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The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus

  • Obesity (KM Gadde, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The endocannabinoid (eCB) system, i.e. the receptors that respond to the psychoactive component of cannabis, their endogenous ligands and the ligand metabolic enzymes, is part of a larger family of lipid signals termed the endocannabinoidome (eCBome). We summarize recent discoveries of the roles that the eCBome plays within peripheral tissues in diabetes, and how it is being targeted, in an effort to develop novel therapeutics for the treatment of this increasingly prevalent disease.

Recent Findings

As with the eCB system, many eCBome members regulate several physiological processes, including energy intake and storage, glucose and lipid metabolism and pancreatic health, which contribute to the development of type 2 diabetes (T2D). Preclinical studies increasingly support the notion that targeting the eCBome may beneficially affect T2D.

Summary

The eCBome is implicated in T2D at several levels and in a variety of tissues, making this complex lipid signaling system a potential source of many potential therapeutics for the treatments for T2D.

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Abbreviations

AcArGs:

1-acyl-sn-2-arachidonoyl-glycerols

2-AG:

2-arachidonoyl-glycerol

2-MAG:

2-mono-acyl-glycerol

2-OG:

2-oleoylglycerol

2-PG:

2-palmitoylglycerol

abn-CBD:

abnormal cannabidiol

AA:

arachidonic acid

AEA:

arachidonoylethanolamide

CB1/2:

cannabinoid receptor type-1/2

THC:

D9-tetrahydrocannabinol

THCV:

D9-Tetrahydrocannabivarin

DAGL:

diacylglycerol lipase

DHEA:

docohexanoylethanolamide

eCB:

endocannabinoid

eCBome:

endocannabinoidome

FAAH:

fatty acid amide hydrolase

GPR119:

G protein-coupled Receptor 119

GPR55:

G protein-coupled Receptor 55

GIP:

glucose-dependent insulinotropic polypeptide

LEA:

linoleoylethanolamide

MAGL:

monoacylglycerol lipase

NAE:

N-acylethanolamine

NAPE-PLD:

N-acyl-phosphatidylethanolamine-specific phospholipase D-like

NArPEs:

N-arachidonoyl-phosphatidylethanolamines

NAFLD:

nonalcoholic fatty liver disease

OEA:

oleoylethanolamide

PEA:

palmitoylethanolamide

SEA:

stearoylethanolamide

TRPV1:

transient receptor potential cation channel subfamily V member 1

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Matsuda LA, Young AC. Structure of a cannabinoid receptor and functional expression of the cloned eDNA. 1990;346:4.

  2. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61–5.

    CAS  PubMed  Google Scholar 

  3. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258:1946–9.

    CAS  PubMed  Google Scholar 

  4. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50:83–90.

    CAS  PubMed  Google Scholar 

  5. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci U S A. 2002;99:10819–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384:83–7.

    CAS  PubMed  Google Scholar 

  7. Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol. 2003;163:463–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N. Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem. 2004;279:5298–305.

    CAS  PubMed  Google Scholar 

  9. Di Marzo V. New approaches and challenges to targeting the endocannabinoid system. Nat Rev Drug Discov. 2018;17:623–39.

    PubMed  Google Scholar 

  10. Blüher M, Engeli S, Klöting N, Berndt J, Fasshauer M, Bátkai S, et al. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes. 2006;55:3053–60.

    PubMed  PubMed Central  Google Scholar 

  11. Engeli S, Böhnke J, Feldpausch M, Gorzelniak K, Janke J, Bátkai S, et al. Activation of the peripheral endocannabinoid system in human obesity. Diabetes. 2005;54:2838–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. van Eyk HJ, van Schinkel LD, Kantae V, Dronkers CEA, Westenberg JJM, de Roos A, et al. Caloric restriction lowers endocannabinoid tonus and improves cardiac function in type 2 diabetes. Nutr Diabetes [Internet]. 2018 [cited 2019 May 8];8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851430/

  13. Fanelli F, Mezzullo M, Repaci A, Belluomo I, Ibarra Gasparini D, Di Dalmazi G, et al. Profiling plasma N-Acylethanolamine levels and their ratios as a biomarker of obesity and dysmetabolism. Mol Metab. 2018;14:82–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Fanelli F, Mezzullo M, Belluomo I, Di Lallo VD, Baccini M, Ibarra Gasparini D, et al. Plasma 2-arachidonoylglycerol is a biomarker of age and menopause related insulin resistance and dyslipidemia in lean but not in obese men and women. Mol Metab. 2017;6:406–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Matias I, Gonthier M-P, Orlando P, Martiadis V, De Petrocellis L, Cervino C, 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. 2006;91:3171–80.

