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Central and Peripheral Cannabinoid Receptors as Therapeutic Targets in the Control of Food Intake and Body Weight

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Appetite Control

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 209))

Abstract

The endocannabinoid system consists of lipid-derived agonists that activate cannabinoid (CB) receptors. CB receptor agonists, namely, the phytocannabinoid Δ9-THC and the endocannabinoid anandamide, increase hunger sensation and food intake. These discoveries led to the clinical use of Δ9-THC derivatives for the treatment of cancer and HIV-related nausea and cachexia. Animal studies clarified the important role of CB1 receptors in the hypothalamus and in the limbic system in mediating orexigenic effects. In parallel, data on CB1-specific blockade either by drugs or by genetic ablation further demonstrated that CB1 inhibition protects against weight gain induced by high-fat feeding and reduces body weight in obese animals and humans. The mechanisms of weight reduction by CB1 blockade are complex: they comprise interactions with several orexigenic and anorexigenic neuropeptides and hormones, regulation of sympathetic activity, influences on mitochondrial function, and on lipogenesis. Although these mechanisms appear to be mainly mediated by the CNS, weight loss also occurs when drugs that do not reach CNS concentrations sufficient to inhibit CB1 signaling are used. The development of peripherally restricted CB1 inverse agonists and antagonists opened new routes in CB1 pharmacology because centrally acting CB1 inverse agonists, e.g., rimonabant and taranabant, exerted unacceptable side effects that precluded their further development and application as weight loss drugs. Tissue and circulating endocannabinoid concentrations are often increased in animal models of obesity and in obese humans, especially those with visceral fat accumulation. Thus, further research on CB1 inhibition is still promising to treat human obesity.

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References

  • Abel EL (1975) Cannabis: effects on hunger and thirst. Behav Biol 15:255–281

    Article  PubMed  CAS  Google Scholar 

  • Abood ME (2005) Molecular biology of cannabinoid receptors. Handb Exp Pharmacol 168:81–115

    Article  PubMed  CAS  Google Scholar 

  • Addy C, Wright H, van Laere K, Gantz I, Erondu N, Musser BJ, Lu K, Yuan J, Sanabria-Bohorquez SM, Stoch A, Stevens C, Fong TM, De Lepeleire I, Cilissen C, Cote J, Rosko K, Gendrano IN III, Nguyen AM, Gumbiner B, Rothenberg P, de Hoon J, Bormans G, Depre M, Eng WS, Ravussin E, Klein S, Blundell J, Herman GA, Burns HD, Hargreaves RJ, Wagner J, Gottesdiener K, Amatruda JM, Heymsfield SB (2008) The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake. Cell Metab 7:68–78

    Article  PubMed  CAS  Google Scholar 

  • Ameloot K, Janssen P, Scarpellini E, Vos R, Boesmans W, Depoortere I, Vanden BP, Tack J (2010) Endocannabinoid control of gastric sensorimotor function in man. Aliment Pharmacol Ther 31:1123–1131

    PubMed  CAS  Google Scholar 

  • Arnone M, Maruani J, Chaperon F, Thiebot MH, Poncelet M, Soubrie P, Le Fur G (1997) Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology (Berl) 132:104–106

    Article  CAS  Google Scholar 

  • Aronne LJ, Tonstad S, Moreno M, Gantz I, Erondu N, Suryawanshi S, Molony C, Sieberts S, Nayee J, Meehan AG, Shapiro D, Heymsfield SB, Kaufman KD, Amatruda JM (2010) A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study. Int J Obes (Lond) 34:919–935

    Article  CAS  Google Scholar 

  • Beal JE, Olson R, Lefkowitz L, Laubenstein L, Bellman P, Yangco B, Morales JO, Murphy R, Powderly W, Plasse TF, Mosdell KW, Shepard KV (1997) Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J Pain Symptom Manage 14:7–14

    Article  PubMed  CAS  Google Scholar 

  • Bedi G, Foltin RW, Gunderson EW, Rabkin J, Hart CL, Comer SD, Vosburg SK, Haney M (2010) Efficacy and tolerability of high-dose dronabinol maintenance in HIV-positive marijuana smokers: a controlled laboratory study. Psychopharmacology (Berl) 212:675–686

