Cannabinoids and Endocannabinoids in Metabolic Disorders with Focus on Diabetes

  • Vincenzo Di Marzo
  • Fabiana Piscitelli
  • Raphael Mechoulam
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 203)

Abstract

The cannabinoid receptors for Δ9-THC, and particularly, the CB1 receptor, as well as its endogenous ligands, the endocannabinoids anandamide and 2-arachidonoylglycerol, are deeply involved in all aspects of the control of energy balance in mammals. While initially it was believed that this endocannabinoid signaling system would only facilitate energy intake, we now know that perhaps even more important functions of endocannabinoids and CB1 receptors in this context are to enhance energy storage into the adipose tissue and reduce energy expenditure by influencing both lipid and glucose metabolism. Although normally well controlled by hormones and neuropeptides, both central and peripheral aspects of endocannabinoid regulation of energy balance can become dysregulated and contribute to obesity, dyslipidemia, and type 2 diabetes, thus raising the possibility that CB1 antagonists might be used for the treatment of these metabolic disorders. On the other hand, evidence is emerging that some nonpsychotropic plant cannabinoids, such as cannabidiol, can be employed to retard β-cell damage in type 1 diabetes. These novel aspects of endocannabinoid research are reviewed in this chapter, with emphasis on the biological effects of plant cannabinoids and endocannabinoid receptor antagonists in diabetes.

Keywords

CB1 receptor Endocannabinoid Lipids Phytocannabinoid Rimonabant 

References

  1. Anderson MS, Bluestone JA (2005) The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 23:447–485PubMedGoogle Scholar
  2. Annuzzi G, Piscitelli F, Di Marino L et al (2010) Differential alterations of the concentrations of endocannabinoids and related lipids in the subcutaneous adipose tissue of obese diabetic patients. Lipids Health Dis 9:43PubMedCentralPubMedGoogle Scholar
  3. Ashton JC, Friberg D, Darlington CL et al (2006) Expression of the cannabinoid CB2 receptor in the rat cerebellum: an immunohistochemical study. Neurosci Lett 396:113–116PubMedGoogle Scholar
  4. Atkinson MA, Leiter EH (1999) The NOD mouse model of type 1 diabetes: as good as it gets? Nat Med 5:601–604PubMedGoogle Scholar
  5. Bellocchio L, Cervino C, Vicennati V et al. (2008) Cannabinoid type 1 receptor: another arrow in the adipocytes' bow. J Neuroendocrinol Suppl 1:130–138 (Review)Google Scholar
  6. Bensaid M, Gary-Bobo M, Esclangon A et al (2003) The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol 63:908–914PubMedGoogle Scholar
  7. Ben-Shabat S, Fride E, Sheskin T et al (1998) An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol 353:23–31PubMedGoogle Scholar
  8. Bermudez-Silva FJ, Serrano A, Diaz-Molina FJ et al (2006) Activation of cannabinoid CB(1) receptors induces glucose intolerance in rats. Eur J Pharmacol 531:282–284Google Scholar
  9. Bermúdez-Silva FJ, Suárez J, Baixeras E et al (2008) Presence of functional cannabinoid receptors in human endocrine pancreas. Diabetologia 51:476–487PubMedGoogle Scholar
  10. Bilfinger TV, Salzet M, Fimiani C, Deutsch DG, Tramu G, Stefano GB (1998) Pharmacological evidence for anandamide amidase in human cardiac and vascular tissues. Int J Cardiol 64 (Suppl 1):S15–S22PubMedGoogle Scholar
  11. Bisogno T, Melck D, De Petrocellis L et al (1999) Phosphatidic acid as the biosynthetic precursor of the endocannabinoid 2-arachidonoylglycerol in intact mouse neuroblastoma cells stimulated with ionomycin. J Neurochem 72:2113–2119PubMedGoogle Scholar
  12. Bisogno T, Howell F, Williams G et al (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 163:463–468PubMedCentralPubMedGoogle Scholar
  13. Bluher M, Engeli S, Kloting N et al (2006) Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes 55:3053–3060PubMedCentralPubMedGoogle Scholar
