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