    CAS  PubMed  Google Scholar 

  16. Côté M, Matias I, Lemieux I, Petrosino S, Alméras N, Després J-P, et al. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes (Lond). 2007;31:692–9.

    Google Scholar 

  17. de Martins CJM, Genelhu V, MMG P, BMJ C, Mangia RF, Aveta T, et al. Circulating endocannabinoids and the polymorphism 385C>A in fatty acid amide hydrolase (FAAH) gene May identify the obesity phenotype related to Cardiometabolic risk: A study conducted in a Brazilian population of complex interethnic admixture. PLoS One. 2015;10:e0142728.

    Google Scholar 

  18. Little TJ, Cvijanovic N, DiPatrizio NV, Argueta DA, Rayner CK, Feinle-Bisset C, et al. Plasma endocannabinoid levels in lean, overweight, and obese humans: relationships to intestinal permeability markers, inflammation, and incretin secretion. Am J Physiol Endocrinol Metab. 2018;315:E489–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Di Marzo V, Côté M, Matias I, Lemieux I, Arsenault BJ, Cartier A, et al. Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors. Diabetologia. 2008;52:213.

    Google Scholar 

  20. Abdulnour J, Yasari S, Rabasa-Lhoret R, Faraj M, Petrosino S, Piscitelli F, et al. Circulating endocannabinoids in insulin sensitive vs. insulin resistant obese postmenopausal women. A MONET group study. Obesity. 2014;22:211–6.

    CAS  PubMed  Google Scholar 

  21. Matias I, Petrosino S, Racioppi A, Capasso R, Izzo AA, Di Marzo V. Dysregulation of peripheral endocannabinoid levels in hyperglycemia and obesity: effect of high fat diets. Mol Cell Endocrinol. 2008;286:S66–78.

    CAS  PubMed  Google Scholar 

  22. Grapov D, Adams SH, Pedersen TL, Garvey WT, Newman JW. Type 2 diabetes associated changes in the plasma non-esterified fatty acids, oxylipins and endocannabinoids. PLoS One. 2012;7:e48852.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Mallipedhi A, Prior SL, Dunseath G, Bracken RM, Barry J, Caplin S, et al. Changes in Plasma Levels of N-Arachidonoyl Ethanolamine and N-Palmitoylethanolamine following Bariatric Surgery in Morbidly Obese Females with Impaired Glucose Homeostasis. J Diabetes Res [Internet]. 2015 [cited 2019 May 8];2015. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385619/

  24. Gruden G, Barutta F, Kunos G, Pacher P. Role of the endocannabinoid system in diabetes and diabetic complications. Br J Pharmacol. 2016;173:1116–27.

    CAS  PubMed  Google Scholar 

  25. Jourdan T, Djaouti L, Demizieux L, Gresti J, Vergès B, Degrace P. CB1 antagonism exerts specific molecular effects on visceral and subcutaneous fat and reverses liver steatosis in diet-induced obese mice. Diabetes. 2010;59:926–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Sidibeh CO, Pereira MJ, Lau Börjesson J, Kamble PG, Skrtic S, Katsogiannos P, et al. Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance. Endocrine. 2017;55:839–52.

    CAS  PubMed  Google Scholar 

  27. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006;27:73–100.

    CAS  PubMed  Google Scholar 

  28. Jourdan T, Godlewski G, Cinar R, Bertola A, Szanda G, Liu J, et al. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat Med. 2013;19:1132–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Pertwee RG. Cannabinoids and the gastrointestinal tract. Gut. 2001;48:859–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Silvestri C, Di Marzo V. The endocannabinoid system in energy Homeostasis and the Etiopathology of metabolic disorders. Cell Metab. 2013;17:475–90.

    CAS  PubMed  Google Scholar 

  31. Ruiz de Azua I, Mancini G, Srivastava RK, Rey AA, Cardinal P, Tedesco L, et al. Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages. J Clin Invest. 127:4148–62.

    PubMed  Google Scholar 

  32. Moreno-Navarrete JM, Catalán V, Whyte L, Díaz-Arteaga A, Vázquez-Martínez R, Rotellar F, et al. The l-α-Lysophosphatidylinositol/GPR55 system and its potential role in human obesity. Diabetes. 2012;61:281–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang LL, Yan Liu D, Ma LQ, Luo ZD, Cao TB, Zhong J, et al. Activation of transient receptor potential Vanilloid Type-1 channel prevents Adipogenesis and obesity. Circ Res. 2007;100:1063–70.

    CAS  PubMed  Google Scholar 

  34. Meadows A, Lee JH, Wu C-S, Wei Q, Pradhan G, Yafi M, et al. Deletion of G-protein-coupled receptor 55 promotes obesity by reducing physical activity. Int J Obes. 2016;40:417–24.

