inactivation, from simple to complex. Drug Discov. Today 15, 474-483 (2010
53. 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
54. Ueda, N., Tsuboi, K., & Uyama, T. Metabolism of endocannabinoids and related N-Acylethanolamines: canonical and alternative pathways. FEBS J. 280, 1874-1894 (2013
55. Di Marzo, V., Stella, N., & Zimmer, A. Endocannabinoid signalling and the deteriorating brain. Nat. Rev. Neurosci. 16, 30-42 (2015
56. 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
57. Deutsch, D. G., Ueda, N., & Yamamoto, S. The fatty acid amide hydrolase (FAAH). Prostaglandins Leukot. Essent. Fatty Acids 66, 201-210 (2002
58. 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
59. 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
60. Bandiera, T., Ponzano, S., & Piomelli, D. Advances in the discovery of N-Acylethanolamine acid amidase inhibitors. Pharmacol. Res. 86, 11-17 (2014
61. Dinh, T. P., et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl Acad. Sci. USA 99, 10819-10824 (2002
62. 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
63. Silvestri, C., & Di Marzo, V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab. 17, 475-490 (2013
64. 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
65. 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
66. 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
67. Cristino, L., Becker, T., & Di Marzo, V. Endocannabinoids and energy homeostasis: an update. Biofactors 40, 389-397 (2014
68. Cristino, L., et al. Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons. Proc. Natl Acad. Sci. USA 110, E2229-E2238 (2013
69. 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
70. 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
71. 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
72. Di Patrizio, N. V., & Piomelli, D. Intestinal lipid-derived signals that sense dietary fat. J. Clin. Invest. 125, 891-898 (2015
73. Piomelli, D. A fatty gut feeling. Trends Endocrinol. Metab. 24, 332-341 (2013
74. 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
75. Hoareau, L., et al. Anti-inflammatory effect of palmitoylethanolamide on human adipocytes. Obesity (Silver Spring) 17, 431-438 (2009
76. Muccioli, G. G., et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol. Syst. Biol. 6, 392 (2010
77. Backhed, F., et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718-15723 (2004
78. Rousseaux, C., et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat. Med. 13, 35-37 (2007
79. 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
80. 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
81. Cani, P. D., et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761-1772 (2007
82. Liu, J., et al. Lipopolysaccharide induces anandamide synthesis in macrophages via CD14/MAPK/phosphoinositide 3-kinase/NF-?B independently of platelet-Activating factor. J. Biol. Chem. 278, 45034-45039 (2003
83. 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
84. Zhu, C., et al. Proinflammatory stimuli control N-Acylphosphatidylethanolamine-specific phospholipase D expression in macrophages. Mol. Pharmacol. 79, 786-792 (2011
85. 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
86. 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
87. 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
88. 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
89. 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
90. Alhamoruni, A., Lee, A. C., Wright, K. L., Larvin, M., & Osullivan, S. E. Pharmacological effects of cannabinoids on the Caco-2 cell culture model of intestinal permeability. J. Pharmacol. Exp. Ther. 335, 92-102 (2010
91. Drucker, D. J. Glucagon-like peptides. Diabetes 47, 159-169 (1998
92. 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
93. 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
94. Everard, A., & Cani, P. D. Gut microbiota and GLP-1. Rev. Endocr. Metab. Disord. 15, 189-196 (2014
95. Everard, A., et al. Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status. Nat. Commun. 5, 5648 (2014
96. 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
97. 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
98. 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
99. 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
100. 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
101. Izzo, A. A., & Sharkey, K. A. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol. Ther. 126, 21-38 (2010
102. 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
103. 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
104. Alhouayek, M., & Muccioli, G. G. Harnessing the anti-inflammatory potential of palmitoylethanolamide. Drug Discov. Today 19, 1632-1639 (2014
105. Borrelli, F., et al. Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti-inflammatory agent. Br. J. Pharmacol. 172, 142-158 (2015
