1. Obesity and Endocannabioid system 이가영 M.D., Ph.D. 인제의대 부산백병원 가정의학과

3. Control of eating

4. Marijuana Cannabis sativa in India 1930s : antimarijuana attitude 1960s: ∆9-tetrahydrocannabioid

5. CH O-R 3 OH NHNH P O- O O O DAG Lipase Fatty Acid Amide Hydrolase Endocannabinoids (EC) (Endogenous Agonists of Cannabinoid Receptors): 1) Are produced as needed 2) Activate cannabinoid receptors locally 3) Are immediately metabolized Phospholipid-derived precursors Endocannabinoids Degradation products OH H2NH2N MAG Lipase O OH HO OH CH OH O O CH OH O NHNH Anandamide2-Arachidonoyl-glycerol NAPE-PLD Phospholipid Remodeling O R1OR1O O-R 2 O O

6. EC Agonists BrainAdiposeTissueMuscleLiverGITract ImmuneSystem CB 1 CB 2 2-Arachidonoylglycerol (2-AG)  9 -Tetrahydrocannabinol Anandamide (AEA) O O CH OH OH N H OH O O OH Receptors

7. EC System : Anabolic Effect ABSORPTION FEEDING METABOLISM TRANSPORT STORAGE Endo- cannabinoid System

8. Function of EC system 스트레스로 부터 회복 항상성 유지 신경 보호 통증감각 조절 운동기능 활발성 조절 기억과정 조절 면역과 염증 반응 완화 심박수, 혈압, 기관지 기능 조절 종양세포의 증식억제

9. Function of EC in brain 식욕 자극 음식을 섭취할 때 느끼는 희열이나 보상반응 강화 섭식의 탈억제 (Disinhibiting eating) – 맛있는 음식이 있으면 배가 불러도 더 먹게 될 때.. -suppress the satiating signial.

10. Neuron stimulated by palatable food or a positive hedonic situation Satiety signals activate the presynaptic neuron Disinhibiting Eating  More Food Is Ingested Neurotransmitter ECs + + – CB1 Presynaptic Neuron: Inhibits activity of post-synaptic neuron + Continued eating Postsynaptic Neuron: Prolongs eating during a meal

11. Central pathway of EC-related appetite stimulation 렙틴과 상호작용할 가능성 arcuate nucleus NPY neurons 의 식욕자 극 효과와는 관련이 없어 보임. mesolymbic dopaminergic system 과 상 호작용할 가능성 –Meal search 를 위한 동기형성과 관련 –This pathway is thought to be strongly involved in addictive behaviours, gambling and alcohol.

12. Kirkham TC et al. Br J Pharmacol. 2002;136:550-557 2-Arachidonoylglycerol (nmol/g Wet Tissue Weight) Control Feeding EC fluctuation in energy homeostatic region Satiated Deprived Control Feeding Satiated Deprived * p<0.05 * * Hypothalamus Cerebellum

13. Eating in Satiated Rats via CB1- Receptor Activation and Blocking Jamshidi N et al. Br J Pharmacol. 2001;134:1151-1154. Cumulative Food Intake (g/100 g Body Weight) *p<0.001 AEA (ng) Rimonabant ———— 50 — 150 — 30 50 30 Rimonabant * Injection of AEA at hypothalamus

14. *p<0.0001 Kirkham TC et al. Br J Pharmacol. 2002;136:550-557 Eating in Satiated Rats via CB1- Receptor Activation and Blocking 1-hour Food Intake (g) 2-AG Dose Administered to NAC **p<0. 01 Rimonabant 0.5 + Rimonabant 00.1250.5 * ** Injection of 2-AG into the Nucleus Accumbens (NAC) in the Limbic System

15. * ** CB1-Receptor Antagonism or Deletion Di Marzo V et al. Nature. 2001;410:822-825. Food Intake (g) WT + Vehicle †† † P < 0.01 P < 0.05 P < 0.01 WT + Rimonabant CB1 Knockout (KO) + Rimonabant CB1 KO + Vehicle 0123 Hours * * † †† ** After deprivation

16. CB1 Receptor – KO Mice : Less Wt gain Ravinet Trillou C, et al. Int J Obes Relat Metab Disord. 2004;28:640-648. Body Weight (g) 0 Days WT – HFD WT–Std D KO–HFD KO–Std D * P < 0.05 ** P < 0.01 1234567891011 (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) * * * * **

17. CB1 Receptor – KO Mice : Reduced Insulin Resistance Ravinet Trillou C et al. Int J Obes Relat Metab Disord. 2004;28:640-648. AUC (0–180) *p<0.01 * Insulin Resistance Index KO–Std DWT–Std DKO–HFD WT–HFD

18. Vehicle RimonabantCombo CB1 Agonism EC Induce lipogenesis in liver Steroid Response Element Binding Protein-1c mRNA (% of control) Osei-Hyiaman D et al. J Clin Invest. 2005;115:1298-1305. Acetyl-CoA Carboxylase (% of control) Fatty Acid Synthase mRNA (% of control) * * *

19. Standard Diet High Fat Diet x 3 weeks High Fat Diet x 14 weeks CB1 Receptor – KO Mice and Hepatosteatosis Osei-Hyiaman D et al. J Clin Invest. 2005;115:1298-1305. CB1 +/+ CB1 –/–