  14. Bouaboula M, Hilairet S, Marchand J et al (2005) Anandamide induced PPARgamma transcriptional activation and 3T3-L1 preadipocyte differentiation. Eur J Pharmacol 517:174–181PubMedGoogle Scholar
  15. Burdyga G, Lal S, Varro A et al (2004) Expression of cannabinoid CB1 receptors by vagal afferent neurons is inhibited by cholecystokinin. J Neurosci 24:2708–2715PubMedGoogle Scholar
  16. Cavuoto P, McAinch AJ, Hatzinikolas G et al (2007) Effects of cannabinoid receptors on skeletal muscle oxidative pathways. Mol Cell Endocrinol 267:63–69PubMedGoogle Scholar
  17. Chambers AP, Sharkey KA, Koopmans HS (2004) Cannabinoid (CB)1 receptor antagonist, AM 251, causes a sustained reduction of daily food intake in the rat. Physiol Behav 82:863–869PubMedGoogle Scholar
  18. Colombo G, Agabio R, Diaz G et al (1998) Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sci 63:113–117Google Scholar
  19. Cota D, Marsicano G, Tschop M et al (2003) The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 112:423–431PubMedCentralPubMedGoogle Scholar
  20. Cota D, Tschop MH, Horvath TL et al (2006) Cannabinoids, opioids and eating behavior: the molecular face of hedonism? Brain Res Rev 51:85–107PubMedGoogle Scholar
  21. Cota D, Steiner MA, Marsicano G et al (2007) Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function. Endocrinology 148: 1574–1581PubMedGoogle Scholar
  22. Cote M, Matias I, Lemieux I et al (2007) Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes (Lond) 31:692–699Google Scholar
  23. Coutts AA, Izzo AA (2004) The gastrointestinal pharmacology of cannabinoids: an update. Curr Opin Pharmacol 4:572–579PubMedGoogle Scholar
  24. Cravatt BF, Giang DK, Mayfield SP et al (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87PubMedGoogle Scholar
  25. De Petrocellis L, Marini P, Matias I et al (2007) Mechanisms for the coupling of cannabinoid receptors to intracellular calcium mobilization in rat insulinoma beta-cells. Exp Cell Res 313:2993–3004PubMedGoogle Scholar
  26. De Petrocellis L, Vellani V, Schiano-Moriello A et al (2008) Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther 325:1007–1015PubMedGoogle Scholar
  27. D'Eon TM, Pierce KA, Roix JJ et al (2008) The role of adipocyte insulin resistance in the pathogenesis of obesity-related elevations in endocannabinoids. Diabetes 57:1262–1268PubMedGoogle Scholar
  28. Després JP, Lemieux I (2006) Abdominal obesity and metabolic syndrome. Nature 444:881–887PubMedGoogle Scholar
  29. Després JP, Golay A, Sjöström L et al (2005) Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121–2134PubMedGoogle Scholar
  30. Devane WA, Dysarz FA, Johnson MR et al (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613PubMedGoogle Scholar
  31. Devane WA, Hanus L, Breuer A et al (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949PubMedGoogle Scholar
  32. Di Marzo V (2008a) Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov 7:438–455PubMedGoogle Scholar
  33. Di Marzo V (2008b) The endocannabinoid system in obesity and type 2 diabetes. Diabetologia 51:1356–1367PubMedGoogle Scholar
  34. Di Marzo V, Després JP (2010) CB1 antagonists for obesity–what lessons have we learned from rimonabant? Nat Rev Endocrinol 5:633–638Google Scholar
  35. Di Marzo V, De Petrocellis L, Sugiura T et al (1996) Potential biosynthetic connections between the two cannabimimetic eicosanoids, anandamide and 2-arachidonoyl-glycerol, in mouse neuroblastoma cells. Biochem Biophys Res Commun 227:281–288PubMedGoogle Scholar
  36. Di Marzo V, Sepe N, De Petrocellis L et al (1998) Trick or treat from food endocannabinoids? Nature 396:636–637PubMedGoogle Scholar
  37. Di Marzo V, Goparaju SK, Wang L et al (2001) Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410:822–825PubMedGoogle Scholar
