PDF herunterladen
Horm Metab Res 2014; 46(08): 529-536
DOI: 10.1055/s-0034-1375653
Review
© Georg Thieme Verlag KG Stuttgart · New York

The Endocannabinoid System – Back to the Scene of Cardiometabolic Risk Factors Control?

C. J. M. Martins
1   Laboratory of Clinical and Experimental Pathophysiology (CLINEX), Rio de Janeiro State University (UERJ), Rio de Janeiro, RJ, Brazil
,
V. Genelhu
1   Laboratory of Clinical and Experimental Pathophysiology (CLINEX), Rio de Janeiro State University (UERJ), Rio de Janeiro, RJ, Brazil
2   Pro-Rector for Research and Postgraduate Education, UNIGRANRIO, Duque de Caxias, RJ, Brazil
,
V. Di Marzo
3   Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli NA, Italy
,
E. A. Francischetti
1   Laboratory of Clinical and Experimental Pathophysiology (CLINEX), Rio de Janeiro State University (UERJ), Rio de Janeiro, RJ, Brazil
2   Pro-Rector for Research and Postgraduate Education, UNIGRANRIO, Duque de Caxias, RJ, Brazil
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 15. Februar 2014

accepted 23. April 2014

Publikationsdatum:
27. Mai 2014 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Abstract

This review examines the impact of the endocannabinoid signaling system on metabolic and cardiovascular health and the new therapeutic strategies that selectively target dysfunctional endocannabinoid action in peripheral tissues, without causing the undesirable central nervous system effects that occurred with the first-generation of CB1 receptor blockers. We first review the components of the endocannabinoid system and the enzymes that synthesize and degrade the endocannabinoids, the critical role of the system in the homeostasis of energy balance, and its hedonic aspects related to the incentive and motivational value of food. Second, we describe the central and peripheral actions of the endocannabinoid system and its interactions with other biological modulators, such as ghrelin and leptin. Third, we summarize data from human clinical trials with the CB1 inverse agonist rimonabant, showing that the drug, although effective in increasing weight loss with accompanying improvements in the metabolic profile of the participants in the RIO (Rimonabant In Obesity) trials, was withdrawn from the market because of the risk of serious adverse events. Finally, we describe: 1) the development of new selective peripheral blockers that interrupt endocannabinoid action selectively in peripheral tissues and that have been suggested as an alternative approach to treat the metabolic consequences of obesity and related diseases, without undesirable central nervous system effects, and 2) the potential for inhibition of enzymes of synthesis, as well as the possible role of endocannabinoid congeners, with opposing effects as compared to CB1 receptor agonists, in the control of metabolic disorders.

Key words

endocannabinoid system - cardiometabolic risk factors - insulin resistance - obesity
 

