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Re-visiting the Endocannabinoid System and Its Therapeutic Potential in Obesity and Associated Diseases

  • Pathogenesis of Type 2 Diabetes and Insulin Resistance (RM Watanabe, Section Editor)
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Abstract

Purpose of review

The purpose of the review was to revisit the possibility of the endocannabinoid system being a therapeutic target for the treatment of obesity by focusing on the peripheral roles in regulating appetite and energy metabolism.

Recent findings

Previous studies with the global cannabinoid receptor blocker rimonabant, which has both central and peripheral properties, showed that this drug has beneficial effects on cardiometabolic function but severe adverse psychiatric side effects. Consequently, focus has shifted to peripherally restricted cannabinoid 1 (CB1) receptor blockers as possible therapeutic agents that mitigate or eliminate the untoward effects in the central nervous system.

Summary

Targeting the endocannabinoid system using novel peripheral CB1 receptor blockers with negligible penetrance across the blood-brain barrier may prove to be effective therapy for obesity and its co-morbidities. Perhaps the future of blockers targeting CB1 receptors will be tissue-specific neutral antagonists (e.g., skeletal muscle specific to treat peripheral insulin resistance, adipocyte-specific to treat fat excess, liver-specific to treat fatty liver and hepatic insulin resistance).

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References

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

  1. • Sellayah D, Cagampang FR, Cox RD. On the evolutionary origins of obesity: a new hypothesis. Endocrinology. 2014;155(5):1573–88. This study underscores the need to combat obesity

    Article  PubMed  Google Scholar 

  2. Apovian CM. The clinical and economic consequences of obesity. Am J Manag Care. 2013;19(11):S219–S28.

    Google Scholar 

  3. Haffner SM. Abdominal adiposity and cardiometabolic risk: do we have all the answers? Am J Med. 2007;120(9 Suppl 1):S10–6. discussion S6-7

    Article  CAS  PubMed  Google Scholar 

  4. Haffner SM. Type 2 diabetes and the metabolic syndrome: National Cholesterol Education Program guidelines and supporting evidence. Crit Pathw Cardiol. 2004;3(3 Suppl):S12-4.

    Article  PubMed  Google Scholar 

  5. Cervino C, Pasquali R, Pagotto U. Cannabinoid receptor antagonists and the metabolic syndrome: novel promising therapeutical approaches. Mini-Rev Med Chem. 2007;7(1):21–30.

    Article  CAS  PubMed  Google Scholar 

  6. Bellocchio L, Mancini G, Vicennati V, Pasquali R, Pagotto U. Cannabinoid receptors as therapeutic targets for obesity and metabolic diseases. Curr Opin Pharmacol. 2006;6(6):586–91.

    Article  CAS  PubMed  Google Scholar 

  7. Despres JP, Lemieux I, Almeras N. Contribution of CB1 blockade to the management of high-risk abdominal obesity. Int J Obes. 2006;30:S44–52.

    Article  CAS  Google Scholar 

  8. Felder CC, Briley EM, Axelrod J, Simpson JT, Mackie K, Devane WA. Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal-transduction. Proc Natl Acad Sci U S A. 1993;90(16):7656–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946–9.

    Article  CAS  PubMed  Google Scholar 

  10. Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev. 2010;62(4):588–631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Piomelli D. More surprises lying ahead. The endocannabinoids keep us guessing. Neuropharmacology. 2014;76 Pt B:228–34.

    Article  PubMed  Google Scholar 

  12. Kunos G, Osei-Hyiaman D, Liu J, Godlewski G, Batkai S. Endocannabinoids and the control of energy homeostasis. J Biol Chem. 2008;283(48):33021–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nat Neurosci. 2005;8(5):585–9.

    Article  PubMed  Google Scholar 

  14. Cota D, Marsicano G, Lutz B, Vicennati V, Stalla GK, Pasquali R, et al. Endogenous cannabinoid system as a modulator of food intake. Int J Obes Relat Metab Disord. 2003;27(3):289–301.