  38. Di Marzo V, Bifulco M, De Petrocellis L (2004) The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3:771–784PubMedGoogle Scholar
  39. Di Marzo V, De Petrocellis L, Di Marzo V, De Petrocellis L (2005) Non-CB1, non-CB2 receptors for endocannabinoids. In: Onaivi ES, Sugiura T, Di Marzo V (eds) Endocannabinoids: The Brain and Body’s Marijuana and Beyond. CRC Press, Taylor & Francis Group, Boca Raton, FL, pp 151–174Google Scholar
  40. Di Marzo V, Côté M, Matias I et al (2009a) Changes in plasma endocannabinoid levels in viscerally obese men following a one-year lifestyle modification program and waist circumference reduction: associations with changes in metabolic risk factors. Diabetologia 52:213–217PubMedGoogle Scholar
  41. Di Marzo V, Verrijken A, Hakkarainen A et al (2009b) Role of insulin as a negative regulator of plasma endocannabinoid levels in obese and nonobese subjects. Eur J Endocrinol 161:715–722PubMedGoogle Scholar
  42. Dinh TP, Carpenter D, Leslie FM et al (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 99:10819–10824PubMedCentralPubMedGoogle Scholar
  43. DiPatrizio NV, Simansky KJ (2008a) Activating parabrachial cannabinoid CB1 receptors selectively stimulates feeding of palatable foods in rats. J Neurosci 28:9702–9709PubMedCentralPubMedGoogle Scholar
  44. Dipatrizio NV, Simansky KJ (2008) Inhibiting parabrachial fatty acid amide hydrolase activity selectively increases the intake of palatable food via cannabinoid CB1 receptors. Am J Physiol Regul Integr Comp Physiol [Epub ahead of print]Google Scholar
  45. Doyon C, Denis RG, Baraboi ED et al (2006) Effects of rimonabant (SR141716) on fasting-induced hypothalamic-pituitary-adrenal axis and neuronal activation in lean and obese Zucker rats. Diabetes 55:3403–3410PubMedGoogle Scholar
  46. Ellis J, Pediani JD, Canals M et al (2006) Orexin-1 receptor-cannabinoid CB1 receptor heterodimerization results in both ligand-dependent and -independent coordinated alterations of receptor localization and function. J Biol Chem 281:38812–38824PubMedGoogle Scholar
  47. Engeli S, Bohnke J, Feldpausch M et al (2005) Activation of the peripheral endocannabinoid system in human obesity. Diabetes 54:2838–2843PubMedCentralPubMedGoogle Scholar
  48. Esposito I, Proto MC, Gazzerro P et al (2008) The cannabinoid CB1 receptor antagonist Rimonabant stimulates 2-deoxyglucose uptake in skeletal muscle cells by regulating phosphatidylinositol-3-kinase activity. Mol Pharmacol 74(6):1678–1686PubMedGoogle Scholar
  49. Fride E, Ginzburg Y, Breuer A et al (2001) Critical role of the endogenous cannabinoid system in mouse pup suckling and growth. Eur J Pharmacol 419:207–214PubMedGoogle Scholar
  50. Gallate JE, Saharov T, Mallet PE et al (1999) Increased motivation for beer in rats following administration of a cannabinoid CB1 receptor agonist. Eur J Pharmacol 370:233–240PubMedGoogle Scholar
  51. Gaoni Y, Mechoulam R (1964) Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem So 86:1646–1647Google Scholar
  52. Gary-Bobo M, Elachouri G, Scatton B et al (2006) The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits cell proliferation and increases markers of adipocyte maturation in cultured mouse 3T3 F442A preadipocytes. Mol Pharmacol 69:471–478PubMedGoogle Scholar
  53. Gary-Bobo M, Elachouri G, Gallas JF et al (2007) Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology 46:122–129PubMedGoogle Scholar
  54. Gasperi V, Fezza F, Pasquariello N et al (2007) Endocannabinoids in adipocytes during differentiation and their role in glucose uptake. Cell Mol Life Sci 64:219–229PubMedGoogle Scholar
  55. Getty-Kaushik L, Richard A-MT, Deeney JT, Shirihai O, Corkey B (2009) The CB1 antagonist, rimonabant, decreases insulin hypersecretion in rat pancreatic islets. Obesity 17:1856–1860PubMedGoogle Scholar
