The Endocannabinoid
System
Role in energy homeostasis and peripheral
lipid and glucose metabolism
Cannabinoid classification with selected
examples
OH
Exogenous
cannabinoids
Plant-derived
(phytocannabinoids)
Δ9-Tetrahydrocannabinol
O
O
Synthetic cannabinoids
OH
Nabilone
O
Endogenous
cannabinoids
Endocannabinoids
Anandamide
O
OH
NH
2-Arachidonoyl
glycerol
O
OH
O
OH
Pacher P et al. Pharmacol Rev. 2006;58:389-462.
ECS: Widely distributed with multiple
cardiometabolic effects
Central nervous system
Peripheral tissue
Liver
Adipose tissue
Hypothalamus
Limbic
system
Appetite
Motivation
to eat
ECS = endocannabinoid system
Satiety signals
Fat storage
GI tract
Skeletal muscle
Lipid and glucose
metabolism
Matias I, Di Marzo V. Trends Endocrinol Metab. 2007;18:27-37.
Pagotto U et al. Endocr Rev. 2006;27:73-100.
Potential therapeutic implications of CB1
receptor blockade
Site of action
Mechanism(s)
Addresses
Food intake
Body weight
Waist circumference
Adiponectin
Lipogenesis
Dyslipidemia
Insulin resistance
Glucose uptake
Insulin resistance
Lipogenesis
Dyslipidemia
Insulin resistance
Satiety signals
Body weight
Hollander P. Am J Med. 2007;120:S18-28.
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)
2-AG = 2-arachidonoyl glycerol
sc obese
(n = 20)
Visceral obese
(n = 20)
Blüher M et al. Diabetes. 2006;55:3053-60.
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)
Rimonabant (g)
*P < 0.001 vs vehicle-only control
0
0
50
0
0
30
50
30
Jamshidi N, Taylor DA. Br J Pharmacol. 2001;134:1151-4.
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
10
(kcal)
Body
weight
(g)
*
5
30
0
26
0–8 9–16 17–24 25–32 33–40
Treatment period (days)
HF diet veh
*P < 0.01
HF diet + R 10 mg
*
34
0
ST diet veh
8
16
24
Days
32
40
ST diet + R 10 mg
Courtesy of Pagotto U. 2007.
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.
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.
CB1 receptor blockade increases skeletal muscle
glucose uptake in obese mice
Isolated soleus muscle from genetically obese ob/ob mice
30
68%
25
Glucose uptake
and phosphorylation
(mol/h per g)
P < 0.05
20
15
10
5
0
Vehicle
Rimonabant
Liu YL et al. Int J Obes. 2005;29:183-7.
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†
*Porsolt forced swim test
†Elevated plus maze assay
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.
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