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Cannabinoids and Endocannabinoids in Metabolic Disorders with Focus on Diabetes

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Diabetes - Perspectives in Drug Therapy

Part of the book series: Handbook of Experimental Pharmacology ((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.

This article is dedicated to the loving memory of Ester Fride (1953–2010).

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References

  • Anderson MS, Bluestone JA (2005) The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 23:447–485

    CAS  PubMed  Google Scholar 

  • 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 9:43

    PubMed Central  PubMed  Google Scholar 

  • Ashton JC, Friberg D, Darlington CL et al (2006) Expression of the cannabinoid CB2 receptor in the rat cerebellum: an immunohistochemical study. Neurosci Lett 396:113–116

    CAS  PubMed  Google Scholar 

  • Atkinson MA, Leiter EH (1999) The NOD mouse model of type 1 diabetes: as good as it gets? Nat Med 5:601–604

    CAS  PubMed  Google Scholar 

  • 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 

  • 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 63:908–914

    CAS  PubMed  Google Scholar 

  • 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 353:23–31

    CAS  PubMed  Google Scholar 

  • 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 531:282–284

    Google Scholar 

  • Bermúdez-Silva FJ, Suárez J, Baixeras E et al (2008) Presence of functional cannabinoid receptors in human endocrine pancreas. Diabetologia 51:476–487

    PubMed  Google Scholar 

  • 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–S22

    PubMed  Google Scholar 

  • 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 72:2113–2119

    CAS  PubMed  Google Scholar 

  • 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 163:463–468

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bluher M, Engeli S, Kloting N et al (2006) Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes 55:3053–3060

    PubMed Central  PubMed  Google Scholar 

  • Bouaboula M, Hilairet S, Marchand J et al (2005) Anandamide induced PPARgamma transcriptional activation and 3T3-L1 preadipocyte differentiation. Eur J Pharmacol 517:174–181

    CAS  PubMed  Google Scholar 

  • Burdyga G, Lal S, Varro A et al (2004) Expression of cannabinoid CB1 receptors by vagal afferent neurons is inhibited by cholecystokinin. J Neurosci 24:2708–2715

    CAS  PubMed  Google Scholar 

  • Cavuoto P, McAinch AJ, Hatzinikolas G et al (2007) Effects of cannabinoid receptors on skeletal muscle oxidative pathways. Mol Cell Endocrinol 267:63–69

    CAS  PubMed  Google Scholar 

  • 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 82:863–869

    CAS  PubMed  Google Scholar 

  • Colombo G, Agabio R, Diaz G et al (1998) Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sci 63:113–117

    Google Scholar 

  • 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 112:423–431

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cota D, Tschop MH, Horvath TL et al (2006) Cannabinoids, opioids and eating behavior: the molecular face of hedonism? Brain Res Rev 51:85–107

    CAS  PubMed  Google Scholar 

  • 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: 1574–1581

    CAS  PubMed  Google Scholar 

  • 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) 31:692–699

    CAS  Google Scholar 

  • Coutts AA, Izzo AA (2004) The gastrointestinal pharmacology of cannabinoids: an update. Curr Opin Pharmacol 4:572–579

    CAS  PubMed  Google Scholar 

  • Cravatt BF, Giang DK, Mayfield SP et al (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87

    CAS  PubMed  Google Scholar 

  • 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 313:2993–3004

    PubMed  Google Scholar 

  • 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 325:1007–1015

    PubMed  Google Scholar 

  • 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 57:1262–1268

    PubMed  Google Scholar 

  • Després JP, Lemieux I (2006) Abdominal obesity and metabolic syndrome. Nature 444:881–887

    PubMed  Google Scholar 

  • 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 353:2121–2134

    PubMed  Google Scholar 

  • Devane WA, Dysarz FA, Johnson MR et al (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613

    CAS  PubMed  Google Scholar 

  • Devane WA, Hanus L, Breuer A et al (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949