    CAS  Google Scholar 

  35. • Lipina C, Walsh SK, Mitchell SE, Speakman JR, Wainwright CL, Hundal HS. GPR55 deficiency is associated with increased adiposity and impaired insulin signaling in peripheral metabolic tissues. FASEB J. 2019;33:1299–312 Findings from this study demonstrate that GPR55, a widely expressed OEA and PEA receptor, is a positive regulator of adipogenesis and insulin action in skeletal muscle, adipose tissue and liver.

    CAS  PubMed  Google Scholar 

  36. Alhouayek M, Masquelier J, Muccioli GG. Lysophosphatidylinositols, from cell membrane constituents to GPR55 ligands. Trends Pharmacol Sci. 2018;39:586–604.

    CAS  PubMed  Google Scholar 

  37. Kang J-H, Tsuyoshi G, Han I-S, Kawada T, Kim YM, Yu R. Dietary capsaicin reduces obesity-induced insulin resistance and hepatic steatosis in obese mice fed a high-fat diet. Obesity. 2010;18:780–7.

    CAS  PubMed  Google Scholar 

  38. Lee E, Jung DY, Kim JH, Patel PR, Hu X, Lee Y, et al. Transient receptor potential vanilloid type-1 channel regulates diet-induced obesity, insulin resistance, and leptin resistance. FASEB J. 2015;29:3182–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kuipers EN, Kantae V, Maarse BCE, van den Berg SM, van Eenige R, Nahon KJ, et al. High Fat Diet Increases Circulating Endocannabinoids Accompanied by Increased Synthesis Enzymes in Adipose Tissue. Front Physiol [Internet]. 2019 [cited 2019 May 15];9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335353/

  40. Eckardt K, Sell H, Taube A, Koenen M, Platzbecker B, Cramer A, et al. Cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle. Diabetologia. 2009;52:664–74.

    CAS  PubMed  Google Scholar 

  41. Lindborg KA, Teachey MK, Jacob S, Henriksen EJ. Effects of in vitro antagonism of endocannabinoid-1 receptors on the glucose transport system in normal and insulin-resistant rat skeletal muscle. Diabetes Obes Metab. 2010;12:722–30.

    CAS  PubMed  Google Scholar 

  42. •• Geurts L, Everard A, Van Hul M, Essaghir A, Duparc T, Matamoros S, et al. Adipose tissue NAPE-PLD controls fat mass development by altering the browning process and gut microbiota. Nature Communications [Internet]. 2015 [cited 2018 Aug 3];6. Available from: http://www.nature.com/articles/ncomms7495. This study simultaneously demonstrates the complexity of NAPE-PLD enzyme activity in the regulation of eCBome mediator levels within adipocytes and its critical role in regulating adipose tissue physiology, obesity and whole-body glucose metabolism. Significantly, it also identifies the gut μB as a key factor in mediating the development of this phenotype, highlighting the importance of an adipose tissue eCBome - gut μB axis to metabolic health.

  43. Kargl J, Balenga N, Parzmair GP, Brown AJ, Heinemann A, Waldhoer M. The cannabinoid receptor CB1 modulates the signaling properties of the Lysophosphatidylinositol receptor GPR55. J Biol Chem. 2012;287:44234–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Zelber-Sagi S, Azar S, Nemirovski A, Webb M, Halpern Z, Shibolet O, et al. Serum levels of endocannabinoids are independently associated with nonalcoholic fatty liver disease. Obesity. 2017;25:94–101.

    CAS  PubMed  Google Scholar 

  45. Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:1298–305.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Tedesco L, Valerio A, Dossena M, Cardile A, Ragni M, Pagano C, et al. Cannabinoid receptor stimulation impairs mitochondrial biogenesis in mouse White adipose tissue, muscle, and liver. Diabetes. 2010;59:2826–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Chanda D, Kim D-K, Li T, Kim Y-H, Koo S-H, Lee C-H, et al. Cannabinoid receptor type 1 (CB1R) signaling regulates hepatic gluconeogenesis via induction of endoplasmic reticulum-bound transcription factor cAMP-responsive element-binding protein H (CREBH) in primary hepatocytes. J Biol Chem. 2011;286:27971–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu J, Zhou L, Xiong K, Godlewski G, Mukhopadhyay B, Tam J, et al. Hepatic Cannabinoid Receptor-1 Mediates Diet-Induced Insulin Resistance via Inhibition of Insulin Signaling and Clearance in Mice. Gastroenterology. 2012;142:1218–1228.e1.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong W, et al. Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J Clin Invest. 2008;118:3160–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Jourdan T, Nicoloro SM, Zhou Z, Shen Y, Liu J, Coffey NJ, et al. Decreasing CB1 receptor signaling in Kupffer cells improves insulin sensitivity in obese mice. Molecular Metabolism. 2017;6:1517–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Li L, Li L, Chen L, Lin X, Xu Y, Ren J, et al. Effect of oleoylethanolamide on diet-induced nonalcoholic fatty liver in rats. J Pharmacol Sci. 2015;127:244–50.

