Role of the Dysregulated Endocannabinoid System in Determining Cardiometabolic Risk

1. Role of the Dysregulated Endocannabinoid System in Determining Cardiometabolic Risk Vincenzo Di Marzo, PhDIstituto di Chimica BiomolecolarePozzuoli (NA), Italy

2. Endocannabinoids (Endogenous Agonists of Cannabinoid Receptors) Phospholipid-derivedprecursors Endocannabinoids Degradation products Phospholipid Remodelling R1O O R2 O R3 O P O CH O O O OH NAPE-PLD DAG Lipase OH OH O O O O NH Anandamide 2-arachidonoylglycerol O NH Fatty Acid Amide Hydrolase MAG Lipase OH OH OH CH CH HO O H2N OH OH 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

3. The CB1 Receptor Stimulates Adipocyte Differentiation and Lipogenesis % forskolin-induced cAMP inhibition Forskolin 1M HU21020 nM HU210200 nM SR120nM SR1200nM HU210 SR1 20nM HU210 SR1 200nM HU210: cannabinoid receptor agonist SR1: rimonabant *** p<0.005 vs. vehicle ## p<0.01 vs. HU210 Adapted from Matias I et al. J Clin Endocrinol Metab 2006; 91: 3171-80 Reproduced with permission

4. Overactive Endocannabinoid System in Adipose Tissue and Liver of Mice with Diet-Induced Obesity 1.6 1.2 Anandamide (pmol/g) 2-AG (nmol/g) 0.8 Adapted from Matias I et al. J Clin Endocrinol Metab 2006; 91: 3171-80 Reproduced with permission 0.4 0.0 AEA: anandamide2-AG: 2-arachidonoylglycerol Adapted from Osei-Hyiaman D et al. J Clin Invest 2005; 115: 1298-1305

5. The Overactive Endocannabinoid System in Human Obesity and Type 2 Diabetes Blood of type 2 diabetic patients Blood of obese women Fat of obese patients p<0.005 Anandamide (pmol/ml) ** p≤0.01 vs. controls *** p≤0.005 vs. controls ** p≤0.01 vs. visceral fat from normoweight volunteers ## p≤0.01 vs. visceral fat from obese patients Adapted from Matias I et al. J Clin Endocrinol Metab 2006; 91: 3171-80 Reproduced with permission From Monteleone P et al. Neuropsychopharmacology 2005; 30: 1216-21 Reproduced with permission 2-AG: 2-arachidonoylglycerol BED: binge-eating disorder

6. Metabolic Effects of CB1 Blockade in Mice with Diet-Induced Obesity 10 mg/kg/day for five weeks in HFD Mice * p<0.001 vs. STD-veh** p<0.001 vs. HFD-veh 2.0 * 1.6 1.2 ** 0.8 0.4 0.0 STD-veh: standard diet vehicle HFD-veh: high fat diet vehicle HFD-SR10 mg: high fat diet + rimonabant 10 mg Adapted from Ravinet Trillou C et al. Am J Physiol Integr Comp Physiol 2003; 284: R345-5 Reproduced with permission

7. Metabolic Effects of CB1 Blockade in Mice with Diet-Induced Obesity Lipoprotein cholesterol distribution in obese mice following a 10-week treatment with rimonabant 6 * p<0.001 vs. other groups† p<0.01 vs. STD groups‡ p<0.05 vs. STD vehicle group * 50 4 † † grams 40 mmol/l ‡ STD 2 Switched to STD 30 Standard diet (STD) HFD + Vehicle High fat diet (HFD) 20 0 Body weight HDL-C HFD + Rimonabant 0 24 0 24 34 (Weeks) ‡ 12 12 1.00 * 0.75 10 10 mmol/l * 0.50 8 8 0.25 * STD vehicle HFD vehicle HFD + Rimonabant Switched to STD vehicle HDL-C: HDL cholesterol HDL/LDL: HDL cholesterol/LDL cholesterol LDL-C: LDL cholesterol TG: triglycerides 6 6 0.00 LDL-C TG HDL/LDL Adapted from Poirier B et al. Diabetes Obes Metab 2005; 7: 65-72

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9. www.cardiometabolic-risk.org