    CAS  PubMed  Google Scholar 

  • Di Marzo V (2008a) Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov 7:438–455

    PubMed  Google Scholar 

  • Di Marzo V (2008b) The endocannabinoid system in obesity and type 2 diabetes. Diabetologia 51:1356–1367

    CAS  PubMed  Google Scholar 

  • Di Marzo V, Després JP (2010) CB1 antagonists for obesity–what lessons have we learned from rimonabant? Nat Rev Endocrinol 5:633–638

    Google Scholar 

  • 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 227:281–288

    PubMed  Google Scholar 

  • Di Marzo V, Sepe N, De Petrocellis L et al (1998) Trick or treat from food endocannabinoids? Nature 396:636–637

    PubMed  Google Scholar 

  • Di Marzo V, Goparaju SK, Wang L et al (2001) Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410:822–825

    PubMed  Google Scholar 

  • Di Marzo V, Bifulco M, De Petrocellis L (2004) The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3:771–784

    PubMed  Google Scholar 

  • 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 151–174

    Google Scholar 

  • 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 52:213–217

    CAS  PubMed  Google Scholar 

  • 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 161:715–722

    PubMed  Google Scholar 

  • Dinh TP, Carpenter D, Leslie FM et al (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 99:10819–10824

    PubMed Central  CAS  PubMed  Google Scholar 

  • DiPatrizio NV, Simansky KJ (2008a) Activating parabrachial cannabinoid CB1 receptors selectively stimulates feeding of palatable foods in rats. J Neurosci 28:9702–9709

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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 

  • 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 55:3403–3410

    CAS  PubMed  Google Scholar 

  • 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 281:38812–38824

    CAS  PubMed  Google Scholar 

  • Engeli S, Bohnke J, Feldpausch M et al (2005) Activation of the peripheral endocannabinoid system in human obesity. Diabetes 54:2838–2843

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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):1678–1686

    CAS  PubMed  Google Scholar 

  • 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 419:207–214

    CAS  PubMed  Google Scholar 

  • 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 370:233–240

    CAS  PubMed  Google Scholar 

  • Gaoni Y, Mechoulam R (1964) Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem So 86:1646–1647

    CAS  Google Scholar 

  • 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 69:471–478

    CAS  PubMed  Google Scholar 

  • 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 46:122–129

    CAS  PubMed  Google Scholar 

  • Gasperi V, Fezza F, Pasquariello N et al (2007) Endocannabinoids in adipocytes during differentiation and their role in glucose uptake. Cell Mol Life Sci 64:219–229

    CAS  PubMed  Google Scholar 

  • 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 17:1856–1860

    CAS  PubMed  Google Scholar 

  • Glass M, Northup JK (1999) Agonist selective regulation of G proteins by cannabinoid CB(1) and CB(2) receptors. Mol Pharmacol 56:1362–1369

    CAS  PubMed  Google Scholar 

  • Gomez R, Navarro M, Ferrer B et al (2002) A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 22:9612–9617

    CAS  PubMed  Google Scholar 

  • Gong JP, Onaivi ES, Ishiguro H et al (2006) Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res 1071:10–23

    CAS  PubMed  Google Scholar 

  • Gonzalez S, Manzanares J, Berrendero F et al (1999) Identification of endocannabinoids and cannabinoid CB(1) receptor mRNA in the pituitary gland. Neuroendocrinology 70:137–145

    CAS  PubMed  Google Scholar 

  • 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 49–75

    Google Scholar 

  • 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 983:144–151

    CAS  PubMed  Google Scholar 

  • 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–E832

    CAS  PubMed  Google Scholar 

  • 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 149:2557–2566

    CAS  PubMed  Google Scholar 

  • 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) 32:1363–1372

    CAS  Google Scholar 

  • 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 278:23731–23737

    CAS  PubMed  Google Scholar 

  • 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 33:605–607

    Google Scholar 

  • 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 158:451–461

    Google Scholar 

  • 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):1345–1357

    CAS  PubMed  Google Scholar 

  • 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 19:1567–1569

    CAS  PubMed  Google Scholar 

  • Jo YH, Chen YJ, Chua SC Jr et al (2005) Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit. Neuron 48:1055–1066