    CAS  PubMed  Google Scholar 

  52. Yang JW, Kim HS, Im JH, Kim JW, Jun DW, Lim SC, et al. GPR119: a promising target for nonalcoholic fatty liver disease. FASEB J. 2016;30:324–35.

    CAS  PubMed  Google Scholar 

  53. Hiriart M, Velasco M, Larqué C, Diaz-Garcia CM. Metabolic syndrome and ionic channels in pancreatic beta cells. Vitam Horm. 2014;95:87–114.

    CAS  PubMed  Google Scholar 

  54. González-Mariscal I, Egan JM. Endocannabinoids in the islets of Langerhans: the ugly, the bad, and the good facts. Am J Physiol Endocrinol Metab. 2018;315:E174–9.

    PubMed  PubMed Central  Google Scholar 

  55. Kim W, Doyle ME, Liu Z, Lao Q, Shin Y-K, Carlson OD, et al. Cannabinoids inhibit insulin receptor signaling in pancreatic β-cells. Diabetes. 2011;60:1198–209.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Li C, Vilches-Flores A, Zhao M, Amiel SA, Jones PM, Persaud SJ. Expression and function of monoacylglycerol lipase in mouse β-cells and human islets of Langerhans. Cell Physiol Biochem. 2012;30:347–58.

    PubMed  Google Scholar 

  57. Malenczyk K, Keimpema E, Piscitelli F, Calvigioni D, Björklund P, Mackie K, et al. Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture. Proc Natl Acad Sci U S A. 2015;112:E6185–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Bermudez-Silva FJ, Sanchez-Vera I, Suárez J, Serrano A, Fuentes E, Juan-Pico P, et al. Role of cannabinoid CB2 receptors in glucose homeostasis in rats. Eur J Pharmacol. 2007;565:207–11.

    CAS  PubMed  Google Scholar 

  59. González-Mariscal I, Krzysik-Walker SM, Doyle ME, Liu Q-R, Cimbro R, Santa-Cruz Calvo S, et al. Human CB1 receptor isoforms, present in hepatocytes and β-cells, are involved in regulating metabolism. Sci Rep. 2016;6:33302.

    PubMed  PubMed Central  Google Scholar 

  60. Duvivier VF, Delafoy-Plasse L, Delion V, Lechevalier P, Le Bail J-C, Guillot E, et al. Beneficial effect of a chronic treatment with rimonabant on pancreatic function and beta-cell morphology in Zucker fatty rats. Eur J Pharmacol. 2009;616:314–20.

    CAS  PubMed  Google Scholar 

  61. McKillop AM, Moran BM, Abdel-Wahab YHA, Gormley NM, Flatt PR. Metabolic effects of orally administered small-molecule agonists of GPR55 and GPR119 in multiple low-dose streptozotocin-induced diabetic and incretin-receptor-knockout mice. Diabetologia. 2016;59:2674–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Romero-Zerbo SY, Rafacho A, Díaz-Arteaga A, Suárez J, Quesada I, Imbernon M, et al. A role for the putative cannabinoid receptor GPR55 in the islets of Langerhans. J Endocrinol. 2011;211:177–85.

    CAS  PubMed  Google Scholar 

  63. Aichler M, Borgmann D, Krumsiek J, Buck A, MacDonald PE, Fox JEM, et al. N-acyl Taurines and Acylcarnitines Cause an Imbalance in Insulin Synthesis and Secretion Provoking β Cell Dysfunction in Type 2 Diabetes. Cell Metab. 2017;25:1334–1347.e4.

    CAS  PubMed  Google Scholar 

  64. Koch KL. Diabetic gastropathy: gastric neuromuscular dysfunction in diabetes mellitus: a review of symptoms, pathophysiology, and treatment. Dig Dis Sci. 1999;44:1061–75.

    CAS  PubMed  Google Scholar 

  65. Di Marzo V, Capasso R, Matias I, Aviello G, Petrosino S, Borrelli F, et al. The role of endocannabinoids in the regulation of gastric emptying: alterations in mice fed a high-fat diet. Br J Pharmacol. 2008;153:1272–80.

