1. The endocannabinoid system

2. The endocannabinoid system is a modulatory system • Endocannabinoids: • Synthesized on demand from lipid precursors in postsynaptic cell • Activate CB1 receptors presynaptically, then degrade immediately • Act as retrograde messengers • Inhibit neurotransmitter release • CB1 receptors: • Play a key role in energy balance and lipid and glucose metabolism Di Marzo V, Matias I. Nature Neurosci. 2005;8:585-589.Di Marzo V, Melck D, et al. Trends Neurosci. 1998;21:521-528.Wilson RI, Nicholl RA. Science. 2002;296:678-682.

3. Feeding activity ECS Central endocannabinoid system activity modulates animal feeding behaviour • Food deprivation raises and feeding lowers hypothalamic endocannabinoid levels1 • CB1 receptor deletion or antagonism blunts refeeding behaviour in fasted animals2 • Endocannabinoid injections into the ventromedial nucleus of the hypothalamus3 or the nucleus accumbens promotes feeding in satiated animals, which is blocked by rimonabant ECS: endocannabinoid system Kirkham TC, et al. Br J Pharmacol. 2002;136:550-557.Di Marzo V, et al. Nature. 2001;410:822-825.Jamshidi N, et al. Br J Pharmacol. 2001;134:1151-1154.

4. Brain Peripheral tissues Adipose Liver Muscle tissue GI tract Hypothalamus: Nucleus accumbens: ^ ^ hunger motivation to eat Insulin resistance ^ HDL-cholesterol Triglycerides ^ Increased food intake Glucose uptake Increased fat storage Adiponectin Central and peripheral targets of the endocannabinoid system and effects of overactivity HDL: high-density lipoprotein Bensaid M, Gary-Bobo M, etal. Mol Pharmacol. 2003;63:908-914.Pagotto U, Vicennati V, et al. Ann Med. 2005;37:270-275.Osei-Hyiaman D, DePetrillo M, et al. J Clin Invest. 2005;115:1298-1305.Di Marzo V, Matias I. Nature Neurosci. 2005;8:585-589.Liu YL, Connoley IP, et al. Int J Obes Relat Metab Disord. 2005;29:183-187.

5. Sites of CB1 receptors and potential effects of CB1 receptor blockade Di Marzo M, etal. Nature. 2001;410:822-825.Ravinet Trillou C, Arnone M, et al. Am J Physiol Regul Integr Comp Physiol. 2003;284:R345-353.Cota D, Marsicano G, et al. Int J Obes Relat Metab Disord. 2003;27:289-301.Pagotto U, Pasquali R. Lancet. 2005;365:1363-1364.Van Gaal L, et al. Lancet. 2005;365:1389-1397.Liu YL, et al. Int J Obes Relat Metab Disord.2005;29:183-187.Osei-Hyiaman D, DePetrillo, et al. Clin Invest. 2005;115:1298-1305.Massa F, et al.J Mol Med. 2005;83:944-954.

6.  SREBP1c High fat diet AEA*  CB1R  FA synthase  AcCoA cbxlase  FA oxidation  FA synthesis *Anandamide  Hepatic lipid content  VLDL production  Insulin resistance  Triglyceride flux CB1 blockade Hepatic endocannabinoid system dysregulation promotes hepatic lipogenesis and insulin resistance in diet-induce obesity mice Osei-Hyiaman D, et al. J Clin Invest, 2005:115:1298-1305.

7. Feeding ECS CB-1 blockade Weight Dyslipidaemia Type 2 diabetes Peripheral insulinresistance Hepatic insulinresistance Hepaticglucoseoutput Small,denseLDL-C LowHDL-C CETP,lipolysis Adiponectin Lipolysis FFA TG-richVLDL-C FFA Portal circulation ECS Liver Visceral fat ECS CB-1 blockade CB-1 blockade Central/peripheral endocannabinoid system dysregulation leads to weight-dependent and direct effects by CB1 blockade Weight-dependent Weight Independent Endocannabinoid system ECS Modified from: Lam TK, et al. Am J Physiol Endocrinol Metab. 2003;284:E863-8673. Carr D, et al. Diabetes. 2004 Aug;53(8):2087-2094. Eckel R, et al. Lancet. 2005;365(9468):1415-1428. Pagotto U, Pasquali R. Lancet. 2005;365:1363-1364. Di Marzo V, Matias I. Nature Neuroscience. 2005;8:585-589. FFA=free fatty acids CETP=cholesterol ester transfer protein