    Article  CAS  Google Scholar 

  • Bensaid M, Gary-Bobo M, Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F, Soubrie P (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

    Article  PubMed  CAS  Google Scholar 

  • Blüher M, Engeli S, Klöting N, Berndt J, Fasshauer M, Batkai S, Pacher P, Schön MR, Jordan J, Stumvoll M (2006) Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes 55:3053–3060

    Article  PubMed  CAS  Google Scholar 

  • Burdyga G, Lal S, Varro A, Dimaline R, Thompson DG, Dockray GJ (2004) Expression of cannabinoid CB1 receptors by vagal afferent neurons is inhibited by cholecystokinin. J Neurosci 24:2708–2715

    Article  PubMed  CAS  Google Scholar 

  • Burdyga G, Varro A, Dimaline R, Thompson DG, Dockray GJ (2006) Ghrelin receptors in rat and human nodose ganglia: putative role in regulating CB-1 and MCH receptor abundance. Am J Physiol Gastrointest Liver Physiol 290:G1289–G1297

    Article  PubMed  CAS  Google Scholar 

  • Burdyga G, Varro A, Dimaline R, Thompson DG, Dockray GJ (2010) Expression of cannabinoid CB1 receptors by vagal afferent neurons: kinetics and role in influencing neurochemical phenotype. Am J Physiol Gastrointest Liver Physiol 299:G63–G69

    Article  PubMed  CAS  Google Scholar 

  • Burns HD, van Laere K, Sanabria-Bohorquez S, Hamill TG, Bormans G, Eng WS, Gibson R, Ryan C, Connolly B, Patel S, Krause S, Vanko A, van Hecken A, Dupont P, De Lepeleire I, Rothenberg P, Stoch SA, Cote J, Hagmann WK, Jewell JP, Lin LS, Liu P, Goulet MT, Gottesdiener K, Wagner JA, de Hoon J, Mortelmans L, Fong TM, Hargreaves RJ (2007) [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Proc Natl Acad Sci U S A 104:9800–9805

    Article  PubMed  CAS  Google Scholar 

  • Cani PD, Montoya ML, Neyrinck AM, Delzenne NM, Lambert DM (2004) Potential modulation of plasma ghrelin and glucagon-like peptide-1 by anorexigenic cannabinoid compounds, SR141716A (rimonabant) and oleoylethanolamide. Br J Nutr 92:757–761

    Article  PubMed  CAS  Google Scholar 

  • Carai MA, Colombo G, Maccioni P, Gessa GL (2006) Efficacy of rimonabant and other cannabinoid CB1 receptor antagonists in reducing food intake and body weight: preclinical and clinical data. CNS Drug Rev 12:91–99

    Article  PubMed  CAS  Google Scholar 

  • Cavuoto P, McAinch AJ, Hatzinikolas G, Cameron-Smith D, Wittert GA (2007) Effects of cannabinoid receptors on skeletal muscle oxidative pathways. Mol Cell Endocrinol 267:63–69

    Article  PubMed  CAS  Google Scholar 

  • Colombo G, Agabio R, Diaz G, Lobina C, Reali R, Gessa GL (1998) Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sci 63:L113–L117

    Article  Google Scholar 

  • Cota D, Marsicano G, Tschöp M, Grubler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thöne-Reineke C, Ortmann S, Tomassoni F, Cervino C, Nisoli E, Linthorst AC, Pasquali R, Lutz B, Stalla GK, Pagotto U (2003) The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 112:423–431

    PubMed  CAS  Google Scholar 

  • Coté M, Matias I, Lemieux I, Petrosino S, Almeras N, Després JP, Di Marzo V (2007) Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes (Lond) 31:692–699

    Google Scholar 

  • Després JP, Golay A, Sjöström L (2005) Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121–2134

    Article  PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949

    Article  PubMed  CAS  Google Scholar 

  • Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G (2001) Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410:822–825

    Article  PubMed  Google Scholar 

  • Di Marzo V, De Petrocellis L, Bisogno T (2005) The biosynthesis, fate and pharmacological properties of endocannabinoids. Handb Exp Pharmacol 168:147–185