    PubMed  PubMed Central  Google Scholar 

  66. Capasso R, Orlando P, Pagano E, Aveta T, Buono L, Borrelli F, et al. Palmitoylethanolamide normalizes intestinal motility in a model of post-inflammatory accelerated transit: involvement of CB1 receptors and TRPV1 channels. Br J Pharmacol. 2014;171:4026–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Cluny NL, Keenan CM, Duncan M, Fox A, Lutz B, Sharkey KA. Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (SAB378), a peripherally restricted cannabinoid CB1/CB2 receptor agonist, inhibits gastrointestinal motility but has no effect on experimental colitis in mice. J Pharmacol Exp Ther. 2010;334:973–80.

    CAS  PubMed  Google Scholar 

  68. Lin X-H, Yuece B, Li Y-Y, Feng Y-J, Feng J-Y, Yu L-Y, et al. A novel CB receptor GPR55 and its ligands are involved in regulation of gut movement in rodents. Neurogastroenterol Motil. 2011;23:862–e342.

    CAS  PubMed  Google Scholar 

  69. Troy-Fioramonti S, Demizieux L, Gresti J, Muller T, Vergès B, Degrace P. Acute activation of cannabinoid receptors by anandamide reduces gastrointestinal motility and improves postprandial glycemia in mice. Diabetes. 2015;64:808–18.

    CAS  PubMed  Google Scholar 

  70. Fu J, Kim J, Oveisi F, Astarita G, Piomelli D. Targeted enhancement of oleoylethanolamide production in proximal small intestine induces across-meal satiety in rats. Am J Physiol Regul Integr Comp Physiol. 2008;295:R45–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Everard A, Plovier H, Rastelli M, Van Hul M, de Wouters d’Oplinter A, Geurts L, et al. Intestinal epithelial N-acylphosphatidylethanolamine phospholipase D links dietary fat to metabolic adaptations in obesity and steatosis. Nat Commun. 2019;10:457.

    PubMed  PubMed Central  Google Scholar 

  72. Stricker-Krongrad A, Beck B, Burlet C. Nitric oxide mediates hyperphagia of obese Zucker rats: relation to specific changes in the microstructure of feeding behavior. Life Sci. 1996;58:PL9–15.

    CAS  PubMed  Google Scholar 

  73. Hankir MK, Seyfried F, Hintschich CA, Diep T-A, Kleberg K, Kranz M, et al. Gastric bypass surgery recruits a gut PPAR-α-striatal D1R pathway to reduce fat appetite in obese rats. Cell Metab. 2017;25:335–44.

    CAS  PubMed  Google Scholar 

  74. Overton HA, Babbs AJ, Doel SM, Fyfe MCT, Gardner LS, Griffin G, et al. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 2006;3:167–75.

    CAS  PubMed  Google Scholar 

  75. Hansen KB, Rosenkilde MM, Knop FK, Wellner N, Diep TA, Rehfeld JF, et al. 2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans. J Clin Endocrinol Metab. 2011;96:E1409–17.

    CAS  PubMed  Google Scholar 

  76. Lauffer LM, Iakoubov R, Brubaker PL. GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell. Diabetes. 2009;58:1058–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Schwartz GJ, Fu J, Astarita G, Li X, Gaetani S, Campolongo P, et al. The lipid messenger OEA links dietary fat intake to satiety. Cell Metab. 2008;8:281–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Igarashi M, DiPatrizio NV, Narayanaswami V, Piomelli D. Feeding-induced oleoylethanolamide mobilization is disrupted in the gut of diet-induced obese rodents. Biochim Biophys Acta. 1851;2015:1218–26.

    Google Scholar 

  79. Duszka K, Oresic M, Le May C, König J, Wahli W. PPARγ modulates long chain fatty acid processing in the intestinal epithelium. Int J Mol Sci. 2017;18.

    PubMed Central  Google Scholar 

  80. Karwad MA, Couch DG, Theophilidou E, Sarmad S, Barrett DA, Larvin M, et al. The role of CB1 in intestinal permeability and inflammation. FASEB J. 2017;31:3267–77.

    CAS  PubMed  Google Scholar 

  81. Alhamoruni A, Wright KL, Larvin M, O’Sullivan SE. Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability. Br J Pharmacol. 2012;165:2598–610.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. . Karwad MA, Macpherson T, Wang B, Theophilidou E, Sarmad S, Barrett DA, et al. Oleoylethanolamine and palmitoylethanolamine modulate intestinal permeability in vitro via TRPV1 and PPARα. FASEB J. 2017;31:469–81 This in vitro study identifies a potential endogenous role for the eCBome mediators OEA and PEA in regulating intestinal permeability associated with inflammation. Both OEA, via TRPV1, and PEA, via PPARA, decrease cytokine-induced transepithelial permeability.