  • References

  • 1 Finucane MM, Stevens GA, Cowan MJ, Danaei G, Lin JK, Paciorek CJ, Singh GM, Gutierrez HR, Lu Y, Bahalim AN, Farzadfar F, Riley LM, Ezzati M. Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Body Mass Index) . National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 2011; 377: 557-567
    CrossrefPubMedSuche in Google Scholar
  • 2 Drenick EJ, Bale GS, Seltzer F, Johnson DG. Excessive mortality and causes of death in morbidly obese men. JAMA 1980; 243: 443-445
    CrossrefPubMedSuche in Google Scholar
  • 3 Vague J. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout and uric calculous disease. Am J Clin Nutr 1956; 4: 20-34
    PubMedSuche in Google Scholar
  • 4 Balkau B, Deanfield JE, Després JP, Bassand JP, Fox KA, Smith Jr SC, Barter P, Tan CE, Van Gaal L, Wittchen HU, Massien C, Haffner SM. International Day for the Evaluation of Abdominal Obesity (IDEA): a study of waist circumference, cardiovascular disease, and diabetes mellitus in 168,000 primary care patients in 63 countries. Circulation 2007; 116: 1942-1951
    CrossrefPubMedSuche in Google Scholar
  • 5 Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol 2009; 6: 399-409
    CrossrefPubMedSuche in Google Scholar
  • 6 Genelhu VA, Celoria BM, Duarte SF, Cabello PH, Francischetti EA. Not all obese subjects of multiethnic origin are at similar risk for developing hypertension and type 2 diabetes. Eur J Intern Med 2009; 20: 289-295
    CrossrefPubMedSuche in Google Scholar
  • 7 Stefan N, Kantartzis K, Machann J, Schick F, Thamer C, Rittig K, Balletshofer B, Machicao F, Fritsche A, Häring HU. Identification and Characterization of Metabolically Benign Obesity in Humans. Arch Intern Med 2008; 168: 1609-1616
    CrossrefPubMedSuche in Google Scholar
  • 8 Gaoni Y, Mechoulam R. The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish. J Am Chem Soc 1971; 93: 217-224
    CrossrefPubMedSuche in Google Scholar
  • 9 Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002; 54: 161-202
    CrossrefPubMedSuche in Google Scholar
  • 10 Martin BR, Mechoulam R, Razdan RK. Discovery and characterization of endogenous cannabinoids. Life Sci 1999; 65: 573-595
    CrossrefPubMedSuche in Google Scholar
  • 11 Bermudez-Silva FJ, Viveros MP, McPartland JM, Rodriguez de Fonseca F. The endocannabinoid system, eating behavior and energy homeostasis: The end or a new beginning?. Pharmacol Biochem Behave 2010; 95: 375-382
    PubMedSuche in Google Scholar
  • 12 Matias I, Gonthier MP, Petrosino S, Docimo L, Capasso R, Hoareau L, Monteleone P, Roche R, Izzo AA, Di Marzo V. Role and regulation of acylethanolamides in energy balance: focus on adipocytes and beta-cells. Br J Pharmacol 2007; 152: 676-690
    CrossrefPubMedSuche in Google Scholar
  • 13 Silvestri C, Di Marzo V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab 2013; 17: 475-490
    CrossrefPubMedSuche in Google Scholar
  • 14 Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 1996; 384: 83-87
    CrossrefPubMedSuche in Google Scholar
  • 15 Marsicano G, Lutz B. Neuromodulatory functions of the endocannabinoid system. J Endocrinol Invest 2006; 29: 27-46
    CrossrefPubMedSuche in Google Scholar
  • 16 Matias I, Di Marzo V. Endocannabinoids and the control of energy balance. Trends Endocrinol Metab 2007; 18: 27-37
    CrossrefPubMedSuche in Google Scholar
  • 17 Kirkham TC. Cannabinoids and appetite: food craving and food pleasure. Int Rev Psychiatry 2009; 21: 163-171
    CrossrefPubMedSuche in Google Scholar
  • 18 Kola B, Farkas I, Christ-Crain M, Wittmann G, Lolli F, Amin F, Harvey-White J, Liposits Z, Kunos G, Grossman AB, Fekete C, Korbonits M. The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS One 2008; 3: e1797
    CrossrefPubMedSuche in Google Scholar