    Article  PubMed  Google Scholar 

  • Di Marzo V, Capasso R, Matias I, Aviello G, Petrosino S, Borrelli F, Romano B, Orlando P, Capasso F, Izzo AA (2008) The role of endocannabinoids in the regulation of gastric emptying: alterations in mice fed a high-fat diet. Br J Pharmacol 153:1272–1280

    Article  PubMed  CAS  Google Scholar 

  • Di Marzo V, Verrijken A, Hakkarainen A, Petrosino S, Mertens I, Lundbom N, Piscitelli F, Westerbacka J, Soro-Paavonen A, Matias I, Van GL, Taskinen MR (2009a) Role of insulin as a negative regulator of plasma endocannabinoid levels in obese and nonobese subjects. Eur J Endocrinol 161:715–722

    Article  PubMed  CAS  Google Scholar 

  • Di Marzo V, Coté M, Matias I, Lemieux I, Arsenault BJ, Cartier A, Piscitelli F, Petrosino S, Almeras N, Després JP (2009b) 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 52:213–217

    Article  PubMed  CAS  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 295:R1409–R1414

    Article  PubMed  CAS  Google Scholar 

  • Engeli S (2008a) Dysregulation of the endocannabinoid system in obesity. J Neuroendocrinol 20(Suppl 1):110–115

    Article  PubMed  CAS  Google Scholar 

  • Engeli S (2008b) Peripheral metabolic effects of endocannabinoids and cannabinoid receptor blockade. Obes Facts 1:8–15

    Article  PubMed  CAS  Google Scholar 

  • Engeli S, Böhnke J, Feldpausch M, Gorzelniak K, Janke J, Batkai S, Pacher P, Harvey-White J, Luft FC, Sharma AM, Jordan J (2005) Activation of the peripheral endocannabinoid system in human obesity. Diabetes 54:2838–2843

    Article  PubMed  CAS  Google Scholar 

  • Foltin RW, Fischman MW, Byrne MF (1988) Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory. Appetite 11:1–14

    Article  PubMed  CAS  Google Scholar 

  • Fong TM, Heymsfield SB (2009) Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions. Int J Obes (Lond) 33:947–955

    Article  CAS  Google Scholar 

  • Fong TM, Guan XM, Marsh DJ, Shen CP, Stribling DS, Rosko KM, Lao J, Yu H, Feng Y, Xiao JC, Van der Ploeg LH, Goulet MT, Hagmann WK, Lin LS, Lanza TJ Jr, Jewell JP, Liu P, Shah SK, Qi H, Tong X, Wang J, Xu SS, Francis B, Strack AM, MacIntyre DE, Shearman LP (2007) Antiobesity efficacy of a novel cannabinoid-1 receptor inverse agonist, N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(t rifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), in rodents. J Pharmacol Exp Ther 321:1013–1022

    Article  PubMed  CAS  Google Scholar 

  • Gagnon MA, Elie R (1975) Effects of marijuana and D-amphetamine on the appetite, food consumption and various cardio-respiratory variables in man. Union Med Can 104:914–921

    PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Gary-Bobo M, Elachouri G, Gallas JF, Janiak P, Marini P, Ravinet Trillou C, Chabbert M, Cruccioli N, Pfersdorff C, Roque C, Arnone M, Croci T, Soubrie P, Oury-Donat F, Maffrand JP, Scatton B, Lacheretz F, Le Fur G, Herbert JM, Bensaid M (2007) Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology 46:122–129

    Article  PubMed  CAS  Google Scholar 

  • Gomez R, Navarro M, Ferrer B, Trigo JM, Bilbao A, Del Arco I, Cippitelli A, Nava F, Piomelli D, Rodriguez dF (2002) A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 22:9612–9617

    PubMed  CAS  Google Scholar 

  • Gorter R, Seefried M, Volberding P (1992) Dronabinol effects on weight in patients with HIV infection. AIDS 6:127

    Article  PubMed  CAS  Google Scholar 

  • Greenberg I, Kuehnle J, Mendelson JH, Bernstein JG (1976) Effects of marihuana use on body weight and caloric intake in humans. Psychopharmacology (Berl) 49:79–84

    CAS  Google Scholar 

  • Harrold JA, Elliott JC, King PJ, Widdowson PS, Williams G (2002) Down-regulation of cannabinoid-1 (CB-1) receptors in specific extrahypothalamic regions of rats with dietary obesity: a role for endogenous cannabinoids in driving appetite for palatable food? Brain Res 952:232–238

