1. The Endocannabinoid System Role in energy homeostasis and peripheral lipid and glucose metabolism

2. Exogenous cannabinoids Plant-derived (phytocannabinoids) Δ 9 -Tetrahydro- cannabinol Synthetic cannabinoidsNabilone Endogenous cannabinoids EndocannabinoidsAnandamide 2-Arachidonoyl glycerol Cannabinoid classification with selected examples Pacher P et al. Pharmacol Rev. 2006;58:389-462. OH O O O NH OH O O O

3. ECS: Widely distributed with multiple cardiometabolic effects Central nervous systemPeripheral tissue AppetiteMotivation to eat Matias I, Di Marzo V. Trends Endocrinol Metab. 2007;18:27-37. Pagotto U et al. Endocr Rev. 2006;27:73-100. Satiety signals Fat storage Adipose tissue LiverGI tract Skeletal muscle HypothalamusLimbic system Lipid and glucose metabolism ECS = endocannabinoid system

4. Potential therapeutic implications of CB 1 receptor blockade Hollander P. Am J Med. 2007;120:S18-28. Site of actionMechanism(s)Addresses  Food intake Body weight Waist circumference  Glucose uptake Insulin resistance  Lipogenesis Dyslipidemia Insulin resistance  Satiety signals Body weight  Adiponectin  Lipogenesis Dyslipidemia Insulin resistance

5. Circulating 2-AG elevated in persons with visceral vs sc adiposity Blüher M et al. Diabetes. 2006;55:3053-60. 2-AG = 2-arachidonoyl glycerol 0 2 4 8 12 Lean (n = 20) sc obese (n = 20) Visceral obese (n = 20) 2-AG (pmol/mL) P < 0.01 P < 0.05 10 6

6. CB 1 receptor blockade blunts overeating in rats *P < 0.001 vs vehicle-only control Jamshidi N, Taylor DA. Br J Pharmacol. 2001;134:1151-4. 1.8 1.2 0.6 0 050 0 0030 Cumulative food intake (g/100 g body weight) Anandamide (ng) Rimonabant (  g) * Anandamide administered via injection to rat hypothalamus

7. Daily food intake (kcal) No difference in food intake after Day 8 Body weight (g) Body weight significantly reduced Courtesy of Pagotto U. 2007. CB 1 receptor blockade: Weight reduction independent of food intake in obese mice Treatment period (days) 0 5 10 15 20 Days 0816243240 26 30 34 38 42 * 0–80–89–1617–2425–3233–40 * *P < 0.01 HF diet vehHF diet + R 10 mg ST diet veh ST diet + R 10 mg

8. CB 1 receptor blockade modulates adipocyte function in mice Jbilo O et al. FASEB J. 2005;19:1567-9.  Adipose mass  Lipolysis  Energy expenditure  Glucose transporter-4 expression  Adiponectin mRNA  Pro-inflammatory genes

9. CB 1 receptors modulate liver lipogenesis in mice Osei-Hyiaman D et al. J Clin Invest. 2005;115:1298-305. Wild-type and CB 1 receptor knockout mice CB 1 +/+ CB 1 -/- Normal diet High-fat diet x 3 wks High-fat diet x 14 wks Fat deposition Fat deposition

10. CB 1 receptor blockade increases skeletal muscle glucose uptake in obese mice Isolated soleus muscle from genetically obese ob/ob mice Liu YL et al. Int J Obes. 2005;29:183-7. 0 5 10 15 20 25 30 Glucose uptake and phosphorylation (  mol/h per g)  68% VehicleRimonabant P < 0.05

11. CB 1 receptor blockade and mood: Range of effects observed in animal models Direct effects reported: Anxiolytic/antidepressant Neutral Anxiogenic Studies with antidepressants: No acute interaction with SSRI (fluoxetine) or tricyclic antidepressant (desipramine)* Transient  anxiety with chronic desipramine + CB 1 blocker use † Hypothalamus Limbic system Net effect? Gobshtis N et al. Eur J Pharmacol. 2007;554:155-63. Griebel G et al. Biol Psychiatry. 2005;57:261-7. *Porsolt forced swim test † Elevated plus maze assay

12. Endocannabinoid system overview Receptors and ligands of the ECS are widely distributed in both central and peripheral compartments Adiposity is associated with ECS overactivation Inhibition of the ECS modulates food intake and metabolic pathways through multiple mechanisms of action