    CAS  PubMed  Google Scholar 

  83. Acharya N, Penukonda S, Shcheglova T, Hagymasi AT, Basu S, Srivastava PK. Endocannabinoid system acts as a regulator of immune homeostasis in the gut. Proc Natl Acad Sci U S A. 2017;114:5005–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Grunewald ZI, Lee S, Kirkland R, Ross M, de La Serre CB. Cannabinoid receptor type-1 partially mediates metabolic endotoxemia-induced inflammation and insulin resistance. Physiol Behav. 2019;199:282–91.

    CAS  PubMed  Google Scholar 

  85. Couch DG, Tasker C, Theophilidou E, Lund JN, O’Sullivan SE. Cannabidiol and palmitoylethanolamide are anti-inflammatory in the acutely inflamed human colon. Clin Sci. 2017;131:2611–26.

    CAS  PubMed  Google Scholar 

  86. Esposito G, Capoccia E, Turco F, Palumbo I, Lu J, Steardo A, et al. Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation. Gut. 2014;63:1300–12.

    CAS  PubMed  Google Scholar 

  87. Després J-P, Golay A, Sjöström L. Effects of Rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;14.

  88. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S, RIO-Europe Study Group. 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. 2005;365:1389–97.

    PubMed  Google Scholar 

  89. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. RIO-North America Study Group. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 2006;295:761–75.

    CAS  PubMed  Google Scholar 

  90. Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF, RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet. 2006;368:1660–72.

    CAS  PubMed  Google Scholar 

  91. Sam AH, Salem V, Ghatei MA. Rimonabant: From RIO to Ban. J Obes [Internet]. 2011 [cited 2019 May 11];2011. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136184/

  92. Silvestri C, Marzo VD. Second generation CB1 receptor blockers and other inhibitors of peripheral endocannabinoid overactivity and the rationale of their use against metabolic disorders. Expert Opin Investig Drugs. 2012;21:1309–22.

    CAS  PubMed  Google Scholar 

  93. Tam J, Hinden L, Drori A, Udi S, Azar S, Baraghithy S. The therapeutic potential of targeting the peripheral endocannabinoid/CB1 receptor system. Eur J Intern Med. 2018;49:23–9.

    CAS  PubMed  Google Scholar 

  94. Cinar R, Godlewski G, Liu J, Tam J, Jourdan T, Mukhopadhyay B, et al. Hepatic cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing de novo synthesis of long-chain ceramides. Hepatology. 2014;59:143–53.

    CAS  PubMed  Google Scholar 

  95. Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab. 2012;16:167–79.

    CAS  PubMed  Google Scholar 

  96. Romero-Zerbo SY, Ruz-Maldonado I, Espinosa-Jiménez V, Rafacho A, Gómez-Conde AI, Sánchez-Salido L, et al. The cannabinoid ligand LH-21 reduces anxiety and improves glucose handling in diet-induced obese pre-diabetic mice. Sci Rep. 2017;7:3946.

    PubMed  PubMed Central  Google Scholar 

  97. Tam J, Vemuri VK, Liu J, Bátkai S, Mukhopadhyay B, Godlewski G, et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest. 2010;120:2953–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Ma H, Zhang G, Mou C, Fu X, Chen Y. Peripheral CB1 Receptor Neutral Antagonist, AM6545, Ameliorates Hypometabolic Obesity and Improves Adipokine Secretion in Monosodium Glutamate Induced Obese Mice. Front Pharmacol [Internet]. 2018 [cited 2019 May 12];9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869198/

  99. Cluny NL, Chambers AP, Vemuri VK, Wood JT, Eller LK, Freni C, et al. The neutral cannabinoid CB1 receptor antagonist A M4113 regulates body weight through changes in energy intake in the rat. Pharmacol Biochem Behav. 2011;97:537–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Agudo J, Martin M, Roca C, Molas M, Bura AS, Zimmer A, et al. Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increases food intake and obesity with age. Diabetologia. 2010;53:2629–40.

    CAS  PubMed  Google Scholar 

  101. Deveaux V, Cadoudal T, Ichigotani Y, Teixeira-Clerc F, Louvet A, Manin S, et al. Cannabinoid CB2 receptor potentiates obesity-associated inflammation, Insulin Resistance and Hepatic Steatosis. PLOS ONE. 2009;4:e5844.

    PubMed  PubMed Central  Google Scholar 

  102. Zhang X, Gao S, Niu J, Li P, Deng J, Xu S, et al. Cannabinoid 2 receptor agonist improves systemic sensitivity to insulin in high-fat diet/Streptozotocin-induced diabetic mice. CPB. 2016;40:1175–85.

    Google Scholar 

  103. Imtiaz S, Rehm J. The relationship between cannabis use and diabetes: results from the National Epidemiologic Survey on alcohol and related conditions III. Drug Alcohol Rev. 2018;37:897–902.