    Article  PubMed  CAS  Google Scholar 

  • Hollister LE (1971) Hunger and appetite after single doses of marihuana, alcohol, and dextroamphetamine. Clin Pharmacol Ther 12:44–49

    PubMed  CAS  Google Scholar 

  • Howlett AC (2005) Cannabinoid receptor signaling. Handb Exp Pharmacol 168:53–79

    Article  PubMed  CAS  Google Scholar 

  • Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202

    Article  PubMed  CAS  Google Scholar 

  • Izzo AA, Piscitelli F, Capasso R, Aviello G, Romano B, Borrelli F, Petrosino S, Di Marzo V (2009) Peripheral endocannabinoid dysregulation in obesity: relation to intestinal motility and energy processing induced by food deprivation and re-feeding. Br J Pharmacol 158:451–461

    Article  PubMed  CAS  Google Scholar 

  • Jamshidi N, Taylor DA (2001) Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol 134:1151–1154

    Article  PubMed  CAS  Google Scholar 

  • Jbilo O, Ravinet Trillou C, Arnone M, Buisson I, Bribes E, Peleraux A, Penarier G, Soubrie P, Le Fur G, Galiegue S, Casellas P (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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Jones D (2008) End of the line for cannabinoid receptor 1 as an anti-obesity target? Nat Rev Drug Discov 7:961–962

    Article  PubMed  CAS  Google Scholar 

  • Jordan J, Schlaich M, Redon J, Narkiewicz K, Luft FC, Grassi G, Dixon J, Lambert G, Engeli S (2011) European Society of Hypertension Working Group on Obesity: obesity drugs and cardiovascular outcomes. J Hypertens 29:189–193

    Article  PubMed  CAS  Google Scholar 

  • Kipnes MS, Hollander P, Fujioka K, Gantz I, Seck T, Erondu N, Shentu Y, Lu K, Suryawanshi S, Chou M, Johnson-Levonas AO, Heymsfield SB, Shapiro D, Kaufman KD, Amatruda JM (2010) A one-year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes. Diabetes Obes Metab 12:517–531

    Article  PubMed  CAS  Google Scholar 

  • Kirkham TC, Williams CM (2001) Endogenous cannabinoids and appetite. Nutr Res Rev 14:65–86

    Article  PubMed  CAS  Google Scholar 

  • Kirkham TC, Williams CM, Fezza F, Di Marzo V (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

    Article  PubMed  CAS  Google Scholar 

  • Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, Williams LM, Hawley SA, Hardie DG, Grossman AB, Korbonits M (2005) Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem 280:25196–25201

    Article  PubMed  CAS  Google Scholar 

  • Kunz I, Meier MK, Bourson A, Fisseha M, Schilling W (2008) Effects of rimonabant, a cannabinoid CB1 receptor ligand, on energy expenditure in lean rats. Int J Obes (Lond) 32:863–870

    Article  CAS  Google Scholar 

  • Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, Bohme GA, Imperato A, Pedrazzini T, Roques BP, Vassart G, Fratta W, Parmentier M (1999) Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283:401–404

    Article  PubMed  CAS  Google Scholar 

  • Lin LS, Lanza TJ Jr, Jewell JP, Liu P, Shah SK, Qi H, Tong X, Wang J, Xu SS, Fong TM, Shen CP, Lao J, Xiao JC, Shearman LP, Stribling DS, Rosko K, Strack A, Marsh DJ, Feng Y, Kumar S, Samuel K, Yin W, Van der Ploeg LH, Goulet MT, Hagmann WK (2006) Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. J Med Chem 49:7584–7587

    Article  PubMed  CAS  Google Scholar 

  • Liu YL, Connoley IP, Wilson CA, Stock MJ (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

    Article  CAS  Google Scholar 

  • LoVerme J, Duranti A, Tontini A, Spadoni G, Mor M, Rivara S, Stella N, Xu C, Tarzia G, Piomelli D (2009) Synthesis and characterization of a peripherally restricted CB1 cannabinoid antagonist, URB447, that reduces feeding and body-weight gain in mice. Bioorg Med Chem Lett 19:639–643