  • 19 Lim CT, Kola B, Feltrin D, Perez-Tilve D, Tschöp MH, Grossman AB, Korbonits M. Ghrelin and cannabinoids require the ghrelin receptor to affect cellular energy metabolism. Mol Cell Endocrinol 2013; 365: 303-308
    CrossrefPubMedSuche in Google Scholar
  • 20 Di Marzo V, Goparaju SK, Wang L, Liu J, Bátkai S, Járai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001; 410: 822-825
    CrossrefPubMedSuche in Google Scholar
  • 21 Di Marzo V, Ligresti A, Cristino L. The endocannabinoid system as a link between homoeostatic and hedonic pathways involved in energy balance regulation. Int J Obes (Lond) 2009; 33 (Suppl. 02) S18-S24
    CrossrefPubMedSuche in Google Scholar
  • 22 Yoshida R, Ohkuri T, Jyotaki M, Yasuo T, Horio N, Yasumatsu K, Sanematsu K, Shigemura N, Yamamoto T, Margolskee RF, Ninomiya Y. Endocannabinoids selectively enhance sweet taste. Proc Natl Acad Sci USA 2010; 107: 935-939
    CrossrefPubMedSuche in Google Scholar
  • 23 Liu P, Shah BP, Croasdell S, Gilbertson TA. Transient receptor potential channel type M5 is essential for fat taste. J Neurosci 2011; 31: 8634-8642
    CrossrefPubMedSuche in Google Scholar
  • 24 Degrace-Passilly P, Besnard P. CD36 and taste of fat. Curr Opin Clin Nutr Metab Care 2012; 15: 107-111
    CrossrefPubMedSuche in Google Scholar
  • 25 Zhang XJ, Zhou LH, Ban X, Liu DX, Jiang W, Liu XM. Decreased expression of CD36 in circumvallate taste buds of high-fat diet induced obese rats. Acta Histochem 2011; 113: 663-667
    CrossrefPubMedSuche in Google Scholar
  • 26 Greenberg D, Smith GP. The controls of fat intake. Psychosom Med 1996; 58: 559-569
    CrossrefPubMedSuche in Google Scholar
  • 27 Di Marzo V. Endocannabinoids: an appetite for fat. Proc Natl Acad Sci USA 2011; 108: 12567-12568
    CrossrefPubMedSuche in Google Scholar
  • 28 DiPatrizio NV, Joslin A, Jung KM, Piomelli D. Endocannabinoid signaling in the gut mediates preference for dietary unsaturated fats. FASEB J 2013; 27: 2513-2520
    CrossrefPubMedSuche in Google Scholar
  • 29 Di Marzo V. The endocannabinoid system in obesity and type 2 diabetes. Diabetologia 2008; 51: 1356-1367
    CrossrefPubMedSuche in Google Scholar
  • 30 Silvestri C, Di Marzo V. Second generation CB1 receptor blockers and other inhibitors of peripheral endocannabinoid overactivity and the rationale of their use against metabolic disorders. Expert Opin Investig Drugs 2012; 21: 1309-1322
    CrossrefPubMedSuche in Google Scholar
  • 31 Cota D, Marsicano G, Tschöp M, Grübler 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. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 2003; 112: 423-431
    CrossrefPubMedSuche in Google Scholar
  • 32 Vettor R, Pagano C. The role of the endocannabinoid system in lipogenesis and fatty acid metabolism. Best Pract Res Clin Endocrinol Metab 2009; 23: 51-63
    CrossrefPubMedSuche in Google Scholar
  • 33 Vida M, Rivera P, Gavito AL, Suárez J, Pavón FJ, Arrabal S, Romero-Cuevas M, Bautista D, Martínez A, de Fonseca FR, Serrano A, Baixeras E. CB1 Blockade Potentiates Down-Regulation of Lipogenic Gene Expression in Perirenal Adipose Tissue in High Carbohydrate Diet-Induced Obesity. PLoS One 2014; 9: e90016
    CrossrefPubMedSuche in Google Scholar
  • 34 Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, Harvey-White J, Mackie K, Offertáler L, Wang L, Kunos G. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005; 115: 1298-1305
    CrossrefPubMedSuche in Google Scholar
  • 35 Tedesco L, Valerio A, Dossena M, Cardile A, Ragni M, Pagano C, Pagotto U, Carruba MO, Vettor R, Nisoli E. Cannabinoid receptor stimulation impairs mitochondrial biogenesis in mouse white adipose tissue, muscle, and liver: the role of eNOS, p38 MAPK, and AMPK pathways. Diabetes 2010; 59: 2826-2836
    CrossrefPubMedSuche in Google Scholar