    Article  CAS  PubMed  Google Scholar 

  15. Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest. 2003;112(3):423–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kunos G, Osei-Hyiaman D, Bátkai S, Sharkey KA, Makriyannis A. Should peripheral CB(1) cannabinoid receptors be selectively targeted for therapeutic gain? Trends Pharmacol Sci. 2009;30(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  17. Tam J, Vemuri VK, Liu J, Batkai S, Mukhopadhyay B, Godlewski G, et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest. 2010;120(8):2953–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Engeli S, Bohnke J, Feldpausch M, Gorzelniak K, Janke J, Batkai S, et al. Activation of the peripheral endocannabinoid system in human obesity. Diabetes. 2005;54(10):2838–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mechoulam R, Devane WA, Glaser R. Cannabinoid geometry and biological activity. In: Nahas G, Sutin KM, Harvey D, Agurell S, Pace N, Camcro R, editors. Marihuana and Medicine. Ottawa: Humana Press; 1999. p. 65-90.

  20. Mechoulam R, Fride E, Di Marzo V. Endocannabinoids. Eur J Pharmacol. 1998;359(1):1–18.

    Article  CAS  PubMed  Google Scholar 

  21. Struwe M, Kaempfer SH, Geiger CJ, Pavia AT, Plasse TF, Shepard KV, et al. Effect of dronabinol on nutritional status in HIV infection. Ann Pharmacother. 1993;27(7–8):827–31.

    Article  CAS  PubMed  Google Scholar 

  22. Di Marzo V, Maccarrone M. FAAH and anandamide: is 2-AG really the odd one out? Trends Pharmacol Sci. 2008;29(5):229–33.

    Article  PubMed  Google Scholar 

  23. Matias I, Di Marzo V. Endocannabinoid synthesis and degradation, and their regulation in the framework of energy balance. J Endocrinol Investig. 2006;29(3 Suppl):15–26.

    CAS  Google Scholar 

  24. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S, Group R-ES. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005;365(9468):1389–97.

    Article  PubMed  Google Scholar 

  25. Van Gaal L, Pi-Sunyer X, Després JP, McCarthy C, Scheen A. 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. 2008;31(Suppl 2):S229–40.

    Article  PubMed  Google Scholar 

  26. Despres JP, Golay A, Sjostrom L. Rimonabant Obesity Lipids Study G. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353(20):2121–34.

    Article  CAS  PubMed  Google Scholar 

  27. Chambers AP, Vemuri VK, Peng Y, Wood JT, Olszewska T, Pittman QJ, et al. A neutral CB1 receptor antagonist reduces weight gain in rat. Am J Physiol Regul Integr Comp Physiol. 2007;293(6):R2185–93.

    Article  CAS  PubMed  Google Scholar 

  28. Ward SJ, Raffa RB. Rimonabant redux and strategies to improve the future outlook of CB1 receptor neutral-antagonist/inverse-agonist therapies. Obesity (Silver Spring). 2011;19(7):1325–34.

    Article  CAS  Google Scholar 

  29. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J, Group R-NAS. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 2006;295(7):761–75.

    Article  CAS  PubMed  Google Scholar 

  30. Scheen AJ. CB1 receptor blockade and its impact on cardiometabolic risk factors: overview of the RIO programme with rimonabant. J Neuroendocrinol. 2008;20(Suppl 1):139–46.

    Article  CAS  PubMed  Google Scholar 

  31. Ducobu J, Sternon J. Rimonabant (Acomplia), specific inhibitor of the endocannabinoid system. J Pharm Belg. 2005;60(3):89–91.

    CAS  PubMed  Google Scholar 

  32. Di Marzo V, Szallasi A. Rimonabant in rats with a metabolic syndrome: good news after the depression. Br J Pharmacol. 2008;154(5):915–7.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Cote M, Matias I, Lemieux I, Petrosino S, Almeras N, Despres JP, et al. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes. 2007;31(4):692–9.