    Article  PubMed  CAS  Google Scholar 

  • Maccarrone M, Fride E, Bisogno T, Bari M, Cascio MG, Battista N, Finazzi AA, Suris R, Mechoulam R, Di Marzo V (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

    Article  PubMed  CAS  Google Scholar 

  • Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgansberger W, Di Marzo V, Lutz B (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534

    Article  PubMed  CAS  Google Scholar 

  • Matias I, Gonthier MP, Orlando P, Martiadis V, De Petrocellis L, Cervino C, Petrosino S, Hoareau L, Festy F, Pasquali R, Roche R, Maj M, Pagotto U, Monteleone P, Di Marzo V (2006) Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab 91:3171–3180

    Article  PubMed  CAS  Google Scholar 

  • Matias I, Vergoni AV, Petrosino S, Ottani A, Pocai A, Bertolini A, Di Marzo V (2008) Regulation of hypothalamic endocannabinoid levels by neuropeptides and hormones involved in food intake and metabolism: insulin and melanocortins. Neuropharmacology 54:206–212

    Article  PubMed  CAS  Google Scholar 

  • Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564

    Article  PubMed  CAS  Google Scholar 

  • Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90

    Article  PubMed  CAS  Google Scholar 

  • Moreira FA, Grieb M, Lutz B (2009) Central side-effects of therapies based on CB1 cannabinoid receptor agonists and antagonists: focus on anxiety and depression. Best Pract Res Clin Endocrinol Metab 23:133–144

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Nogueiras R, Veyrat-Durebex C, Suchanek PM, Klein M, Tschöp J, Caldwell C, Woods SC, Wittmann G, Watanabe M, Liposits Z, Fekete C, Reizes O, Rohner-Jeanrenaud F, Tschöp MH (2008) Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats. Diabetes 57:2977–2991

    Article  PubMed  CAS  Google Scholar 

  • O’Hare JD, Zielinski E, Cheng B, Scherer T, Buettner C (2011) Central endocannabinoid signaling regulates hepatic glucose production and systemic lipolysis. Diabetes 60:1055–1062

    Article  PubMed  CAS  Google Scholar 

  • Osei-Hyiaman D, Depetrillo M, Harvey-White J, Bannon AW, Cravatt BF, Kuhar MJ, Mackie K, Palkovits M, Kunos G (2005a) Cocaine- and amphetamine-related transcript is involved in the orexigenic effect of endogenous anandamide. Neuroendocrinology 81:273–282

    Article  PubMed  CAS  Google Scholar 

  • Osei-Hyiaman D, Depetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, Harvey-White J, Mackie K, Offertaler L, Wang L, Kunos G (2005b) Endocannabinoid activation at hepatic CB(1) receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 115:1298–1305

    PubMed  CAS  Google Scholar 

  • Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI, Batkai S, Marsicano G, Lutz B, Buettner C, Kunos G (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

    Article  PubMed  CAS  Google Scholar 

  • Pacher P, Batkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58:389–462

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG (2005) Pharmacological actions of cannabinoids. Handb Exp Pharmacol 168:1–51

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 62:588–631

    Article  PubMed  CAS  Google Scholar 

  • Perwitz N, Fasshauer M, Klein J (2006) Cannabinoid receptor signaling directly inhibits thermogenesis and alters expression of adiponectin and visfatin. Horm Metab Res 38:356–358

    Article  PubMed  CAS  Google Scholar 

  • Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4:873–884

    Article  PubMed  CAS  Google Scholar 

  • Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J (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

    Article  PubMed  CAS  Google Scholar 

  • Plasse TF, Gorter RW, Krasnow SH, Lane M, Shepard KV, Wadleigh RG (1991) Recent clinical experience with dronabinol. Pharmacol Biochem Behav 40:695–700

    Article  PubMed  CAS  Google Scholar 

  • Proietto J, Rissanen A, Harp JB, Erondu N, Yu Q, Suryawanshi S, Jones ME, Johnson-Levonas AO, Heymsfield SB, Kaufman KD, Amatruda JM (2010) A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study. Int J Obes (Lond) 34:1243–1254

