What is the endocannabinoid system?

The endocannabinoid system (ECS) is a widespread nerve-signalling system found in the brain, spinal cord, peripheral nervous system, and digestive tract.

It regulates a variety of functions and processes in the body, including: memory, mood, stress response, pain processing, appetite and eating behaviour, inflammation, temperature control, fertility, and energy balance.
  

KEY POINTS

• The endocannabinoid system is a nerve signalling system in the brain and body that regulates various functions, including eating behaviour and energy balance.

 

What are the components of the endocannabinoid system?

There are three main components of the ECS:

• Cannabinoid receptors (including CB1 and CB2 receptors)
• Endogenous cannabinoids (endocannabinoids)
• Enzymes that produce and break down endocannabinoids

Let’s take a look at each of these components individually.

Cannabinoid receptors

Cannabinoid receptors are receptors found on the surface of nerves and other cells. There are two major types of cannabinoid receptors: CB1 and CB2.

- CB1 receptors

CB1 receptors are typically found in the central nervous system (brain and spinal cord), where they are located on the surfaces of nerve (neuron) endings. In particular, CB1 receptors are mainly located on presynaptic neurons: the nerve endings just before the gaps (synapse) between neurons.   

When CB1 receptors are activated, they alter the release of neurotransmitters (e.g. dopamine) from nerve endings, thereby changing nerve activity. More specifically, activation of the CB1 receptor typically inhibits the release of neurotransmitters from the presynaptic neuron. This means less neurotransmitter binds to and activates the postsynaptic neuron, thereby altering the transmission of nerve signals across the synapse and changing nerve activity.

It is largely these changes in nerve activity that underlie the effects of the endocannabinoid system on mood, pain, appetite, and eating behaviour.

For example, THC (tetrahydrocannabinol), the main psychoactive compound of cannabis / marijuana, produces its ‘high’ sensation by binding to the CB1 receptor and altering the activity of neurons in various brain circuits.

- CB2 receptors

CB2 receptors are more commonly found in cells and tissues of the immune system, where they a play a role in the regulation of inflammation.

The effects of the endocannabinoid system on eating behaviour are largely thought to be mediated by CB1 rather than CB2 receptors.

Endocannabinoids

Endocannabinoids (or endogenous cannabinoids) are molecules, naturally produced by the body, that bind to and activate cannabinoid receptors.

There are two major endocannabinoids produced by the body:

• Anandamide (AEA)
• 2-arachidonoylglycerol (2-AG)

In the central and peripheral nervous system, these endocannabinoids are produced by nerve cells.

In particular, endocannabinoids are produced from lipids by postsynaptic neurons: the nerve endings just after the gap (synapse) between neurons. Once released, endocannabinoids travel back across the synapse and bind to cannabinoid receptors on the presynaptic neuron. This inhibits neurotransmitter release and alters nerve activity. This whole process is known as retrograde signalling.

Enzymes

The endocannabinoid system also includes the various enzymes used to synthesise and break down endocannabinoid molecules (anandamide and 2-AG).

Enzymes that break down the endocannabinoids are important as they help to terminate the action of endocannabinoids on nerve activity. One of the key enzymes in this respect is FAAH, which breaks down anandamide and, to a lesser extent, 2-AG.

KEY POINTS

• The endocannabinoid system includes cannabinoid receptors, endocannabinoids, and enzymes.
• Cannabinoid receptors (CB1 and CB2) change nerve activity when activated.
• Endocannabinoids are naturally occurring molecules that bind to and activate cannabinoid receptors.
• The main endocannabinoids are anandamide (AEA) and 2-AG.
• Activation of CB1 receptors in the brain and nervous system can alter behaviour, cognition, pain perception and other complex functions.

 

What is anandamide (AEA)?

As described in the previous section, anandamide (AEA) is one the major endocannabinoids naturally produced by the body.

Anandamide binds more strongly to the CB1 receptor found in the brain and spinal cord (central nervous system) compared to the CB2 receptor. By binding to the CB1 receptor and altering nerve activity in various brain circuits, anandamide is thought to play a role in memory, appetite, pain perception and emotion, including feelings of pleasure.

On this note, the name ‘anandamide’ comes from the Sanskrit word “ananda,” which means “bliss”.

KEY POINTS

• Anandamide (AEA) is one of two main endocannabinoids naturally produced by the body.
• Anandamide (AEA) binds to and activates CB1 receptors.
• By binding to CB1 receptors on neurons in the brain and peripheral nervous system, anandamide can influence eating behaviour.
  
  

 

How do AEA and the endocannabinoid system affect eating behaviour?

Activation of the endocannabinoid system has been shown to stimulate appetite and promote food intake.