  56. Glass M, Northup JK (1999) Agonist selective regulation of G proteins by cannabinoid CB(1) and CB(2) receptors. Mol Pharmacol 56:1362–1369PubMedGoogle Scholar
  57. Gomez R, Navarro M, Ferrer B et al (2002) A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 22:9612–9617PubMedGoogle Scholar
  58. Gong JP, Onaivi ES, Ishiguro H et al (2006) Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res 1071:10–23PubMedGoogle Scholar
  59. Gonzalez S, Manzanares J, Berrendero F et al (1999) Identification of endocannabinoids and cannabinoid CB(1) receptor mRNA in the pituitary gland. Neuroendocrinology 70:137–145PubMedGoogle Scholar
  60. Hanus L, Mechoulam R (2008) Plant and brain cannabinoids: The chemistry of major new players in physiology. In: Ikan R (ed) Selected topics in the chemistry of natural products. World Scientific Publishing Company. Imperial College Press, London, pp 49–75Google Scholar
  61. Hanus L, Avraham Y, Ben-Shushan D et al (2003) Short term fasting and prolonged semistarvation have opposite effect on 2-AG levels in mouse brain. Brain Res 983:144–151PubMedGoogle Scholar
  62. Herling AW, Gossel M, Haschke G et al (2007) CB1 receptor antagonist AVE1625 affects primarily metabolic parameters independently of reduced food intake in Wistar rats. Am J Physiol Endocrinol Metab 293:E826–E832PubMedGoogle Scholar
  63. Herling AW, Kilp S, Elvert R et al (2008a) Increased energy expenditure contributes more to the body weight-reducing effect of rimonabant than reduced food intake in candy-fed wistar rats. Endocrinology 149:2557–2566PubMedGoogle Scholar
  64. Herling AW, Kilp S, Juretschke HP et al (2008b) Reversal of visceral adiposity in candy-diet fed female Wistar rats by the CB1 receptor antagonist rimonabant. Int J Obes (Lond) 32:1363–1372Google Scholar
  65. Hilairet S, Bouaboula M, Carrière D et al (2003) Hypersensitization of the Orexin 1 receptor by the CB1 receptor: evidence for cross-talk blocked by the specific CB1 antagonist, SR141716. J Biol Chem 278:23731–23737PubMedGoogle Scholar
  66. Hollander PA, Amod A, Litwak LE, Chaudhari U; ARPEGGIO Study Group (2010) Effect of rimonabant on glycemic control in insulin-treated type 2 diabetes: the ARPEGGIO trial. Diabetes Care 33:605–607Google Scholar
  67. Izzo AA, Piscitelli F, Capasso R et al (2009) Peripheral endocannabinoid dysregulation in two experimental models of obesity: potential relationships with intestinal motility and food deprivation/refeeding-induced energy processing. Br J Pharmacol 158:451–461Google Scholar
  68. Janiak P, Poirier B, Bidouard JP et al (2007) Blockade of cannabinoid CB1 receptors improves renal function, metabolic profile, and increased survival of obese Zucker rats. Kidney Int 72(11):1345–1357PubMedGoogle Scholar
  69. Jbilo O, Ravinet-Trillou C, Arnone M et al (2005) The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J 19:1567–1569PubMedGoogle Scholar
  70. Jo YH, Chen YJ, Chua SC Jr et al (2005) Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit. Neuron 48:1055–1066PubMedCentralPubMedGoogle Scholar
  71. Juan-Pico P, Fuentes E, Bermudez-Silva FJ et al (2006) Cannabinoid receptors regulate Ca(2+) signals and insulin secretion in pancreatic beta-cell. Cell Calcium 39:155–162PubMedGoogle Scholar
  72. Kirkham TC, Williams CM, Fezza F et al (2002) Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol 136:550–557PubMedCentralPubMedGoogle Scholar
  73. Klein TW (2005) Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol 5:400–411PubMedGoogle Scholar
  74. Koch JE (2001) Delta(9)-THC stimulates food intake in Lewis rats: effects on chow, high-fat and sweet high-fat diets. Pharmacol Biochem Behav 68:539–543PubMedGoogle Scholar
  75. Kola B, Hubina E, Tucci SA et al (2005) Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem 280:25196–25201PubMedGoogle Scholar
  76. Kola B, Farkas I, Christ-Crain M et al (2008) The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS ONE 3:1797Google Scholar