  • 36 Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI, Bátkai S, Marsicano G, Lutz B, Buettner C, Kunos G. Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J Clin Invest 2008; 118: 3160-3169
    CrossrefPubMedSuche in Google Scholar
  • 37 Song D, Bandsma RH, Xiao C, Xi L, Shao W, Jin T, Lewis GF. Acute cannabinoid receptor type 1 (CB1R) modulation influences insulin sensitivity by an effect outside the central nervous system in mice. Diabetologia 2011; 54: 1181-1189
    CrossrefPubMedSuche in Google Scholar
  • 38 Eckardt K, Sell H, Taube A, Koenen M, Platzbecker B, Cramer A, Horrighs A, Lehtonen M, Tennagels N, Eckel J. Cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle. Diabetologia 2009; 52: 664-674
    CrossrefPubMedSuche in Google Scholar
  • 39 Abdul-Ghani MA, DeFronzo RA. Pathogenesis of insulin resistance in skeletal muscle. J Biomed Biotechnol 2010; 2010 476279
    PubMedSuche in Google Scholar
  • 40 Bermúdez-Silva FJ, Suárez J, Baixeras E, Cobo N, Bautista D, Cuesta-Muñoz AL, Fuentes E, Juan-Pico P, Castro MJ, Milman G, Mechoulam R, Nadal A, Rodríguez de Fonseca F. Presence of functional cannabinoid receptors in human endocrine pancreas. Diabetologia 2008; 51: 476-487
    CrossrefPubMedSuche in Google Scholar
  • 41 Li C, Jones PM, Persaud SJ. Cannabinoid receptors are coupled to stimulation of insulin secretion from mouse MIN6 beta-cells. Cell Physiol Biochem 2010; 26: 187-196
    CrossrefPubMedSuche in Google Scholar
  • 42 Kim W, Lao Q, Shin YK, Carlson OD, Lee EK, Gorospe M, Kulkarni RN, Egan JM. Cannabinoids induce pancreatic β-cell death by directly inhibiting insulin receptor activation. Sci Signal 2012; 5 ra23
    PubMedSuche in Google Scholar
  • 43 Jourdan T, Godlewski G, Cinar R, Bertola A, Szanda G, Liu J, Tam J, Han T, Mukhopadhyay B, Skarulis MC, Ju C, Aouadi M, Czech MP, Kunos G. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat Med 2013; 19: 1132-1140
    CrossrefPubMedSuche in Google Scholar
  • 44 Egecioglu E, Skibicka KP, Hansson C, Alvarez-Crespo M, Friberg PA, Jerlhag E, Engel JA, Dickson SL. Hedonic and incentive signals for body weight control. Rev Endocr Metab Disord 2011; 12: 141-151
    CrossrefPubMedSuche in Google Scholar
  • 45 Power ML, Schulkin J. The Evolution of Obesity. Baltimore: The Johns Hopkins University Press; 2009: 10-11
    Suche in Google Scholar
  • 46 Davis C, Strachan S, Berkson M. Sensitivity to reward: implications for overeating and overweight. Appetite 2004; 42: 131-138
    CrossrefPubMedSuche in Google Scholar
  • 47 Di Marzo V, Côté M, Matias I, Lemieux I, Arsenault BJ, Cartier A, Piscitelli F, Petrosino S, Alméras N, Després JP. 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: 213-217
    CrossrefPubMedSuche in Google Scholar
  • 48 Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489: 242-249
    CrossrefPubMedSuche in Google Scholar
  • 49 Muccioli GG, Naslain D, Bäckhed F, Reigstad CS, Lambert DM, Delzenne NM, Cani PD. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol 2010; 6: 392
    CrossrefPubMedSuche in Google Scholar
  • 50 Engeli S, Böhnke J, Feldpausch M, Gorzelniak K, Janke J, Bátkai S, Pacher P, Harvey-White J, Luft FC, Sharma AM, Jordan J. Activation of the peripheral endocannabinoid system in human obesity. Diabetes 2005; 54: 2838-2843
    CrossrefPubMedSuche in Google Scholar
  • 51 Côté M, Matias I, Lemieux I, Petrosino S, Alméras N, Després JP, Di Marzo V. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes (Lond) 2007; 31: 692-699
    PubMedSuche in Google Scholar
  • 52 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419
    Suche in Google Scholar
  • 53 Lipina C, Rastedt W, Irving AJ, Hundal HS. New vistas for treatment of obesity and diabetes? Endocannabinoid signaling and metabolism in the modulation of energy balance. Bioessays 2012; 34: 681-691
    CrossrefPubMedSuche in Google Scholar