    PubMed  Google Scholar 

  104. Penner EA, Buettner H, Mittleman MA. The impact of marijuana use on glucose, insulin, and insulin resistance among US adults. Am J Med. 2013;126:583–9.

    CAS  PubMed  Google Scholar 

  105. Clark T, Jessica Jones, Hall A, Tabner S, Kmiec R. Theoretical Explanation for Reduced Body Mass Index and Obesity Rates in Cannabis Users. 2018 [cited 2019 Jan 8]; Available from: http://www.preprints.org/manuscript/201807.0197/v1

  106. Roger Pertwee, Maria Grazia Cascio. Chapter 6: Known Pharmacological Actions of Delta-9-Tetrahydrocannabinol and of Four Other Chemical Constituents of Cannabis that Activate Cannabinoid Receptors. In: Roger Pertwee, editor. Handbook of Cannabis [Internet]. First Edition. Oxford University Press; 2014. p. 115–136. Available from: https://www.oxfordscholarship.com/view/10.1093/acprof:oso/9780199662685.001.0001/acprof-9780199662685-chapter-6

  107. Wargent ET, Zaibi MS, Silvestri C, Hislop DC, Stocker CJ, Stott CG, et al. The cannabinoid Δ9-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity. Nutr Diabetes. 2013;3:e68.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Jadoon KA, Ratcliffe SH, Barrett DA, Thomas EL, Stott C, Bell JD, et al. Efficacy and safety of Cannabidiol and Tetrahydrocannabivarin on glycemic and lipid parameters in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, Parallel Group Pilot Study. Diabetes Care. 2016;39:1777–86.

    CAS  PubMed  Google Scholar 

  109. Gross B, Pawlak M, Lefebvre P, Staels B. PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol. 2017;13:36–49.

    CAS  PubMed  Google Scholar 

  110. Moriconi A, Cerbara I, Maccarrone M, Topai A. GPR55: current knowledge and future perspectives of a purported “Type-3” cannabinoid receptor. Curr Med Chem. 2010;17:1411–29.

    CAS  PubMed  Google Scholar 

  111. McKillop AM, Moran BM, Abdel-Wahab YHA, Flatt PR. Evaluation of the insulin releasing and antihyperglycaemic activities of GPR55 lipid agonists using clonal beta-cells, isolated pancreatic islets and mice. Br J Pharmacol. 2013;170:978–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Yang JW, Kim HS, Choi Y-W, Kim Y-M, Kang KW. Therapeutic application of GPR119 ligands in metabolic disorders. Diabetes Obes Metab. 2018;20:257–69.

    CAS  PubMed  Google Scholar 

  113. Ritter K, Buning C, Halland N, Pöverlein C, Schwink L. G protein-coupled receptor 119 (GPR119) agonists for the treatment of diabetes: recent Progress and prevailing challenges. J Med Chem. 2016;59:3579–92.

    CAS  PubMed  Google Scholar 

  114. Ohishi T, Yoshida S. The therapeutic potential of GPR119 agonists for type 2 diabetes. Expert Opin Investig Drugs. 2012;21:321–8.

    CAS  PubMed  Google Scholar 

  115. Hansen KB, Rosenkilde MM, Knop FK, Wellner N, Diep TA, Rehfeld JF, et al. 2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans. J Clin Endocrinol Metab. 2011;96:E1409–17.

    CAS  PubMed  Google Scholar 

  116. Mandøe MJ, Hansen KB, Windeløv JA, Knop FK, Rehfeld JF, Rosenkilde MM, et al. Comparing olive oil and C4-dietary oil, a prodrug for the GPR119 agonist, 2-oleoyl glycerol, less energy intake of the latter is needed to stimulate incretin hormone secretion in overweight subjects with type 2 diabetes. Nutr Diabetes. 2018;8:2.

    PubMed  PubMed Central  Google Scholar 

  117. Effect of Dietary Oils as G-protein-coupled Receptor Agonists on Glucose Tolerance - Full Text View - ClinicalTrials.gov [Internet]. [cited 2019 May 13]. Available from: https://clinicaltrials.gov/ct2/show/NCT03774095

  118. Song J-X, Ren H, Gao Y-F, Lee C-Y, Li S-F, Zhang F, et al. Dietary Capsaicin Improves Glucose Homeostasis and Alters the Gut Microbiota in Obese Diabetic ob/ob Mice. Frontiers in Physiology [Internet]. 2017 [cited 2018 Jul 25];8. Available from: http://journal.frontiersin.org/article/10.3389/fphys.2017.00602/full

  119. Kang J-H, Tsuyoshi G, Le Ngoc H, Kim H-M, Tu TH, Noh H-J, et al. Dietary capsaicin attenuates metabolic dysregulation in genetically obese diabetic mice. J Med Food. 2011;14:310–5.

