The endocannabinoid system
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The endocannabinoid system The endocannabinoid system is a modulatory system Endocannabinoids: Synthesized on demand from lipid precursors in postsynaptic cell Activate CB 1 receptors presynaptically, then degrade immediately Act as retrograde messengers

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The endocannabinoid system is a modulatory system l.jpg
The endocannabinoid system is a modulatory system

  • Endocannabinoids:

    • Synthesized on demand from lipid precursors in postsynaptic cell

    • Activate CB1 receptors presynaptically, then degrade immediately

    • Act as retrograde messengers

    • Inhibit neurotransmitter release

  • CB1 receptors:

    • Play a key role in energy balance and lipid and glucose metabolism

Di Marzo V, Matias I. Nature Neurosci. 2005;8:585-589.Di Marzo V, Melck D, et al. Trends Neurosci. 1998;21:521-528.Wilson RI, Nicholl RA. Science. 2002;296:678-682.


Central endocannabinoid system activity modulates animal feeding behaviour l.jpg

Feeding activity

ECS

Central endocannabinoid system activity modulates animal feeding behaviour

  • Food deprivation raises and feeding lowers hypothalamic endocannabinoid levels1

  • CB1 receptor deletion or antagonism blunts refeeding behaviour in fasted animals2

  • Endocannabinoid injections into the ventromedial nucleus of the hypothalamus3 or the nucleus accumbens promotes feeding in satiated animals, which is blocked by rimonabant

ECS: endocannabinoid system

Kirkham TC, et al. Br J Pharmacol. 2002;136:550-557.Di Marzo V, et al. Nature. 2001;410:822-825.Jamshidi N, et al. Br J Pharmacol. 2001;134:1151-1154.


Central and peripheral targets of the endocannabinoid system and effects of overactivity l.jpg

Brain

Peripheral tissues

Adipose

Liver

Muscle

tissue

GI tract

Hypothalamus:

Nucleus accumbens:

^

^

hunger

motivation to eat

Insulin resistance

^

HDL-cholesterol

Triglycerides

^

Increased food intake

Glucose uptake

Increased fat storage

Adiponectin

Central and peripheral targets of the endocannabinoid system and effects of overactivity

HDL: high-density lipoprotein

Bensaid M, Gary-Bobo M, etal. Mol Pharmacol. 2003;63:908-914.Pagotto U, Vicennati V, et al. Ann Med. 2005;37:270-275.Osei-Hyiaman D, DePetrillo M, et al. J Clin Invest. 2005;115:1298-1305.Di Marzo V, Matias I. Nature Neurosci. 2005;8:585-589.Liu YL, Connoley IP, et al. Int J Obes Relat Metab Disord. 2005;29:183-187.


Sites of cb 1 receptors and potential effects of cb 1 receptor blockade l.jpg
Sites of CB1 receptors and potential effects of CB1 receptor blockade

Di Marzo M, etal. Nature. 2001;410:822-825.Ravinet Trillou C, Arnone M, et al. Am J Physiol Regul Integr Comp Physiol. 2003;284:R345-353.Cota D, Marsicano G, et al. Int J Obes Relat Metab Disord. 2003;27:289-301.Pagotto U, Pasquali R. Lancet. 2005;365:1363-1364.Van Gaal L, et al. Lancet. 2005;365:1389-1397.Liu YL, et al. Int J Obes Relat Metab Disord.2005;29:183-187.Osei-Hyiaman D, DePetrillo, et al. Clin Invest. 2005;115:1298-1305.Massa F, et al.J Mol Med. 2005;83:944-954.


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 SREBP1c

High fat diet

AEA*

 CB1R

 FA synthase

 AcCoA cbxlase

 FA oxidation

 FA synthesis

*Anandamide

 Hepatic lipid content

 VLDL production

 Insulin resistance

 Triglyceride flux

CB1 blockade

Hepatic endocannabinoid system dysregulation promotes hepatic lipogenesis and insulin resistance in diet-induce obesity mice

Osei-Hyiaman D, et al. J Clin Invest, 2005:115:1298-1305.


Slide7 l.jpg

Feeding

ECS

CB-1 blockade

Weight

Dyslipidaemia

Type 2 diabetes

Peripheral insulinresistance

Hepatic insulinresistance

Hepaticglucoseoutput

Small,denseLDL-C

LowHDL-C

CETP,lipolysis

Adiponectin

Lipolysis

FFA

TG-richVLDL-C

FFA

Portal circulation

ECS

Liver

Visceral fat

ECS

CB-1 blockade

CB-1 blockade

Central/peripheral endocannabinoid system dysregulation leads to weight-dependent and direct effects by CB1 blockade

Weight-dependent

Weight Independent

Endocannabinoid system

ECS

Modified from: Lam TK, et al. Am J Physiol Endocrinol Metab. 2003;284:E863-8673.

Carr D, et al. Diabetes. 2004 Aug;53(8):2087-2094.

Eckel R, et al. Lancet. 2005;365(9468):1415-1428.

Pagotto U, Pasquali R. Lancet. 2005;365:1363-1364.

Di Marzo V, Matias I. Nature Neuroscience. 2005;8:585-589.

FFA=free fatty acids

CETP=cholesterol

ester transfer protein


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