  • 54 Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S. RIO-Europe Study Group . Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005; 365: 1389-1397
    CrossrefPubMedSuche in Google Scholar
  • 55 Després JP, Golay A, Sjöström L. Rimonabant in Obesity-Lipids Study Group . Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005; 353: 2121-2134
    CrossrefPubMedSuche in Google Scholar
  • 56 Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. RIO-North America Study Group . Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 2006; 295: 761-775
    CrossrefPubMedSuche in Google Scholar
  • 57 Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF. RIO-Diabetes Study Group . Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006; 368: 1660-1672
    CrossrefPubMedSuche in Google Scholar
  • 58 Patti ME. Rehashing endocannabinoid antagonists: can we selectively target the periphery to safely treat obesity and type 2 diabetes?. J Clin Invest 2010; 120: 2646-2648
    CrossrefPubMedSuche in Google Scholar
  • 59 Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomized trials. Lancet 2007; 370: 1706-1713
    CrossrefPubMedSuche in Google Scholar
  • 60 Tam J, Vemuri VK, Liu J, Bátkai S, Mukhopadhyay B, Godlewski G, Osei-Hyiaman D, Ohnuma S, Ambudkar SV, Pickel J, Makriyannis A, Kunos G. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest 2010; 120: 2953-2966
    CrossrefPubMedSuche in Google Scholar
  • 61 Alonso M, Serrano A, Vida M, Crespillo A, Hernandez-Folgado L, Jagerovic N, Goya P, Reyes-Cabello C, Perez-Valero V, Decara J, Macías-González M, Bermúdez-Silva FJ, Suárez J, Rodríguez de Fonseca F, Pavón FJ. Anti-obesity efficacy of LH-21, a cannabinoid CB(1) receptor antagonist with poor brain penetration, in diet-induced obese rats. Br J Pharmacol 2012; 165: 2274-2291
    CrossrefPubMedSuche in Google Scholar
  • 62 Pavón FJ, Serrano A, Pérez-Valero V, Jagerovic N, Hernández-Folgado L, Bermúdez-Silva FJ, Macías M, Goya P, de Fonseca FR. Central versus peripheral antagonism of cannabinoid CB1 receptor in obesity: effects of LH-21, a peripherally acting neutral cannabinoid receptor antagonist, in Zucker rats. J Neuroendocrinol 2008; 20 (Suppl. 01) 116-123
    CrossrefPubMedSuche in Google Scholar
  • 63 Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, Szanda G, Mukhopadhyay B, Chedester L, Liow JS, Innis RB, Cheng K, Rice KC, Deschamps JR, Chorvat RJ, McElroy JF, Kunos G. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab 2012; 16: 167-179
    CrossrefPubMedSuche in Google Scholar
  • 64 Cinar R, Godlewski G, Liu J, Tam J, Jourdan T, Mukhopadhyay B, Harvey-White J, Kunos G. Hepatic cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing de novo synthesis of long-chain ceramides. Hepatology 2014; 59: 143-153
    CrossrefPubMedSuche in Google Scholar
  • 65 Bisogno T, Mahadevan A, Coccurello R, Chang JW, Allarà M, Chen Y, Giacovazzo G, Lichtman A, Cravatt B, Moles A, Di Marzo V. A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects. Br J Pharmacol 2013; 169: 784-793
    CrossrefPubMedSuche in Google Scholar
  • 66 Di Marzo V, De Petrocellis L. Endocannabinoids as regulators of transient receptor potential (TRP) channels: A further opportunity to develop new endocannabinoid-based therapeutic drugs. Curr Med Chem 2010; 17: 1430-1449
    CrossrefPubMedSuche in Google Scholar
  • 67 Luo Z, Ma L, Zhao Z, He H, Yang D, Feng X, Ma S, Chen X, Zhu T, Cao T, Liu D, Nilius B, Huang Y, Yan Z, Zhu Z. TRPV1 activation improves exercise endurance and energy metabolism through PGC-1α upregulation in mice. Cell Res 2012; 22: 551-564
    CrossrefPubMedSuche in Google Scholar
  • 68 Schwartz GJ, Fu J, Astarita G, Li X, Gaetani S, Campolongo P, Cuomo V, Piomelli D. The lipid messenger OEA links dietary fat intake to satiety. Cell Metab 2008; 8: 281-288
    CrossrefPubMedSuche in Google Scholar