  77. Kunz I, Meier MK, Bourson A et al (2008) Effects of rimonabant, a cannabinoid CB1 receptor ligand, on energy expenditure in lean rats. Int J Obes (Lond) 32:863–70Google Scholar
  78. Leung D, Saghatelian A, Simon GM et al (2006) Inactivation of N-acyl phosphatidylethanolamine phospholipase d reveals multiple mechanisms for the biosynthesis of endocannabinoids. Biochemistry 45:4720–4726PubMedCentralPubMedGoogle Scholar
  79. Liu YL, Connoley IP, Wilson CA et al (2005) Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep(ob)/Lep(ob) mice. Int J Obes (Lond) 29:183–187Google Scholar
  80. Maccarrone M, Di Rienzo M, Finazzi-Agro A et al (2003) Leptin activates the anandamide hydrolase promoter in human T lymphocytes through STAT3. J Biol Chem 278:13318–13324PubMedGoogle Scholar
  81. Maccarrone M, Fride E, Bisogno T et al (2005) Up-regulation of the endocannabinoid system in the uterus of leptin knockout (ob/ob) mice and implications for fertility. Mol Hum Reprod 11:21–28PubMedGoogle Scholar
  82. Malcher-Lopes R, Di S, Marcheselli VS et al (2006) Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release. J Neurosci 26:6643–6650PubMedGoogle Scholar
  83. Mandrup-Poulsen T (2003) Beta cell death and protection. Ann NY Acad Sci 1005:32–42PubMedGoogle Scholar
  84. Matias I, Di Marzo V (2007) Endocannabinoids and the control of energy balance. Trends Endocrinol Metab 18:27–37PubMedGoogle Scholar
  85. Matias I, Gonthier MP, Orlando P et al (2006) Regulation, function and dysregulation of endocannabinoids in models of adipose and β-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab 91:3171–80PubMedGoogle Scholar
  86. Matias I, Petrosino S, Racioppi A et al (2008) Dysregulation of peripheral endocannabinoid levels in hyperglycemia and obesity: Effect of high fat diets. Mol Cell Endocrinol 286:S66–78PubMedGoogle Scholar
  87. McAllister SD, Glass M (2002) CB(1) and CB(2) receptor-mediated signaling: a focus on endocannabinoids. Prostaglandins Leukot Essent Fatty Acids 66:161–171PubMedGoogle Scholar
  88. McLaughlin PJ, Winston K, Swezey L et al (2003) The cannabinoid CB1 antagonists SR 141716A and AM 251 suppress food intake and food-reinforced behavior in a variety of tasks in rats. Behav Pharmacol 14:583–588PubMedGoogle Scholar
  89. Mechoulam R (1970) Marihuana chemistry. Science 168:1159–66PubMedGoogle Scholar
  90. Mechoulam R (2005) Plant cannabinoids: a neglected pharmacological treasure trove. Br J Pharmacol 146:913–915PubMedCentralPubMedGoogle Scholar
  91. Mechoulam R, Hanus L (2002) Cannabidiol: An overview of some chemical and pharmacological aspects. Part I: Chemical Aspects Chem Phys Lipids 121:35–43Google Scholar
  92. Mechoulam R, Ben-Shabat S, Hanus L et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90PubMedGoogle Scholar
  93. Mechoulam R, Parker LA, Gallily R (2002) Cannabidiol: An overview of some pharmacological aspects. J Clin Pharmacol 42:11S–19SPubMedGoogle Scholar
  94. Mechoulam R, Berry EM, Avraham Y et al (2006) Endocannabinoids, feeding and suckling – from our perspective. Int J Obes (Lond) 30:S24–S28Google Scholar
  95. Mechoulam R, Peters M, Murillo-Rodriguez E et al (2007) Cannabidiol – recent advances. Chem Biodivers 4:1678–1692PubMedGoogle Scholar
  96. Monteleone P, Matias I, Martiadis V et al (2005) Blood levels of the endocannabinoid anandamide are increased in anorexia nervosa and in binge-eating disorder, but not in bulimia nervosa. Neuropsychopharmacology 30:1216–1221PubMedGoogle Scholar
  97. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65PubMedGoogle Scholar
  98. Murdolo G, Kempf K, Hammarstedt A, Murdolo G, Kempf K, Hammarstedt A et al (2007) Insulin differentially modulates the peripheral endocannabinoid system in human subcutaneous abdominal adipose tissue from lean and obese individuals. J Endocrinol Invest 30:RC17–RC21PubMedGoogle Scholar
