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

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

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

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

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

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

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 obesity1

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


Role of the dysregulated endocannabinoid system in determining cardiometabolic risk

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Role of the dysregulated endocannabinoid system in determining cardiometabolic risk

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