106. Esposito, G., et al. Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-? activation. Gut 63, 1300-1312 (2014
107. Mattace Raso, G., et al. Palmitoylethanolamide prevents metabolic alterations and restores leptin sensitivity in ovariectomized rats. Endocrinology 155, 1291-1301 (2014
108. 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
109. Ley, R. E., et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070-11075 (2005
110. Alhamoruni, A., Wright, K. L., Larvin, M., & Osullivan, S. E. Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability. Br. J. Pharmacol. 165, 2598-2610 (2012
111. Ligresti, A., et al. Possible endocannabinoid control of colorectal cancer growth. Gastroenterology 125, 677-687 (2003
112. Wright, K., et al. Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Gastroenterology 129, 437-453 (2005
113. Dargenio, G., et al. Overactivity of the intestinal endocannabinoid system in celiac disease and in methotrexate-Treated rats. J. Mol. Med. 85, 523-530 (2007
114. 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
115. Di Marzo, V., & Izzo, A. A. Endocannabinoid overactivity and intestinal inflammation. Gut 55, 1373-1376 (2006
116. Smid, S. D. Gastrointestinal endocannabinoid system: multifaceted roles in the healthy and inflamed intestine. Clin. Exp. Pharmacol. Physiol. 35, 1383-1387 (2008
117. 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
118. 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
119. 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
120. Tam, J., et al. Endocannabinoids in liver disease. Hepatology 53, 346-355 (2011
121. Bowles, N. P., et al. A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome. Proc. Natl Acad. Sci. USA 112, 285-290 (2015
122. 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
123. Tam, J., et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J. Clin. Invest. 120, 2953-2966 (2010
124. Tam, J., et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab. 16, 167-179 (2012
125. Chorvat, R. J. Peripherally restricted CB1 receptor blockers. Bioorg. Med. Chem. Lett. 23, 4751-4760 (2013
126. 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
127. 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
128. 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
129. 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
130. 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
131. Ohishi, T., & Yoshida, S. The therapeutic potential of GPR119 agonists for type 2 diabetes. Expert Opin. Investig. Drugs 21, 321-328 (2012
132. Bisogno, T., et al. Development of the first potent and specific inhibitors of endocannabinoid biosynthesis. Biochim. Biophys. Acta 1761, 205-212 (2006
133. Powell, D. R., et al. Diacylglycerol lipase ? knockout mice demonstrate metabolic and behavioral phenotypes similar to those of cannabinoid receptor 1 knockout mice. Front. Endocrinol. (Lausanne) 6, 86 (2015
134. 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
135. 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
136. Thomas, G., et al. The serine hydrolase ABHD6 is a critical regulator of the metabolic syndrome. Cell Rep. 5, 508-520 (2013
137. Zhao, S., et al. ?/β-hydrolase domain-6-Accessible monoacylglycerol controls glucose-stimulated insulin secretion. Cell. Metab. 19, 993-1007 (2014
138. 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
139. Janssen, F. J., et al. Discovery of glycine sulfonamides as dual inhibitors of sn-1-diacylglycerol lipase ? and ?/β-hydrolase domain 6. J. Med. Chem. 57, 6610-6622 (2014
140. 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
141. Wangensteen, T., Akselsen, H., Holmen, J., Undlien, D., & Retterst?l, 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
142. 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
143. 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
144. Gillum, M. P., et al. N-Acylphosphatidylethanolamine, a gut-derived circulating factor induced by fat ingestion, inhibits food intake. Cell 135, 813-824 (2008
145. 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
146. Rodriguez de Fonseca, F., et al. An anorexic lipid mediator regulated by feeding. Nature 414, 209-212 (2001
147. 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
148. 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
149. 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
150. Banni, S., et al. Krill oil significantly decreases 2-Arachidonoylglycerol plasma levels in obese subjects. Nutr. Metab. (Lond) 8, 7 (2011
151. 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
152. Chen, Z., et al. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. J. Clin. Invest. 124, 3391-3406 (2014
153. 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