  99. Nogueiras R, Veyrat-Durebex C, Suchanek PM et al (2008) Peripheral, but not central, CB1 antagonism provides food intake independent metabolic benefits in diet-induced obese rats. Diabetes 57(11):2977–2991PubMedCentralPubMedGoogle Scholar
  100. Okamoto Y, Morishita J, Tsuboi K et al (2004) Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 279:5298–5305PubMedGoogle Scholar
  101. Osei-Hyiaman D, Depetrillo M, Harvey-White J et al (2005a) Cocaine- and amphetamine-related transcript is involved in the orexigenic effect of endogenous anandamide. Neuroendocrinology 81:273–282PubMedGoogle Scholar
  102. Osei-Hyiaman D, DePetrillo M, Pacher P et al (2005b) Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 115:1298–1305PubMedCentralPubMedGoogle Scholar
  103. Osei-Hyiaman D, Liu J, Zhou L et al (2008) Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J Clin Invest 118:3160–3169PubMedCentralPubMedGoogle Scholar
  104. Pagano C, Pilon C, Calcagno A et al (2007) The endogenous cannabinoid system stimulates glucose uptake in human fat cells via PI3-kinase and calcium-dependent mechanisms. J Clin Endocrinol Metab 92(12):4810–4819PubMedGoogle Scholar
  105. Pagotto U, Marsicano G, Cota D et al (2006) The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev 27:73–100PubMedGoogle Scholar
  106. Partosoedarso ER, Abrahams TP, Scullion RT et al (2003) Cannabinoid1 receptor in the dorsal vagal complex modulates lower oesophageal sphincter relaxation in ferrets. J Physiol 550:149–158PubMedCentralPubMedGoogle Scholar
  107. Pi-Sunyer FX, Aronne LJ, Heshmati HM et al (2006) 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 295:761–775PubMedGoogle Scholar
  108. Poirier B, Bidouard JP, Cadrouvele C et al (2005) The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Diabetes Obes Metab 7:65–72PubMedGoogle Scholar
  109. Qin N, Neeper MP, Liu Y et al (2008) TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. J Neurosci 28:6231–6238PubMedGoogle Scholar
  110. Ravinet Trillou C, Arnone M, Delgorge C et al (2003) Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol 284:345–353Google Scholar
  111. Ravinet Trillou C, Delgorge C, Menet C et al (2004) CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord 28:640–648PubMedGoogle Scholar
  112. Rinaldi-Carmona M, Barth F, Heaulme M et al (1994) SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350:240–244PubMedGoogle Scholar
  113. Robbe D, Kopf M, Remaury A et al (2002) Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci USA 99:8384–8388PubMedCentralPubMedGoogle Scholar
  114. Roche R, Hoareau L, Bes-Houtmann S et al (2006) Presence of the cannabinoid receptors, CB1 and CB2, in human omental and subcutaneous adipocytes. Histochem Cell Biol 4:1–11Google Scholar
  115. Rosenstock J, Hollander P, Chevalier S et al (2008) SERENADE trial: effects of monotherapy with rimonabant, the first selective cb1 receptor antagonist, on glycemic control, body weight and lipid profile in drug-naive type 2 diabetes. Diabetes Care 31(11):2169–2176PubMedCentralPubMedGoogle Scholar
  116. Ruby MA, Nomura DK, Hudak CS et al (2008) Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins. Proc Natl Acad Sci USA 105:14561–14566PubMedCentralPubMedGoogle Scholar
  117. Schäfer A, Pfrang J, Neumüller J et al (2008) The cannabinoid receptor-1 antagonist rimonabant inhibits platelet activation and reduces pro-inflammatory chemokines and leukocytes in Zucker rats. Br J Pharmacol 154:1047–1054PubMedCentralPubMedGoogle Scholar
  118. Scheen AJ, Finer N, Hollander P et al (2006) Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 368:1660–1672PubMedGoogle Scholar
  119. Schlicker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22:565–572PubMedGoogle Scholar