    CAS  Google Scholar 

  34. Di Marzo V, Cote M, Matias I, Lemieux I, Arsenault BJ, Cartier A, et al. Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors. Diabetologia. 2009;52(2):213–7.

    Article  CAS  PubMed  Google Scholar 

  35. Matias I, Petrosino S, Racioppi A, Capasso R, Izzo AA, Di Marzo V. Dysregulation of peripheral endocannabinoid levels in hyperglycemia and obesity: effect of high fat diets. Mol Cell Endocrinol. 2008;286(1–2 Suppl 1):S66–78.

    Article  CAS  PubMed  Google Scholar 

  36. Di Marzo V. The endocannabinoid system in obesity and type 2 diabetes. Diabetologia. 2008;51(8):1356–67.

    Article  CAS  PubMed  Google Scholar 

  37. Starowicz KM, Cristino L, Matias I, Capasso R, Racioppi A, Izzo AA, et al. Endocannabinoid dysregulation in the pancreas and adipose tissue of mice fed with a high-fat diet. Obesity (Silver Spring). 2008;16(3):553–65.

    Article  CAS  Google Scholar 

  38. Di Marzo V, Petrosino S. Endocannabinoids and the regulation of their levels in health and disease. Curr Opin Lipidol. 2007;18(2):129–40.

    Article  PubMed  Google Scholar 

  39. Herling AW, Kilp S, Juretschke HP, Neumann-Haefelin C, Gerl M, Kramer W. Reversal of visceral adiposity in candy-diet fed female Wistar rats by the CB1 receptor antagonist rimonabant. Int J Obes. 2008;32(9):1363–72.

    Article  CAS  Google Scholar 

  40. Richey JM, Woolcott OO, Stefanovski D, Harrison LN, Zheng D, Lottati M, et al. Rimonabant prevents additional accumulation of visceral and subcutaneous fat during high-fat feeding in dogs. Am J Physiol Endocrinol Metab. 2009;296(6):E1311–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vessby B, Uusitupa M, Hermansen K, Riccardi G, Rivellese AA, Tapsell LC, et al. Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: the KANWU Study. Diabetologia. 2001;44(3):312–9.

    Article  CAS  PubMed  Google Scholar 

  42. Artmann A, Petersen G, Hellgren LI, Boberg J, Skonberg C, Nellemann C, et al. Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine. Biochim Biophys Acta. 2008;1781(4):200–12.

    Article  CAS  PubMed  Google Scholar 

  43. Berger A, Crozier G, Bisogno T, Cavaliere P, Innis S, Di Marzo V. Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets. Proc Natl Acad Sci U S A. 2001;98(11):6402–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. •• Argueta DA, DiPatrizio NV. Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity. Physiol Behav. 2017;171:32–9. Study demonstrates enhanced endocannabinoid signaling at peripheral CB1 receptors with fat feeding

    Article  CAS  PubMed  Google Scholar 

  45. Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115(5):1298–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hansen HS, Artmann A. Endocannabinoids and nutrition. J Neuroendocrinol. 2008;20(Suppl 1):94–9.

    Article  CAS  PubMed  Google Scholar 

  47. Engeli S, Lehmann AC, Kaminski J, Haas V, Janke J, Zoerner AA, et al. Influence of dietary fat intake on the endocannabinoid system in lean and obese subjects. Obesity (Silver Spring). 2014;22(5):E70–6.

    Article  CAS  Google Scholar 

  48. Kim SP, Woolcott OO, Hsu IR, Stefanoski D, Harrison LN, Zheng D, et al. CB(1) antagonism restores hepatic insulin sensitivity without normalization of adiposity in diet-induced obese dogs. Am J Physiol Endocrinol Metab. 2012;302(10):E1261–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kabir M, Stefanovski D, Hsu IR, Iyer M, Woolcott OO, Zheng D, et al. Large size cells in the visceral adipose depot predict insulin resistance in the canine model. Obesity (Silver Spring). 2011;19(11):2121–9.