    Article  CAS  Google Scholar 

  • Quarta C, Bellocchio L, Mancini G, Mazza R, Cervino C, Braulke LJ, Fekete C, Latorre R, Nanni C, Bucci M, Clemens LE, Heldmaier G, Watanabe M, Leste-Lassere T, Maitre M, Tedesco L, Fanelli F, Reuss S, Klaus S, Srivastava RK, Monory K, Valerio A, Grandis A, De Giorgio R, Pasquali R, Nisoli E, Cota D, Lutz B, Marsicano G, Pagotto U (2010) CB(1) signaling in forebrain and sympathetic neurons is a key determinant of endocannabinoid actions on energy balance. Cell Metab 11:273–285

    Article  PubMed  CAS  Google Scholar 

  • Ravinet Trillou C, Arnone M, Delgorge C, Gonalons N, Keane P, Maffrand JP, Soubrie P (2003) Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol 284:R345–R353

    PubMed  Google Scholar 

  • Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrie P (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

    Article  PubMed  CAS  Google Scholar 

  • Rinaldi-Carmona M, Barth F, Heaulme M, Shire D, Calandra B, Congy C, Martinez S, Maruani J, Neliat G, Caput D (1994) SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350:240–244

    Article  PubMed  CAS  Google Scholar 

  • Robson P (2005) Human studies of cannabinoids and medicinal cannabis. Handb Exp Pharmacol 168:719–756

    Article  PubMed  CAS  Google Scholar 

  • Russell JC, Kelly SE, Diane A, Wang Y, Mangat R, Novak S, Vine DF, Proctor SD (2010) Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cp rat model of prediabetic metabolic syndrome. Am J Physiol Gastrointest Liver Physiol 299:G507–G516

    Article  PubMed  CAS  Google Scholar 

  • Sallan SE, Cronin C, Zelen M, Zinberg NE (1980) Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. N Engl J Med 302:135–138

    Article  PubMed  CAS  Google Scholar 

  • Scheen AJ, Finer N, Hollander P, Jensen MD, van Gaal LF (2006) Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 368:1660–1672

    Article  PubMed  CAS  Google Scholar 

  • Siler JF, Sheep WL, Bates LB, Clark GF, Cook GW, Smith WH (1933) Marihuana smoking in Panama. Mil Surg 73:269–280

    Google Scholar 

  • Simiand J, Keane M, Keane PE, Soubrie P (1998) SR 141716, a CB1 cannabinoid receptor antagonist, selectively reduces sweet food intake in marmoset. Behav Pharmacol 9:179–181

    PubMed  CAS  Google Scholar 

  • Soria-Gomez E, Matias I, Rueda-Orozco PE, Cisneros M, Petrosino S, Navarro L, Di Marzo V, Prospero-Garcia O (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

    Article  PubMed  CAS  Google Scholar 

  • Stock MJ (1997) Sibutramine: a review of the pharmacology of a novel anti- obesity agent. Int J Obes Relat Metab Disord 21(Suppl 1):S25–S29

    PubMed  CAS  Google Scholar 

  • Storr MA, Sharkey KA (2007) The endocannabinoid system and gut-brain signalling. Curr Opin Pharmacol 7:575–582

    Article  PubMed  CAS  Google Scholar 

  • Tam J, Vemuri VK, Liu J, Batkai S, Mukhopadhyay B, Godlewski G, Osei-Hyiaman D, Ohnuma S, Ambudkar SV, Pickel J, Makriyannis A, Kunos G (2010) Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest 120:2953–2966

    Article  PubMed  CAS  Google Scholar 

  • Tart CT (1970) Marijuana intoxication common experiences. Nature 226:701–704

    Article  PubMed  CAS  Google Scholar 

  • Tedesco L, Valerio A, Cervino C, Cardile A, Pagano C, Vettor R, Pasquali R, Carruba MO, Marsicano G, Lutz B, Pagotto U, Nisoli E (2008) Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white adipocytes. Diabetes 57:2028–2036

    Article  PubMed  CAS  Google Scholar 

  • Tedesco L, Valerio A, Dossena M, Cardile A, Ragni M, Pagano C, Pagotto U, Carruba MO, Vettor R, Nisoli E (2010) Cannabinoid receptor stimulation impairs mitochondrial biogenesis in mouse white adipose tissue, muscle, and liver: the role of eNOS, p38 MAPK, and AMPK pathways. Diabetes 59:2826–2836

