Source: International Chair on Cardiometabolic Risk Role of the Dysregulated Endocannabinoid System in Determining Cardiometabolic Risk Vincenzo Di Marzo, PhD Istituto di Chimica Biomolecolare Pozzuoli (NA), Italy

Source: International Chair on Cardiometabolic Risk Endocannabinoids (Endogenous Agonists of Cannabinoid Receptors) Phospholipid-derived precursors Endocannabinoids Degradation products NAPE-PLD DAG Lipase O 2-arachidonoylglycerol O Anandamide NHNH OH H2NH2N O Fatty Acid Amide Hydrolase MAG Lipase NH O O Phospholipid Remodelling O OH HO OH CH OH O CH OH O O CH R3R3 P O O O OR2R2 R1OR1O DAG Lipase : diacylglycerol lipase MAG Lipase : monoacylglycerol lipase NAPE-PLD : N-acylphosphatidyethanolamine-hydrolyzing phospholipase D 1) are produced “on demand” 2) activate cannabinoid receptors locally 3) are immediately metabolized

Source: International Chair on Cardiometabolic Risk The CB1 Receptor Stimulates Adipocyte Differentiation and Lipogenesis Adapted from Matias I et al. J Clin Endocrinol Metab 2006; 91: Reproduced with permission *** p<0.005 vs. vehicle ## p<0.01 vs. HU210 HU210: cannabinoid receptor agonist SR1: rimonabant Forskolin 1  M HU nM HU nM SR1 20nM SR1 200nM HU210 SR1 20nM HU210 SR1 200nM % forskolin-induced cAMP inhibition

Source: International Chair on Cardiometabolic Risk Overactive Endocannabinoid System in Adipose Tissue and Liver of Mice with Diet-Induced Obesity Adapted from Osei-Hyiaman D et al. J Clin Invest 2005; 115: AEA: anandamide 2-AG: 2-arachidonoylglycerol Adapted from Matias I et al. J Clin Endocrinol Metab 2006; 91: Reproduced with permission Anandamide (pmol/g)2-AG (nmol/g)

Source: International Chair on Cardiometabolic Risk The Overactive Endocannabinoid System in Human Obesity and Type 2 Diabetes 2-AG: 2-arachidonoylglycerol BED: binge-eating disorder Adapted from Matias I et al. J Clin Endocrinol Metab 2006; 91: Reproduced with permission ** p≤0.01 vs. visceral fat from normoweight volunteers ## p≤0.01 vs. visceral fat from obese patients Fat of obese patients Blood of type 2 diabetic patients ** p≤0.01 vs. controls *** p≤0.005 vs. controls p<0.005 Anandamide (pmol/ml) Blood of obese women From Monteleone P et al. Neuropsychopharmacology 2005; 30: Reproduced with permission

Source: International Chair on Cardiometabolic Risk Metabolic Effects of CB1 Blockade in Mice with Diet- Induced Obesity Adapted from Ravinet Trillou C et al. Am J Physiol Integr Comp Physiol 2003; 284: R345-5 Reproduced with permission 10 mg/kg/day for five weeks in HFD Mice STD-veh: standard diet vehicle HFD-veh: high fat diet vehicle HFD-SR10 mg: high fat diet + rimonabant 10 mg * p<0.001 vs. STD-veh ** p<0.001 vs. HFD-veh * **

Source: International Chair on Cardiometabolic Risk Metabolic Effects of CB1 Blockade in Mice with Diet- Induced Obesity Adapted from Poirier B et al. Diabetes Obes Metab 2005; 7: (Weeks) Standard diet (STD) High fat diet (HFD) STD Switched to STD HFD + Vehicle HFD + Rimonabant Lipoprotein cholesterol distribution in obese mice following a 10-week treatment with rimonabant HFD + Rimonabant Switched to STD vehicle STD vehicle HFD vehicle * p<0.001 vs. other groups † p<0.01 vs. STD groups ‡ p<0.05 vs. STD vehicle group grams Body weight ‡ * HDL-C † mmol/l HDL/LDL * ‡ LDL-CTG mmol/l * * HDL-C: HDL cholesterol HDL/LDL: HDL cholesterol/LDL cholesterol LDL-C: LDL cholesterol TG: triglycerides

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Source: International Chair on Cardiometabolic Risk 