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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 39:155–162

    CAS  PubMed  Google Scholar 

  • 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 136:550–557

    PubMed Central  CAS  PubMed  Google Scholar 

  • Klein TW (2005) Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol 5:400–411

    CAS  PubMed  Google Scholar 

  • 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 68:539–543

    CAS  PubMed  Google Scholar 

  • 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 280:25196–25201

    CAS  PubMed  Google Scholar 

  • 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 3:1797

    Google Scholar 

  • 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) 32:863–70

    CAS  Google Scholar 

  • 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 45:4720–4726

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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) 29:183–187

    CAS  Google Scholar 

  • 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 278:13318–13324

    CAS  PubMed  Google Scholar 

  • 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 11:21–28

    CAS  PubMed  Google Scholar 

  • 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 26:6643–6650

    CAS  PubMed  Google Scholar 

  • Mandrup-Poulsen T (2003) Beta cell death and protection. Ann NY Acad Sci 1005:32–42

    PubMed  Google Scholar 

  • Matias I, Di Marzo V (2007) Endocannabinoids and the control of energy balance. Trends Endocrinol Metab 18:27–37

    CAS  PubMed  Google Scholar 

  • 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 91:3171–80

    CAS  PubMed  Google Scholar 

  • 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:S66–78

    CAS  PubMed  Google Scholar 

  • McAllister SD, Glass M (2002) CB(1) and CB(2) receptor-mediated signaling: a focus on endocannabinoids. Prostaglandins Leukot Essent Fatty Acids 66:161–171

    CAS  PubMed  Google Scholar 

  • 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 14:583–588

    CAS  PubMed  Google Scholar 

  • Mechoulam R (1970) Marihuana chemistry. Science 168:1159–66

    CAS  PubMed  Google Scholar 

  • Mechoulam R (2005) Plant cannabinoids: a neglected pharmacological treasure trove. Br J Pharmacol 146:913–915

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mechoulam R, Hanus L (2002) Cannabidiol: An overview of some chemical and pharmacological aspects. Part I: Chemical Aspects Chem Phys Lipids 121:35–43

    CAS  Google Scholar 

  • 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 50:83–90

    CAS  PubMed  Google Scholar 

  • Mechoulam R, Parker LA, Gallily R (2002) Cannabidiol: An overview of some pharmacological aspects. J Clin Pharmacol 42:11S–19S

    CAS  PubMed  Google Scholar 

  • Mechoulam R, Berry EM, Avraham Y et al (2006) Endocannabinoids, feeding and suckling – from our perspective. Int J Obes (Lond) 30:S24–S28

    CAS  Google Scholar 

  • Mechoulam R, Peters M, Murillo-Rodriguez E et al (2007) Cannabidiol – recent advances. Chem Biodivers 4:1678–1692

    CAS  PubMed  Google Scholar 

  • 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 30:1216–1221

    CAS  PubMed  Google Scholar 

  • Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65

    CAS  PubMed  Google Scholar 

  • 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–RC21

    CAS  PubMed  Google Scholar 

  • 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):2977–2991

    PubMed Central  CAS  PubMed  Google Scholar 

  • Okamoto Y, Morishita J, Tsuboi K et al (2004) Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 279:5298–5305

    CAS  PubMed  Google Scholar 

  • 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 81:273–282

    CAS  PubMed  Google Scholar 

  • 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 115:1298–1305

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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 118:3160–3169

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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):4810–4819

    CAS  PubMed  Google Scholar 

  • Pagotto U, Marsicano G, Cota D et al (2006) The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev 27:73–100