    Article  CAS  Google Scholar 

  50. Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrie P. CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord. 2004;28(4):640–8.

    Article  CAS  PubMed  Google Scholar 

  51. Jbilo O, Ravinet-Trillou C, Arnone M, Buisson I, Bribes E, Peleraux A, et al. The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J. 2005;19(11):1567–9.

    CAS  PubMed  Google Scholar 

  52. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev. 2005;26(3):439–51.

    Article  CAS  PubMed  Google Scholar 

  53. •• Kabir M, Iyer MS, Richey JM, Woolcott OO, Asare Bediako I, Wu Q, et al. CB1R antagonist increases hepatic insulin clearance in fat-fed dogs likely via upregulation of liver adiponectin receptors. Am J Physiol Endocrinol Metab. 2015;309(8):E747–58. Study demonstrates the importance of adiponectin in improving insulin sensitivity with CB1 antagonism

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Herling AW, Kilp S, Elvert R, Haschke G, Kramer W. Increased energy expenditure contributes more to the body weight-reducing effect of rimonabant than reduced food intake in candy-fed wistar rats. Endocrinology. 2008;149(5):2557–66.

    Article  CAS  PubMed  Google Scholar 

  55. Bellocchio L, Cervino C, Pasquali R, Pagotto U. The endocannabinoid system and energy metabolism. J Neuroendocrinol. 2008;20(6):850–7.

    Article  CAS  PubMed  Google Scholar 

  56. Kunos G, Osei-Hyiaman D. Endocannabinoids and liver disease. IV. Endocannabinoid involvement in obesity and hepatic steatosis. Am J Physiol Gastrointest Liver Physiol. 2008;294(5):G1101–4.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bluher M, Engeli S, Kloting N, Berndt J, Fasshauer M, Batkai S, et al. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes. 2006;55(11):3053–60.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, et al. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem. 2005;280(26):25196–201.

    Article  CAS  PubMed  Google Scholar 

  60. Kola B, Wittman G, Bodnár I, Amin F, Lim CT, Oláh M, et al. The CB1 receptor mediates the peripheral effects of ghrelin on AMPK activity but not on growth hormone release. FASEB J. 2013;27(12):5112–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gamelin FX, Aucouturier J, Iannotti FA, Piscitelli F, Mazzarella E, Aveta T, et al. Effects of chronic exercise on the endocannabinoid system in Wistar rats with high-fat diet-induced obesity. J Physiol Biochem. 2016;72(2):183–99.

    Article  CAS  PubMed  Google Scholar 

  62. Perwitz N, Fasshauer M, Klein J. Cannabinoid receptor signaling directly inhibits thermogenesis and alters expression of adiponectin and visfatin. Horm Metab Res. 2006;38(5):356–8.

    Article  CAS  PubMed  Google Scholar 

  63. Nogueiras R, Veyrat-Durebex C, Suchanek PM, Klein M, Tschop J, Caldwell C, et al. Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats. Diabetes. 2008;57(11):2977–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. •• Chorvat RJ. Peripherally restricted CB1 receptor blockers. Bioorg Med Chem Lett. 2013;23(17):4751–60. This study provides a nice description of peripheral CB1 blockade

    Article  CAS  PubMed  Google Scholar 

  65. Gueye AB, Pryslawsky Y, Trigo JM, Poulia N, Delis F, Antoniou K, et al. The CB1 neutral antagonist AM4113 retains the therapeutic efficacy of the inverse agonist rimonabant for nicotine dependence and weight loss with better psychiatric tolerability. Int J Neuropsychopharmacol. 2016;19(12):pyw068.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Knani I, Earley BJ, Udi S, Nemirovski A, Hadar R, Gammal A, et al. Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome. Mol Metab. 2016;5(12):1187–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chorvat RJ, Berbaum J, Seriacki K, McElroy JF. JD-5006 and JD-5037: peripherally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities. Bioorg Med Chem Lett. 2012;22(19):6173–80.

