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The Endocannabinoid System

The Endocannabinoid System. Role in energy homeostasis and peripheral lipid and glucose metabolism. Cannabinoid classification with selected examples. OH. O. O. O. OH. O. OH. O. OH. NH. O. OH. Pacher P et al. Pharmacol Rev. 2006;58:389-462.

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The Endocannabinoid System

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

  2. Cannabinoid classification with selected examples OH O O O OH O OH O OH NH O OH Pacher P et al. Pharmacol Rev. 2006;58:389-462.

  3. ECS: Widely distributed with multiple cardiometabolic effects Central nervous system Peripheral tissue Liver GI tract Adipose tissue Skeletal muscle Hypothalamus Limbic system Satiety signalsFat storage Lipid and glucose metabolism Appetite Motivation to eat Matias I, Di Marzo V. Trends Endocrinol Metab. 2007;18:27-37.Pagotto U et al. Endocr Rev. 2006;27:73-100. ECS = endocannabinoid system

  4. Potential therapeutic implications of CB1 receptor blockade Site of action Mechanism(s) Addresses Food intake Body weightWaist circumference AdiponectinLipogenesis DyslipidemiaInsulin resistance Glucose uptake Insulin resistance Lipogenesis DyslipidemiaInsulin resistance Satiety signals Body weight Hollander P. Am J Med. 2007;120:S18-28.

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

  6. CB1 receptor blockade blunts overeating in rats Anandamide administered via injection to rat hypothalamus 1.8 * Cumulative food intake (g/100 g body weight) 1.2 0.6 0 Anandamide (ng) 0 50 0 50 Rimonabant (g) 0 0 30 30 *P < 0.001 vs vehicle-only control Jamshidi N, Taylor DA. Br J Pharmacol. 2001;134:1151-4.

  7. CB1 receptor blockade: Weight reduction independent of food intake in obese mice No difference in food intake after Day 8 Body weight significantly reduced 20 42 15 38 Daily food intake (kcal) Body weight(g) * 10 * 34 5 30 26 0 0–8 9–16 17–24 25–32 33–40 0 8 16 24 32 40 Treatment period (days) Days ST diet + R 10 mg HF diet veh HF diet + R 10 mg ST diet veh *P < 0.01 Courtesy of Pagotto U. 2007.

  8. CB1 receptor blockade modulates adipocyte function in mice Adipose massLipolysisEnergy expenditureGlucose transporter-4 expression Adiponectin mRNA Pro-inflammatory genes Jbilo O et al. FASEB J. 2005;19:1567-9.

  9. CB1 receptors modulate liver lipogenesis in mice Wild-type and CB1 receptor knockout mice CB1+/+ CB1-/- Normal diet Fat deposition High-fat diet x 3 wks Fat deposition High-fat diet x 14 wks Osei-Hyiaman D et al. J Clin Invest. 2005;115:1298-305.

  10. CB1 receptor blockade increases skeletal muscle glucose uptake in obese mice Isolated soleus muscle from genetically obese ob/ob mice 30 68% P < 0.05 25 Glucose uptakeand phosphorylation(mol/h per g) 20 15 10 5 0 Vehicle Rimonabant Liu YL et al. Int J Obes.2005;29:183-7.

  11. 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 + CB1 blocker use† CB1 receptor blockade and mood: Range of effects observed in animal models Limbic system Hypothalamus Net effect? *Porsolt forced swim test†Elevated plus maze assay Gobshtis N et al. Eur J Pharmacol. 2007;554:155-63. Griebel G et al. Biol Psychiatry. 2005;57:261-7.

  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

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