  120. Soria-Gómez E, Matias I, Rueda-Orozco PE et al (2007) Pharmacological enhancement of the endocannabinoid system in the nucleus accumbens shell stimulates food intake and increases c-Fos expression in the hypothalamus. Br J Pharmacol 151:1109–1116PubMedCentralPubMedGoogle Scholar
  121. Starowicz K, Cristino L, Matias I et al (2008) Endocannabinoid dysregulation in the pancreas and adipose tissue of mice fed a high fat diet. Obesity 16(3):553–565PubMedGoogle Scholar
  122. Sugiura T, Kondo S, Sukagawa A et al (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97PubMedGoogle Scholar
  123. Sun YX, Tsuboi K, Okamoto Y et al (2004) Biosynthesis of anandamide and N-palmitoylethanolamine by sequential actions of phospholipase A2 and lysophospholipase D. Biochem J 380:749–756PubMedCentralPubMedGoogle Scholar
  124. Tam J, Vemuri VK, Liu J et al (2010) Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest 120:2953–2966PubMedCentralPubMedGoogle Scholar
  125. Thomas EA, Cravatt BF, Danielson PE et al (1997) Fatty acid amide hydrolase, the degradative enzyme for anandamide and oleamide, has selective distribution in neurons within the rat central nervous system. J Neurosci Res 50:1047–1052PubMedGoogle Scholar
  126. Thomas A, Stevenson LA, Wease KN et al (2005) Evidence that the plant cannabinoid Δ9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist. Br J Pharmacol 146:917–926PubMedCentralPubMedGoogle Scholar
  127. Tsou K, Nogueron MI, Muthian S et al (1998) Fatty acid amide hydrolase is located preferentially in large neurons in the rat central nervous system as revealed by immunohistochemistry. Neurosci Lett 254:137–140PubMedGoogle Scholar
  128. Tucci SA, Rogers EK, Korbonits M et al (2004) The cannabinoid CB1 receptor antagonist SR141716 blocks the orexigenic effects of intrahypothalamic ghrelin. Br J Pharmacol 143:520–533PubMedCentralPubMedGoogle Scholar
  129. Van Gaal LF, Rissanen AM, Scheen AJ et al (2005) Effects of the cannabinoid-1 receptor blocker Rimonabant on weight reduction and cardiovascular risk factors in overweight pationts: 1-year experience from the RIO-Europe study. Lancet 365:1389–1397PubMedGoogle Scholar
  130. Van Gaal L, Pi-Sunyer X, Després JP et al (2008) Efficacy and safety of rimonabant for improvement of multiple cardiometabolic risk factors in overweight/obese patients: pooled 1-year data from the Rimonabant in Obesity (RIO) program. Diabetes Care 31:S229–240PubMedGoogle Scholar
  131. Van Sickle MD, Duncan M, Kingsley PJ et al (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:329–332PubMedGoogle Scholar
  132. Weiss L, Zeira M, Reich S et al (2006) Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity 39:143–151PubMedGoogle Scholar
  133. Weiss L, Zeira M, Reich S et al (2008) Cannabidiol arrests onset of autoimmune diabetes in NOD mice. Neuropharmacol 54:244–249Google Scholar
  134. Williams CM, Kirkham TC (1999) Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacol (Berl) 143:315–317Google Scholar
  135. Williams CM, Rogers PJ, Kirkham TC (1998) Hyperphagia in pre-fed rats following oral delta9-THC. Physiol Behav 65:343–346PubMedGoogle Scholar
  136. Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682PubMedGoogle Scholar
  137. Yan ZC, Liu DY, Zhang LL et al (2007) Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-delta. Biochem Biophys Res Commun 354:427–33PubMedGoogle Scholar
  138. Zimmer A, Zimmer AM, Hochmann AG (1999) Increased mortality, hypoactivity and hypoalgesia in cannabinoid CB1 receptor knockout mice. PNAS 96:5780–5785PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Vincenzo Di Marzo
    • 1
  • Fabiana Piscitelli
    • 1
  • Raphael Mechoulam
    • 2
  1. 1.Endocannabinoid Research GroupInstitute of Biomolecular Chemistry, National Research CouncilPozzuoliItaly
  2. 2.Medicinal Chemistry and Natural Products Department, Medical FacultyHebrew University of JerusalemJerusalemIsrael

Personalised recommendations