    Article  CAS  PubMed  Google Scholar 

  68. •• Klumpers LE, Fridberg M, de Kam ML, Little PB, Jensen NO, Kleinloog HD, et al. Peripheral selectivity of the novel cannabinoid receptor antagonist TM38837 in healthy subjects. Br J Clin Pharmacol. 2013;76(6):846–57. Study provides evidence for minimal brain penetrance of a CB1 blocker in humans

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. •• Takano A, Gulyas B, Varnas K, Little PB, Noerregaard PK, Jensen NO, et al. Low brain CB1 receptor occupancy by a second generation CB1 receptor antagonist TM38837 in comparison with rimonabant in nonhuman primates: a PET study. Synapse. 2014;68(3):89–97. Study provides promising results for second-generation CB1 antagonism as an anti-obesity drug

    Article  CAS  PubMed  Google Scholar 

  70. Hung M-S, Chang C-P, Li T-C, Yeh T-K, Song J-S, Lin Y, et al. Discovery of 1-(2,4-dichlorophenyl)-4-ethyl-5-(5-(2-(4-(trifluoromethyl)phenyl)ethynyl)thiophen-2-yl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide as a potential peripheral cannabinoid-1 receptor inverse agonist. Chem Med Chem. 2010;5(9):1439–43.

    Article  CAS  PubMed  Google Scholar 

  71. Mastinu A, Pira M, Pinna GA, Pisu C, Casu MA, Reali R, et al. NESS06SM reduces body weight with an improved profile relative to SR141716A. Pharmacol Res. 2013;74:94–108.

    Article  CAS  PubMed  Google Scholar 

  72. Lazzari P, Serra V, Marcello S, Pira M, Mastinu A. Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats. Eur Neuropsychopharmacol. 2017;27(7):667–78.

    Article  CAS  PubMed  Google Scholar 

  73. Rossi F, Bellini G, Luongo L, Manzo I, Tolone S, Tortora C, et al. Cannabinoid receptor 2 as antiobesity target: inflammation, fat storage, and Browning modulation. J Clin Endocrinol Metab. 2016;101(9):3469–78.

    Article  CAS  PubMed  Google Scholar 

  74. Verty AN, Stefanidis A, McAinch AJ, Hryciw DH, Oldfield B. Anti-obesity effect of the CB2 receptor agonist JWH-015 in diet-induced obese mice. PLoS One. 2015;10(11):e0140592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. LoVerme J, Duranti A, Tontini A, Spadoni G, Mor M, Rivara S, et al. Synthesis and characterization of a peripherally restricted CB1 cannabinoid antagonist, URB447, that reduces feeding and body-weight gain in mice. Bioorg Med Chem Lett. 2009;19(3):639–43.

    Article  CAS  PubMed  Google Scholar 

  76. Matthews JM, McNally JJ, Connolly PJ, Xia M, Zhu B, Black S, et al. Tetrahydroindazole derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists. Bioorg Med Chem Lett. 2016;26(21):5346–9.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Dow RL, Carpino PA, Gautreau D, Hadcock JR, Iredale PA, Kelly-Sullivan D, et al. Design of a potent CB1 receptor antagonist series: potential scaffold for peripherally-targeted agents. ACS Med Chem Lett. 2012;3(5):397–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Joyce M. Richey.

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Joyce M. Richey and Orison Woolcott declare that they have no conflict of interest.

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This article is part of the Topical Collection on Pathogenesis of Type 2 Diabetes and Insulin Resistance

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Richey, J.M., Woolcott, O. Re-visiting the Endocannabinoid System and Its Therapeutic Potential in Obesity and Associated Diseases. Curr Diab Rep 17, 99 (2017). https://doi.org/10.1007/s11892-017-0924-x

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