Some of the initial evidence for this came from observations of cannabis users, who are well known to experience a phenomenon called the “munchies”. This phenomenon is characterised by increased appetite, intense cravings for palatable food, and a strong compulsion to eat foods that are particularly high in fat, salt, and sugar.

The munchies are thought to result from activation of CB1 receptors (by phytocannabinoids present in cannabis), which stimulates brain circuits that promote appetite and food intake.

Similarly, anandamide (AEA) produced naturally by the body, which also activates CB1 receptors in the endocannabinoid system, drives food intake, particularly of high-fat, palatable foods.

Given the wide distribution of CB1 receptors across the body, there are several mechanisms by which anandamide may stimulate eating. Some of these are illustrated in the diagram below and described in further detail afterwards.

- Anandamide may enhance smell and taste perception

CB1 receptors are present on olfactory (smell sensing) and gustatory (taste sensing) nerves in the nose, mouth and brain. Activation of these receptors by anandamide may increase sensitivity to food odours and enhance neural responses to sweet tastes. This, in turn, may drive us to seek out highly palatable foods.

 

- Anandamide activity in the gut drives a preference for high-fat foods

Anandamide acting within the gastrointestinal tract may indirectly influence brain areas that regulate food intake so that we preferentially increase our intake of fat over other nutrients. In line with this, studies have shown that activation of CB1 receptors in the gut leads to the secretion of ghrelin: a ‘hunger hormone’ that stimulates appetite, enhances fat taste perception, and increases the rewarding value of high-fat foods.

 

- Anandamide stimulates brain circuits that promote appetite and food intake

As discussed in the Leptin Resistance trait blog, we have circuits in a brain structure called the hypothalamus that regulate appetite, satiety, and food intake. Specialised neurons in these circuits (known as POMC, AgRP and NPY neurons) have CB1 receptors on their surface. When these receptors are activated by anandamide, it leads to greater food intake and less suppression of appetite.

 

- Anandamide enhances the rewarding and pleasurable aspects of food

Our brain has a reward system that the mediates the pleasurable aspects of stimuli such as food, sex, and drugs, and drives our motivation to obtain these stimuli. This reward system, which includes dopaminergic brain structures such as the ventral tegmental area (VTA) and the nucleus accumbens (NA), becomes activated both in response to eating food and to the anticipation of food from cues such as sights, smells, certain social situations, certain emotions.

By binding to CB1 receptors in these brain areas, anandamide may alter the activity of our neural reward system, thereby increasing the rewarding and pleasurable aspects of food, making us more responsive to food-related cues, and increasing our motivation to eat highly palatable, junk foods.

 

KEY POINTS

• Anandamide (AEA) acts to stimulate appetite and food intake.
• Anandamide (AEA) activates CB1 receptors in various areas of the brain, which promotes food intake, a preference for high-fat foods, greater sensitivity to the smell and taste of food, and a heightened response to rewarding and pleasurable aspects of food.
• The “munchies” experienced by cannabis users also results from activation of CB1 receptors (but by plant cannabinoids rather than endocannabinoids produced by the body).
  

 

AEA levels, endocannabinoid system overactivity and compulsive overeating

Compulsive overeating refers to a collection of uncontrolled eating behaviours such as eating unusually large amounts of food, eating despite not being hungry, eating despite already being full, eating impulsively, and binge eating.

Given the stimulatory effects of anandamide (AEA), CB1 receptor and endocannabinoid system activation on food intake (described in the previous section), it is thought that high anandamide levels and overactivity within the endocannabinoid system can lead to compulsive overeating.

Several lines of evidence support this theory.

In animal studies, directly injecting anandamide into already-fed rats causes them to continue eating large quantities of food. This overeating behaviour results from activation of CB1 receptors and stimulation of the endocannabinoid system in the brain.  

In studies of humans, individuals with obesity and binge eating disorder have been found to have elevated levels of the endocannabinoids anandamide (AEA) and 2-AG compared to healthy control subjects. Researchers suggest that elevated AEA and 2-AG levels are markers of overactivity of the endocannabinoid system.

Another line of evidence comes from studies of the (now discontinued) anti-obesity drug Rimonabant. This drug binds to and inactivates the CB1 receptor, thereby lowering endocannabinoid activity. Rimonabant has been shown in clinical trials to significantly curtail binge eating behaviour. (Alas, the drug was withdrawn in 2008 due to psychiatric side effects).  

KEY POINTS

• Compulsive overeating includes eating large quantities of food despite being full or not being hungry, impulsive eating, and binge eating.
• High anandamide levels and overactivity within the endocannabinoid system is thought to contribute towards compulsive overeating.
  
