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The EndocannabinoidSystem
Role in energy homeostasis and peripheral lipid and glucose metabolism
Exogenous cannabinoids
Plant-derived (phytocannabinoids)
Δ9-Tetrahydro-cannabinol
Synthetic cannabinoids Nabilone
Endogenous cannabinoids
Endocannabinoids Anandamide
2-Arachidonoyl glycerol
Cannabinoid classification with selected examples
Pacher P et al. Pharmacol Rev. 2006;58:389-462.
OH
O
OH
O
O
NHOH
O
OOH
O
OH
ECS: Widely distributed with multiple cardiometabolic effects
Central nervous system Peripheral tissue
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.
Satiety signalsFat storage
Adipose tissue
Liver GI tract
Skeletal muscle
Hypothalamus Limbic system
Lipid and glucose metabolism
ECS = endocannabinoid system
Potential therapeutic implications of CB1 receptor blockade
Hollander P. Am J Med. 2007;120:S18-28.
Site of action Mechanism(s) Addresses
Food intake Body weightWaist circumference
Glucose uptake Insulin resistance
Lipogenesis DyslipidemiaInsulin resistance
Satiety signals Body weight
AdiponectinLipogenesis
DyslipidemiaInsulin resistance
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
CB1 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
0 50 500
0 0 30 30
Cumulativefood intake
(g/100 g body weight)
Anandamide (ng)
Rimonabant (g)
*
Anandamide administered via injection to rat hypothalamus
Daily food intake (kcal)
No difference in food intake after Day 8
Body weight
(g)
Body weight significantly reduced
Courtesy of Pagotto U. 2007.
CB1 receptor blockade: Weight reduction independent of food intake in obese mice
Treatment period (days)
0
5
10
15
20
Days0 8 16 24 32 40
26
30
34
38
42
*
0–8 9–16 17–24 25–32 33–40
*
*P < 0.01
HF diet veh HF diet + R 10 mg ST diet veh ST diet + R 10 mg
CB1 receptor blockade modulates adipocyte function in mice
Jbilo O et al. FASEB J. 2005;19:1567-9.
Adipose massLipolysisEnergy expenditureGlucose transporter-4 expression
Adiponectin mRNA
Pro-inflammatory genes
CB1 receptors modulate liver lipogenesis in mice
Osei-Hyiaman D et al. J Clin Invest. 2005;115:1298-305.
Wild-type and CB1 receptor knockout mice
CB1+/+ CB1
-/-
Normal diet
High-fat diet x 3 wks
High-fat diet x 14 wks
Fat deposition
Fat deposition
CB1 receptor blockade increases skeletal muscle glucose uptake in obese miceIsolated 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 uptakeand phosphorylation
(mol/h per g)
68%
Vehicle Rimonabant
P < 0.05
CB1 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 + CB1 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
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