20. –––– +–+– ++++ CB1-Receptor and Adipocyte Lipoprotein Lipase Activity LPL Activity (% of control) *p<0.05 †p<0.05 CB1 Agonism Rimonabant * Primary Culture of Mouse Adipocytes Cota D et al. J Clin Invest. 2003;112:423-431. –+–+ †

21. Adipocyte CB1-Receptor mRNA in Adipose tissue Bensaid M et al. Mol Pharmacol. 2003;63:908-914. CB1 mRNA (arbitrary units) Obese Zucker Rats Lean Zucker Rats Undiff adipose cell Diff adipose cell In white adipose tissue In mouse 3T3 F442A adipocyte cells

22. Summary of Animal Experiments Energy balance –EC blockade : ↓ food intake and body weight –CB1 knockout mouse : resistance to diet-inducd obesity Feeding behavior –Stimulation of CB1 R: ↑ food intake –CB1 Blockade : ↓ Food intake Glucose metabolism –CB1 KO mouse: Low insulin resistance induced by HFD Hepatic lipogenesis –EC activation and high fat diet : ↑ hepatic lipogenic enzyme –CB1 Blockade attenuate these changes. –CB1 KO mouse: resistant to increased hepatic lipogenic enzyme expression and as the resulting fatty liver by HFD. Adipose tissue –EC activation : ↑ LPL activity –CB1 Blockade attenuate these changes. Increased expression of CB1 receptors in obesity

24. Endocannabinoid Dysregulation in Human Obesity Engeli S et al. Diabetes. 2005;54:2838-2843. Lean Plasma AEA and 2-AG Are Elevated in Obesity AEA (pmol/ml) 2-AG (pmol/ml) ObeseLeanObese *p<0.05 * *

25. EC antagonist effect in human

26. Rimonabant In Obesity (RIO) program RIO-EuropeRIO-LipidsRIO-NARIO-Diabetes N = 1507 BMI ≥30 kg/m 2 or >27 kg/m 2 with comorbidity* N = 1033 BMI 27 – 40 kg/m 2 and dyslipidemia N = 3045 BMI ≥30 kg/m 2 or >27 kg/m 2 with comorbidity* N = 1045 BMI 27 – 40 kg/m 2 and type 2 diabetes 1 year 2 years1 year Randomized, double-blind, placebo-controlled evaluations of rimonabant 5 mg or 20 mg qd added to hypocaloric diet (600 kcal/day deficit) † Weight, waist circumference, metabolic syndrome, and cardiometabolic risk factors assessed Després J-P et al. N Engl J Med. 2005. Pi-Sunyer FX et al. JAMA. 2006. Gelfand EV et al. J Am Coll Cardiol. 2006.

27. RIO clinical trial program: Efficacy overview Rimonabant 5 mg (range) Rimonabant 20 mg (range) Weight (lbs) ↓ 2.9 – 3.6* ↓ 10.4 – 12.0* Waist (in) ↓ 0.2 – 0.6 ↓ 1.4 – 1.9* HDL-C (%) ↑ 2.3 – 3.2 ↑ 7.2 – 8.7* TG (%) ↓ 4.2 –↑ 1.4 ↓ 12.4 – 13.2* Insulin resistance (%) ↓ 0.4 – 0.6 ↓ 0.7 – 0.8* CRP (mg/L) ↑ 0.2 ↓ 0.5 † Adiponectin ( μ g/mL) ↑ 0.3 ↑ 1.5* RIO-Europe, RIO-Lipids, RIO-NA; Placebo-corrected change from baseline at 1 year Van Gaal LF et al. Lancet. 2005. Després J-P et al. N Engl J Med. 2005. Pi-Sunyer FX et al. JAMA. 2006.

28. ↓54% 42.2 52.9 34.8 * 21.2 * 25.8 * 19.6 0 10 20 30 40 50 60 RIO-EuropeRIO-LipidsRIO-NA Patients (%) Baseline1 year Significant decrease in metabolic syndrome Van Gaal LF et al. Lancet. 2005. Després J-P et al. N Engl J Med. 2005. Pi-Sunyer FX et al. JAMA. 2006. Rimonabant 20 mg ↓51% ↓39% (n = 599)(n = 346)(n = 1222) ATP III criteria *P < 0.001 vs placebo

29. RIO clinical trial program: Safety and tolerability overview Most common drug-related adverse event was mild nausea –Rimonabant 5 mg (5.1%–7.2%); 20 mg (11.2%– 12.9%) Adverse event-related discontinuation rate was similar or slightly higher vs placebo –Rimonabant 5 mg (8.3%–9.4%); 20 mg (12.8%– 15.0%); placebo (7.0%–9.2%) Changes in anxiety and depression scores were similar across treatment and placebo groups Van Gaal LF et al. Lancet. 2005. Després J-P et al. N Engl J Med. 2005. Pi-Sunyer FX et al. JAMA. 2006.

30. FDA panel rejects a new weight- loss drug Federal health advisers unanimously rejected a weight-loss drug Wednesday after hearing testimony that it increases the risk of suicidal thoughts, even in patients without a history of depression.