Role of the dysregulated endocannabinoid system in determining cardiometabolic risk
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Role of the Dysregulated Endocannabinoid System in Determining Cardiometabolic Risk. Vincenzo Di Marzo, PhD Istituto di Chimica Biomolecolare Pozzuoli (NA), Italy. Endocannabinoids (Endogenous Agonists of Cannabinoid Receptors). Phospholipid-derived precursors Endocannabinoids

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Role of the Dysregulated Endocannabinoid System in Determining Cardiometabolic Risk

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Role of the Dysregulated Endocannabinoid System in Determining Cardiometabolic Risk

Vincenzo Di Marzo, PhDIstituto di Chimica BiomolecolarePozzuoli (NA), Italy


Endocannabinoids (Endogenous Agonists of Cannabinoid Receptors)

Phospholipid-derivedprecursors

Endocannabinoids

Degradation products

Phospholipid Remodelling

R1O

O

R2

O

R3

O

P

O

CH

O

O

O

OH

NAPE-PLD

DAG Lipase

OH

OH

O

O

O

O

NH

Anandamide

2-arachidonoylglycerol

O

NH

Fatty Acid Amide Hydrolase

MAG Lipase

OH

OH

OH

CH

CH

HO

O

H2N

OH

OH

DAG Lipase : diacylglycerol lipase

MAG Lipase : monoacylglycerol lipase

NAPE-PLD : N-acylphosphatidyethanolamine-hydrolyzing phospholipase D

1) are produced “on demand”

2) activate cannabinoid receptors locally

3) are immediately metabolized


The CB1 Receptor Stimulates Adipocyte Differentiation and Lipogenesis

% forskolin-induced cAMP inhibition

Forskolin 1M

HU21020 nM

HU210200 nM

SR120nM

SR1200nM

HU210 SR1 20nM

HU210 SR1 200nM

HU210: cannabinoid receptor agonist

SR1: rimonabant

*** p<0.005 vs. vehicle

## p<0.01 vs. HU210

Adapted from Matias I et al. J Clin Endocrinol Metab 2006; 91: 3171-80

Reproduced with permission


Overactive Endocannabinoid System in Adipose Tissue and Liver of Mice with Diet-Induced Obesity

1.6

1.2

Anandamide (pmol/g)

2-AG (nmol/g)

0.8

Adapted from Matias I et al. J Clin Endocrinol Metab 2006; 91: 3171-80

Reproduced with permission

0.4

0.0

AEA: anandamide2-AG: 2-arachidonoylglycerol

Adapted from Osei-Hyiaman D et al. J Clin Invest 2005; 115: 1298-1305


The Overactive Endocannabinoid System in Human Obesity and Type 2 Diabetes

Blood of type 2 diabetic patients

Blood of obese women

Fat of obese patients

p<0.005

Anandamide (pmol/ml)

** p≤0.01 vs. controls

*** p≤0.005 vs. controls

** p≤0.01 vs. visceral fat from normoweight volunteers

## p≤0.01 vs. visceral fat from obese patients

Adapted from Matias I et al. J Clin Endocrinol Metab 2006; 91: 3171-80

Reproduced with permission

From Monteleone P et al. Neuropsychopharmacology 2005; 30: 1216-21

Reproduced with permission

2-AG: 2-arachidonoylglycerol

BED: binge-eating disorder


Metabolic Effects of CB1 Blockade in Mice with Diet-Induced Obesity

10 mg/kg/day for five weeks in HFD Mice

* p<0.001 vs. STD-veh** p<0.001 vs. HFD-veh

2.0

*

1.6

1.2

**

0.8

0.4

0.0

STD-veh: standard diet vehicle

HFD-veh: high fat diet vehicle

HFD-SR10 mg: high fat diet + rimonabant 10 mg

Adapted from Ravinet Trillou C et al. Am J Physiol Integr Comp Physiol 2003; 284: R345-5

Reproduced with permission


Metabolic Effects of CB1 Blockade in Mice with Diet-Induced Obesity

Lipoprotein cholesterol distribution in obese mice following a 10-week treatment with rimonabant

6

* p<0.001 vs. other groups† p<0.01 vs. STD groups‡ p<0.05 vs. STD vehicle group

*

50

4

† †

grams

40

mmol/l

STD

2

Switched to STD

30

Standard diet (STD)

HFD + Vehicle

High fat diet (HFD)

20

0

Body weight

HDL-C

HFD + Rimonabant

0 24

0 24

34

(Weeks)

12

12

1.00

*

0.75

10

10

mmol/l

*

0.50

8

8

0.25

*

STD vehicle

HFD vehicle

HFD + Rimonabant

Switched to STD vehicle

HDL-C: HDL cholesterol

HDL/LDL: HDL cholesterol/LDL cholesterol

LDL-C: LDL cholesterol

TG: triglycerides

6

6

0.00

LDL-C

TG

HDL/LDL

Adapted from Poirier B et al. Diabetes Obes Metab 2005; 7: 65-72


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