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- May 12, 2008 |
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"The Endocannabinoid System: A New Therapeutic Target in Metabolic Disorders"Prof. Uberto Pagotto (biography)
English - 2005-04-15 - 25 minutes
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Summary :
Endocannabinoids and in particular anandamide and 2-arachidonoylglycerol are endogenous lipids capable of activating, the two cannabinoid (CB) receptors CB1 and CB2. These receptors belong to the G-protein-coupled family receptors and they were discovered in 1990s while investigating the molecular mode of action of the principal psychoactive component of Cannabis, r9-tetrahydrocannabinol, to which they bind with high affinity. Therefore, one can conclude that CB1 receptors and endocannabinoids are the two components of the endocannabinoid system. Among other sites, this system is an activator of peripheral sites involved in the control of energy balance and body weight as well as in neurons of the hypothalamus controlling food intake and in neuronal cells in mesolimbic system that participate in translating motivation into action. It is well known that endogenous cannabinoids, through stimulation of CB1 receptors, stimulate hunger and promote appetite being increased in fasting condition and reduced after feeding. It has been also recently demonstrated that some chronic pathologic states as obesity lead to long-lasting overstimulation of endocannabinoid synthesis (or hypo-stimulation of their degradation), resulting in permanent overactivation of which may then contribute to the symptoms of this disease. Importantly, at peripheral level CB1 activation has been shown to stimulate lipogenesis into adipocytes, and CB1 antagonists have been found to be important positive modulators of adiponectin secretion. Moreover, recently CB1 have been detected in muscles of mice where the CB1 antagonists stimulate oxygen consumption. Therefore, it is now evident that the endocannabinoid system is an important modulator of a plethora of effects largely impacting food intake control and metabolic processes. These physiological properties of endocannabinoids and CB1 in regulating in a dual way (both central and peripheral) several metabolic functions, the pathologic consequences of an altered cannabinoid tone in obesity, and its pharmacological management against visceral obesity and metabolic disorders associated by using CB1 receptors antagonist as Rimonabant will be discussed in the presentation.
Learning objectives :
After viewing this presentation, participants will be able to discuss:
• The function and sites of action of the endocannabinoids
• Role of cannabanoid receptor type 1 (CB1) in the metabolic syndrome
• The potential benefit of CB1 blockade with agents such as rimonabant
• The mechanism of action of CB1 antagonists
Bibliographic references :
De Petrocellis L, Melck D, Bisogno T, Milone A, Di Marzo V. Finding of the endocannabinoid signalling system in Hydra, a very primitive organism: possible role in the feeding response. Neuroscience. 1999;92(1):377-87.
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 Jun;136(4):550-7.
Jamshidi N, Taylor DA. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol. 2001 Nov;134(6):1151-4.
Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G. Nature. 2001 Apr 12;410(6830):822-5. Nature. 2001 Apr 12;410(6830):822-5.
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 Aug;112(3):423-31.
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 Apr;28(4):640-8.
Colombo G, Agabio R, Diaz G, Lobina C, Reali R, Gessa GL. Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sci. 1998;63(8):PL113-7.
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 Apr;63(4):908-14.
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 Feb;29(2):183-7.
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