    CAS  PubMed  Google Scholar 

  • 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 550:149–158

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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 295:761–775

    CAS  PubMed  Google Scholar 

  • 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 7:65–72

    CAS  PubMed  Google Scholar 

  • 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 28:6231–6238

    CAS  PubMed  Google Scholar 

  • 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 284:345–353

    Google Scholar 

  • 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 28:640–648

    CAS  PubMed  Google Scholar 

  • Rinaldi-Carmona M, Barth F, Heaulme M et al (1994) SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350:240–244

    CAS  PubMed  Google Scholar 

  • 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 99:8384–8388

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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 4:1–11

    Google Scholar 

  • 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):2169–2176

    PubMed Central  PubMed  Google Scholar 

  • 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 105:14561–14566

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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 154:1047–1054

    PubMed Central  PubMed  Google Scholar 

  • 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 368:1660–1672

    CAS  PubMed  Google Scholar 

  • Schlicker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22:565–572

    CAS  PubMed  Google Scholar 

  • 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 151:1109–1116

    PubMed Central  PubMed  Google Scholar 

  • 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):553–565

    CAS  PubMed  Google Scholar 

  • Sugiura T, Kondo S, Sukagawa A et al (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97

    CAS  PubMed  Google Scholar 

  • 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 380:749–756

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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 120:2953–2966

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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 50:1047–1052

    CAS  PubMed  Google Scholar 

  • 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 146:917–926

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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 254:137–140

    CAS  PubMed  Google Scholar 

  • 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 143:520–533

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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 365:1389–1397

    PubMed  Google Scholar 

  • 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:S229–240

    PubMed  Google Scholar 

  • Van Sickle MD, Duncan M, Kingsley PJ et al (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:329–332

    PubMed  Google Scholar 

  • Weiss L, Zeira M, Reich S et al (2006) Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity 39:143–151

    CAS  PubMed  Google Scholar 

  • Weiss L, Zeira M, Reich S et al (2008) Cannabidiol arrests onset of autoimmune diabetes in NOD mice. Neuropharmacol 54:244–249

    CAS  Google Scholar 

  • Williams CM, Kirkham TC (1999) Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacol (Berl) 143:315–317

    CAS  Google Scholar 

  • Williams CM, Rogers PJ, Kirkham TC (1998) Hyperphagia in pre-fed rats following oral delta9-THC. Physiol Behav 65:343–346

    CAS  PubMed  Google Scholar 

  • Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682

    CAS  PubMed  Google Scholar 

  • 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 354:427–33

    CAS  PubMed  Google Scholar 

  • Zimmer A, Zimmer AM, Hochmann AG (1999) Increased mortality, hypoactivity and hypoalgesia in cannabinoid CB1 receptor knockout mice. PNAS 96:5780–5785

    PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Via Campi Flegrei 34 Comprensorio Olivetti, 80078, Pozzuoli, NA, Italy

    Vincenzo Di Marzo & Fabiana Piscitelli

  2. Medicinal Chemistry and Natural Products Department, Medical Faculty, Hebrew University of Jerusalem, Ein Kerem, Jerusalem, 91120, Israel

    Raphael Mechoulam

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  1. Vincenzo Di Marzo
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  2. Fabiana Piscitelli
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  3. Raphael Mechoulam
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  1. Fakultät Lebenswissenschaften Molekulare Pharmakologie und Toxikologie, Technische Universität Braunschweig, Beethovenstraße 55, 38106, Braunschweig, Germany

    Mathias Schwanstecher

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Di Marzo, V., Piscitelli, F., Mechoulam, R. (2011). Cannabinoids and Endocannabinoids in Metabolic Disorders with Focus on Diabetes. In: Schwanstecher, M. (eds) Diabetes - Perspectives in Drug Therapy. Handbook of Experimental Pharmacology, vol 203. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-17214-4_4

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