    Article  PubMed  CAS  Google Scholar 

  • Thakur GA, Tichkule R, Bajaj S, Makriyannis A (2009) Latest advances in cannabinoid receptor agonists. Expert Opin Ther Pat 19:1647–1673

    Article  PubMed  CAS  Google Scholar 

  • Thornton-Jones ZD, Kennett GA, Benwell KR, Revell DF, Misra A, Sellwood DM, Vickers SP, Clifton PG (2006) The cannabinoid CB1 receptor inverse agonist, rimonabant, modifies body weight and adiponectin function in diet-induced obese rats as a consequence of reduced food intake. Pharmacol Biochem Behav 84:353–359

    Article  PubMed  CAS  Google Scholar 

  • Topol EJ, Bousser MG, Fox KA, Creager MA, Després JP, Easton JD, Hamm CW, Montalescot G, Steg PG, Pearson TA, Cohen E, Gaudin C, Job B, Murphy JH, Bhatt DL (2010) Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet 376:517–523

    Article  PubMed  CAS  Google Scholar 

  • Tucci SA, Rogers EK, Korbonits M, Kirkham TC (2004) The cannabinoid CB1 receptor antagonist SR141716 blocks the orexigenic effects of intrahypothalamic ghrelin. Br J Pharmacol 143:520–523

    Article  PubMed  CAS  Google Scholar 

  • van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Röossner S (2005) Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365:1389–1397

    Article  PubMed  CAS  Google Scholar 

  • Volicer L, Stelly M, Morris J, McLaughlin J, Volicer BJ (1997) Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer’s disease. Int J Geriatr Psychiatry 12:913–919

    Article  PubMed  CAS  Google Scholar 

  • Wadden TA, Fujioka K, Toubro S, Gantz I, Erondu NE, Chen M, Suryawanshi S, Carofano W, Johnson-Levonas AO, Shapiro DR, Kaufman KD, Heymsfield SB, Amatruda JM (2010) A randomized trial of lifestyle modification and taranabant for maintaining weight loss achieved with a low-calorie diet. Obesity (Silver Spring) 18:2301–2310

    Article  Google Scholar 

  • Wallerius S, Rosmond R, Ljung T, Holm G, Björntorp P (2003) Rise in morning saliva cortisol is associated with abdominal obesity in men: a preliminary report. J Endocrinol Invest 26:616–619

    PubMed  CAS  Google Scholar 

  • Ware MA, St Arnaud-Trempe E (2010) The abuse potential of the synthetic cannabinoid nabilone. Addiction 105:494–503

    Article  PubMed  Google Scholar 

  • Watanabe S, Doshi M, Hamazaki T (2003) n-3 Polyunsaturated fatty acid (PUFA) deficiency elevates and n-3 PUFA enrichment reduces brain 2-arachidonoylglycerol level in mice. Prostaglandins Leukot Essent Fatty Acids 69:51–59

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Williams CM, Kirkham TC (2002) Observational analysis of feeding induced by Delta9-THC and anandamide. Physiol Behav 76:241–250

    Article  PubMed  CAS  Google Scholar 

  • Wilson RI, Nicoll RA (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410:588–592

    Article  PubMed  CAS  Google Scholar 

  • Wittmann G, Deli L, Kallo I, Hrabovszky E, Watanabe M, Liposits Z, Fekete C (2007) Distribution of type 1 cannabinoid receptor (CB1)-immunoreactive axons in the mouse hypothalamus. J Comp Neurol 503:270–279

    Article  PubMed  CAS  Google Scholar 

  • Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI (1999) Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci USA 96:5780–5785

    Article  PubMed  CAS  Google Scholar 

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  1. Hannover Medical School, Institute of Clinical Pharmacology, Carl-Neuberg-Straße 1, 30625, Hannover, Germany

    Stefan Engeli

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    Hans-Georg Joost

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Engeli, S. (2012). Central and Peripheral Cannabinoid Receptors as Therapeutic Targets in the Control of Food Intake and Body Weight. In: Joost, HG. (eds) Appetite Control. Handbook of Experimental Pharmacology, vol 209. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-24716-3_17

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