    CAS  PubMed  Google Scholar 

  120. Kang C, Wang B, Kaliannan K, Wang X, Lang H, Hui S, et al. Gut Microbiota Mediates the Protective Effects of Dietary Capsaicin against Chronic Low-Grade Inflammation and Associated Obesity Induced by High-Fat Diet. mBio. 2017;8:e00470–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Wang P, Yan Z, Zhong J, Chen J, Ni Y, Li L, et al. Transient receptor potential Vanilloid 1 activation enhances gut glucagon-like Peptide-1 secretion and improves glucose Homeostasis. Diabetes. 2012;61:2155–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Kroff J, Hume DJ, Pienaar P, Tucker R, Lambert EV, Rae DE. The metabolic effects of a commercially available chicken peri-peri (African bird’s eye chilli) meal in overweight individuals. Br J Nutr. 2017;117:635–44.

    CAS  PubMed  Google Scholar 

  123. Urbina SL, Roberts MD, Kephart WC, Villa KB, Santos EN, Olivencia AM, et al. Effects of twelve weeks of capsaicinoid supplementation on body composition, appetite and self-reported caloric intake in overweight individuals. Appetite. 2017;113:264–73.

    PubMed  Google Scholar 

  124. Touska F, Marsakova L, Teisinger J, Vlachova V. A “cute” desensitization of TRPV1. Curr Pharm Biotechnol. 2011;12:122–9.

    CAS  PubMed  Google Scholar 

  125. Gram DX, Hansen AJ. Inhibition of the activity of the capsaicin receptor in the treatment of obesity or obesity-related diseases and disorders [Internet]. 2011 [cited 2019 May 14]. Available from: https://patents.google.com/patent/US7879866B2/en

  126. Clinical Trials Register [Internet]. [cited 2019 May 14]. Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-003843-12/DK#E

  127. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490:55–60.

    CAS  PubMed  Google Scholar 

  128. Karlsson FH, Tremaroli V, Nookaew I, Bergström G, Behre CJ, Fagerberg B, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498:99–103.

    CAS  PubMed  Google Scholar 

  129. Kim YA, Keogh JB, Clifton PM. Probiotics, prebiotics, synbiotics and insulin sensitivity. Nutr Res Rev. 2018;31:35–51.

    CAS  PubMed  Google Scholar 

  130. Muccioli GG, Naslain D, Bäckhed F, Reigstad CS, Lambert DM, Delzenne NM, et al. The endocannabinoid system links gut microbiota to adipogenesis. Molecular Systems Biology [Internet]. 2010 [cited 2018 Aug 3];6. Available from: http://msb.embopress.org/cgi/doi/10.1038/msb.2010.46

  131. Geurts L, Lazarevic V, Derrien M, Everard A, Van Roye M, Knauf C, 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 [Internet]. 2011 [cited 2018 Aug 3];2. Available from: https://www.frontiersin.org/articles/10.3389/fmicb.2011.00149/full

  132. Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. PNAS. 2013;110:9066–71.

    CAS  PubMed  Google Scholar 

  133. Evaluation of the Effects Associated With the Administration of Akkermansia Muciniphila on Parameters of Metabolic Syndrome - Full Text View - ClinicalTrials.gov [Internet]. [cited 2019 May 14]. Available from: https://clinicaltrials.gov/ct2/show/NCT02637115

  134. Brodie JS, Di Marzo V, Guy GW. Polypharmacology shakes hands with complex Aetiopathology. Trends Pharmacol Sci. 2015;36:802–21.

    CAS  PubMed  Google Scholar 

  135. Piscitelli F, Carta G, Bisogno T, Murru E, Cordeddu L, Berge K, et al. Effect of dietary krill oil supplementation on the endocannabinoidome of metabolically relevant tissues from high-fat-fed mice. Nutr Metab (Lond). 2011;8:51.

    CAS  Google Scholar 

  136. Demizieux L, Piscitelli F, Troy-Fioramonti S, Iannotti FA, Borrino S, Gresti J, et al. Early low-fat diet enriched with linolenic acid reduces liver endocannabinoid tone and improves late glycemic control after a high-fat diet challenge in mice. Diabetes. 2016;65:1824–37.

    CAS  PubMed  Google Scholar 

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Alain Veilleux declares no conflict of interest.

Vincenzo Di Marzo reports grants from GW Pharmaceuticals.

Cristoforo Silvestri reports he was a previous employee of GW Pharmaceuticals.

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Veilleux, A., Di Marzo, V. & Silvestri, C. The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus. Curr Diab Rep 19, 117 (2019). https://doi.org/10.1007/s11892-019-1248-9

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