The endocannabinoid system

1
The endocannabinoid system
2
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.
20058585-589.Di Marzo V, Melck D, et al.
Trends Neurosci. 199821521-528.Wilson RI,
Nicholl RA. Science. 2002296678-682.
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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.
2002136550-557.Di Marzo V, et al. Nature.
2001410822-825.Jamshidi N, et al. Br J
Pharmacol. 20011341151-1154.
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Central and peripheral targets of the
endocannabinoid system and effects of overactivity
HDL high-density lipoprotein
Bensaid M, Gary-Bobo M, et al. Mol Pharmacol.
200363908-914.Pagotto U, Vicennati V, et al.
Ann Med. 200537270-275.Osei-Hyiaman D,
DePetrillo M, et al. J Clin Invest.
20051151298-1305.Di Marzo V, Matias I. Nature
Neurosci. 20058585-589.Liu YL, Connoley IP, et
al. Int J Obes Relat Metab Disord.
200529183-187.
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Sites of CB1 receptors and potential effects of
CB1 receptor blockade
Di Marzo M, et al. Nature. 2001410822-825.Ravin
et Trillou C, Arnone M, et al. Am J Physiol Regul
Integr Comp Physiol. 2003284R345-353.Cota D,
Marsicano G, et al. Int J Obes Relat Metab
Disord. 200327289-301.Pagotto U, Pasquali R.
Lancet. 20053651363-1364.Van Gaal L, et al.
Lancet. 20053651389-1397.Liu YL, et al. Int J
Obes Relat Metab Disord.200529183-187.Osei-Hyia
man D, DePetrillo, et al. Clin Invest.
20051151298-1305.Massa F, et al. J Mol Med.
200583944-954.
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Hepatic endocannabinoid system dysregulation
promotes hepatic lipogenesis and insulin
resistance in diet-induce obesity mice
Osei-Hyiaman D, et al. J Clin Invest,
20051151298-1305.
7
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. 2003284E863-8673. Carr D, et
al. Diabetes. 2004 Aug53(8)2087-2094. Eckel R,
et al. Lancet. 2005365(9468)1415-1428. Pagotto
U, Pasquali R. Lancet. 20053651363-1364. Di
Marzo V, Matias I. Nature Neuroscience.
20058585-589.
FFAfree fatty acids CETPcholesterol ester
transfer protein