Background: Since the purification of Δ9-tetrahydrocannabinol (THC) 40 years ago, many studies have concluded that the endocannabinoid system is one of the most important orexigenic systems in the body. Endocannabinoids are endogenous lipids capable of activating the two cannabinoid receptors, CB type 1 (CB1) and CB type 2. These receptors belong to the G-protein-coupled family receptors and they were discovered while investigating the molecular mode of action of THC, to which they bind with high affinity. Endogenous cannabinoids stimulate hunger and promote appetite through activation of the CB1 receptors. The CB1 receptor is expressed in several organs that are involved at both the central and peripheral level in the control of food intake and energy metabolism. These organs include the mesolimbic system, hypothalamus, gastrointestinal tract, adipose tissue, skeletal muscles, hepatocytes and endocrine cells of the pancreas. The endocannabinoid system is believed to play a crucial role in controlling energy balance through the possible targeting of a large variety of peripheral organs while modulating metabolic processes. Conclusions: To better understand the effects of the endocannabinoid system, future studies will require detailed charac- terization of each individual contribution and the reciprocal interactions among the organs. Because the endocannabinoid system is likely overactivated in conditions such as obesity, pharmacologic therapy with a CB1 receptor antagonist like rimonabant might normalize the imbalance induced by this overactivation and produce a viable option in the fight against obesity and its associated comorbid conditions.

Keywords:
Endocannabinoids, Cannabinoid receptor type 1 (CB1) receptor, Rimonabant, Obesity
1.
Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R: The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev 2006;27:73–100.
2.
Piomelli D: The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 2003;4:873–884.
3.
Di Marzo V, Matias I: Endocannabinoid control of food intake and energy balance. Nat Neurosci 2005;8:585–589.
4.
Marsicano G, Lutz B: Neuromodulatory functions of the endocannabinoid system. J Endocrinol Invest 2006;29(suppl 3):27–46.
5.
Cota D, Tschoep MH, Horvath TL, Levine AS: Cannabinoids, opioids and eating behavior: the molecular face of hedonism? Brain Res Brain Res Rev 2006;51:85–107.
6.
Jamshidi N, Taylor DA: Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol 2001;134:1151–1154.
7.
Kirkham TC, Williams CM, Fezza F, Di Marzo V: 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 2002;136:550–557.
8.
Gomez R, Navarro M, Ferrer B, Trigo JM, Bilbao A, Del Arco I, Cippitelli A, Nava F, Piomelli D, Rodríguez de Fonseca F: A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 2002;22:9612–9617.
9.
Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thone-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.
10.
Poirier B, Bidouard JP, Cadrouvele C, Marniquet X, Staels B, O’Connor SE, Janiak P, Herbert J-M: The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Diabetes Obes Metab 2005;7:65–72.
11.
Bensaid M, Gary-Bobo M, Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F, Soubrie P: 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 2003;63:908–914.
12.
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.
13.
Jbilo O, Ravinet-Trillou C, Arnone M, Buisson I, Bribes E, Peleraux A, Penarier G, Soubrie P, Le Fur G, Galliegue S, Casellas P: The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J 2005;19:1567–1569.
14.
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.
15.
Juan-Picò P, Fuentes E, Javier Bermudez-Silva F, Javier Diaz-Molina F, Ripoll C, Rodriguez de Fonseca F, Nadal A: Cannabinoid receptors regulate Ca(2+) signals and insulin secretion in pancreatic beta-cell. Cell Calcium 2006;39:155–162.
16.
Liu YL, Connoley IP, Wilson CA, Stock MJ: 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 Relat Metab Disord 2005;29:183–187.
17.
Blüher M, Engeli S, Klöting N, Berndt J, Fasshauer M, Batkai S, Pacher P, Schön MR, Jordan J, Stumvoll M: Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes 2006;55:3053–3060.
18.
Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S, for the RIO-Europe study Group: Effects of the cannabinoid CB1 receptor blocker rimonabant on weight reduction and cardiovascular risk factor in overweight patients: 1 year experience from the RIO-Europe Study. Lancet2005;365:1389–1397.
19.
Despres JP, Golay A, Sjostrom L, for the RIO-Lipids Study Group: Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353:2121–2134.
20.
Pi-Sunyer FX, Aronne LJ, Heshamati HM, Devin J, Rosenstock J, for the RIO-North America Study Group: Effects of rimonabant, a cannabinoid-1 receptor blocker. On weight and cardiometabolic risk factors in overweight or obese patients. JAMA 2006;295:761–775.
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2007
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