Endogenous Cannabinoids
Lipids Signaling

Author: Gianpiero Pescarmona
Date: 26/11/2007


2013-03-21T19:25:49 - andrea michelauz



Mammals have an adaptive advantage in seeking fat-rich foods, which are nutritionally essential but scarce in most natural habitats. However, when it is not limited by environmental constraints, this innate preference can become maladaptive.
Indeed, the unrestricted availability of fatty foods, which characterizes diets of industrialized societies, is considered to be a key contributing factor for obesity, diabetes, and cardiovascular disease.
This abuse is related with the release of endocannabinoides that brings to an actual addiction to fat-rich foods.
New frontiers in endocrinology of eating disorders,2011

The endocannabinoids are a family of biologically active lipids that bind to and activate cannabinoid receptors (CB1 - CB2), the Gi protein-coupled receptors targeted by Δ9-tetrahydrocannabinol in Cannabis.


CB1 and CB2 share the structure characteristic of all G-protein-coupled receptors, possessing seven transmembrane domains connected by three extracellular and three intracellular loops, an extracellular N-terminal tail, and an intracellular C-terminal tail.These receptors may exist as homodimers or form heterodimers or oligomers when coexpressed with one or more classes of G-protein-coupled receptor.

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Endocannabinoids include several derivatives of arachidonic acid, which are generated on demand by neurons and other cells in response to physiological or pathological stimuli.
The two bestcharacterized endocannabinoids are 2-arachidonoyl-sn-glycerol
(2-AG) and anandamide.
2-AG is produced through a two-step mechanism in which phospholipase C-β activation causes the generation of 1,2-diacylglycerol, which is subsequently cleaved by diacylglycerol lipase-α to yield 2-AG (3).
Anandamide production, however, is thought to occur via phospholipase D mediated hydrolysis of N-arachidonoyl phosphatidylethanolamine.

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The biological actions of 2-AG and anandamide are described as retrograde signaling because they most commonly travel ‘backward’ against the usual synaptic transmitter flow. They are, in effect, released from the postsynaptic cell and act on the presynaptic cell. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled. For instance, when the release of the inhibitory transmitter GABA is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. On the converse, when release of the excitatory neurotransmitter glutamate is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.
Neurotransmitters may also trigger initiation of second messenger cascades. Based on the cell, these effects may result in the on-site synthesis of endogenous cannabinoids anandamide or 2-AG by a process that is not entirely clear, but results from an elevation in intracellular calcium. Expression appears to be exclusive, so that both types of endocannabinoids are not co-synthesized. This exclusion is based on synthesis-specific channel activation: a recent study found that in the bed nucleus of the stria terminalis, calcium entry through voltage-sensitive calcium channels produced an L-type current resulting in 2-AG production, while activation of mGluR1/5 receptors triggered the synthesis of anandamide.
Evidence suggests that the depolarization-induced influx of calcium into the post-synaptic neuron causes the activation of an enzyme called transacylase. This enzyme is suggested to catalyze the first step of endocannabinoid biosynthesis by converting phosphatidylethanolamine, a membrane-resident phospholipid, into N-acyl-phosphatidylethanolamine (NAPE). Experiments have shown that phospholipase D cleaves NAPE to yield anandamide.
The synthesis of 2-AG is less established and warrants further research.Once released into the extracellular space by a putative endocannabinoid transporter, messengers are vulnerable to glial cell inactivation. Endocannabinoids are taken up by a transporter on the glial cell and degraded by fatty acid amide hydrolase (FAAH), which cleaves anandamide into arachidonic acid and ethanolamine or monoacylglycerol lipase (MAGL), and 2-AG into arachidonic acid and glycerol.
Endocannabinoid synthesis, release, and degradation

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These lipid mediators system is a critical component of the positive feedback mechanism originating in the mouth, which drives and maintains fat intake once it has begun.
Stimulation of cannabinoid CB receptors in nucleus accumbens shell has been shown to stimulate feeding and enhance positive 'liking' reactions to intraoral sucrose.
In fact many studies examined the behavioural effects of 2-arachidonoylglycerol following infusion into accumbens shell, on chow intake and food preference in high-fat preferring rats.

Stimulation of accumbens shell CB1 receptors by noladin ether modulates food intake and dietary selection in rats, 2012


Oral stimulation is necessary to elicit conditioned place preference to this nutrient. In fact oral exposure to fat stimulates dopamine outflow in the ventral striatum, a brain region that is critical for the evaluation of rewarding sensory stimuli.
Gustatory neural signals from nutrients, including fats and sugars, are transmitted from the oral cavity to the brain via cranial nerves V, VII, IX, and X. In particular, cranial nerve X, also termed the vagus nerve, contains branches that communicate efferent and afferent food-related signals between brain and gut.
Vagus nerve efferent fibres stimulate releasing Ach jejunal cells decreasing 2-AG-hydrolyzing activity and increasing activities involved in generating 2-AG or its precursor. The same happens with anandamide.

An experimental vagotomy in rats abolished the ability of fat to initiate small-intestinal endocannabinoid production, which indicates that neural communication from the brain to the gut via the vagus nerve is necessary to drive this biochemical reaction.

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(fig.)Vagotomy blocks sham-fat induced mobilization of endocanabinoids in the rat jejunum. Effects of complete subdiaphragmatic vagotomy on levels of 2-AG (Left) and anandamide (Right) in the jejunum of rats sham feeding corn oil for 30 min -, no diet presented; +, diet presented. Results are expressed as mean ± SEM; n = 4–5 per condition. Unpaired t tests, two-tailed, between no diet and diet condition.

Endocannabinoids Fat Control, 2010


Endocannabinoids released by enteric cells reach and bind CB receptors, which are present on enteric neurons and vagal fiber, thus modifying the generation or action of neurohumoral factors and activating positive feedback mechanism which bring fat-rich food overeating.
In fact they act on circuits that participate in specific subcomponents of feeding (e.g., gustatory perception, peripheral feedback relevant to satiety and energy balance, reward coding, etc.) which are found at all levels of the neural axis.

To examine whether small-intestinal endocannabinoid release regulates fat intake, many studies measured sham feeding of corn oil while infusing into the rat duodenum an isotonic solution containing the CB1-type cannabinoid receptor antagonists/inverse agonists, Rimonabant and AM251. Intestinal CB1 receptor blockade caused a dose-dependent inhibition of fat intake.The high potency of this effect suggests that intraduodenal Rimonabant/AM251 antagonized endocannabinoid signals elicited in the gut by fat ingestion rather than acting at central sites.

Responses to the cannabinoid receptor-1 antagonist, AM251, are more robust with age and with high-fat feeding, 2009

A similar experiment done with the CB2-type receptor agonist, JWH-015, failed to
modify fat sham intake; so this set of results indicates that endocannabinoid signaling at CB1 receptors in the gut plays an essential role in driving fat feeding.

Furthermore small-intestinal levels of 2-AG and anandamide rise during food deprivation and fall upon refeeding, suggesting that they may signal energy imbalance and promote caloric intake.

Endocannabinoids Fat Control, 2010
Principles of motivation revealed by the diverse functions of neuropharmacological and neuroanatomical substrates underlying feeding behavior, 2013


Therefore elevations in intestinal 2-AG and anandamide levels might contribute to the orosensory-mediated induction of fat intake, whereas reductions in the intestinal levels of the same compounds might participate in meal termination.

The aforementioned studies do suggest that pharmacological strategies aimed at curbing endocannabinoid activity in the gut might selectively lower the intake of fat-rich foods, a major drive behind eating disorders, without affecting reward systems in the brain.

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