  

What is FAAH?

FAAH stands for fatty acid amino hydrolase. It is an enzyme responsible for breaking down anandamide (AEA) in the central nervous system.

By breaking it down, FAAH terminates the action of anandamide on CB1 receptors and prevents further changes in nerve activity.

As the main pathway for breaking down anandamide, changes in the activity of FAAH can significantly influence levels of anandamide within the endocannabinoid system.

KEY POINTS

• FAAH is the main enzyme that breaks down anandamide (AEA)
• FAAH activity significantly affects your levels of anandamide in the endocannabinoid system.
  
  

 

How do FAAH gene variants affect anandamide levels?

The FAAH enzyme is encoded by your FAAH gene.

A SNP (Single Nucleotide Polymorphism) within the FAAH gene, designated rs324420, causes a change in the DNA code from the letter ‘C’ to the letter ‘A’. This gives rise to two different FAAH gene variants or ‘alleles’ – the ‘C’ allele and the ‘A’ allele.

The ‘A’ allele codes for an FAAH enzyme that is more readily degraded. Consequently, this leads to lower enzyme levels and therefore lower overall activity of the FAAH enzyme.  Due to this reduced enzyme activity, people with the ‘A’ allele of the FAAH gene break down anandamide (AEA) less effectively, resulting in higher anandamide levels in the central nervous system and circulating in the bloodstream.

Elevated anandamide (AEA) levels may, in turn, cause excessive stimulation of CB1 receptors and lead to overactivity within parts of the endocannabinoid system.

 

KEY POINTS

• The rs324420 SNP creates two different FAAH gene variants: ‘A’ and ‘C’ alleles.
• The ‘A’ allele is associated with lower FAAH activity and higher anandamide levels.
• People who carry the ‘A’ allele (i.e. AA or AC genotypes) have higher anandamide levels.
• Higher anandamide levels may lead to overactivity within the endocannabinoid system, which is linked to compulsive eating.

 

How do FAAH gene variants affect eating behaviour?

Studies suggest that people who carry the ‘A’ allele (i.e. AA and AC genotypes) of the FAAH gene (created by the rs324420 SNP) have a greater risk of obesity compared to those with the CC genotype. For example, a 2019 systematic review of studies found the ‘A’ allele to be associated with higher BMI, obesity, and higher blood triglyceride levels.  

It is possible that some of this increased obesity risk may be explained by higher anandamide levels and overactivity of the endocannabinoid system causing a greater propensity to overeat. In line with this, some studies have shown those with the ‘A’ allele to have lower satiety – i.e., they are less likely to feel full after eating.

In one study, people with the ‘A’ allele were able to consume an average of 1395ml of nutrient drink before feeling full. By contrast, those with the CC genotype could maximally tolerate 1175 ml before feeling full.

Neuroimaging studies also suggest that ‘A’ allele carriers may be at greater risk of impulsive eating. Using a technique called fMRI (functional magnetic resonance imaging) to compare changes in brain activity, researchers found that ‘A’ allele carriers have greater reactivity of their ventral striatum – a key part of the brain’s reward system. This suggests that ‘A’ carriers may be more responsive to the rewarding and pleasurable aspects of food and food-related cues.

Similarly, the same study found ‘A’ allele carriers to show steeper delay discounting. This means they were more likely to be biased towards smaller but more immediate rewards over larger but later rewards. Although the study did not assess delay discounting of food rewards, steeper discounting is an established component of impulsive eating behaviour. People who are more sensitive to immediate rewards are more likely to eat unhealthy foods impulsively rather than delay gratification.

KEY POINTS

• The ‘A’ allele of the FAAH gene is linked to a greater risk of obesity, higher BMI and elevated levels of blood fats.
• Studies show that people carrying the ‘A’ allele are less likely to feel full after eating.
• Studies suggest that the ‘A’ allele is associated with greater reactivity of the brain’s reward system and greater sensitivity to immediate rewards. This may promote impulsive eating and make it harder to resist unhealthy foods.

 

How do lifestyle factors affect AEA levels and the endocannabinoid system activity?

Non-genetic or “lifestyle” factors can also strongly affect anandamide levels and activity within the endocannabinoid system.

In this respect, your Compulsive Overeating (FAAH) Trait looks at the function of two key hormones known to affect endocannabinoid activity:

• Insulin
• Leptin

Let’s take a look at these individually.

 

Insulin

Insulin is an important hormone that allows glucose from the bloodstream to enter cells. It has also several other effects on fat and protein metabolism, appetite, and energy balance.

The actions of insulin and the endocannabinoid system show considerable interaction. CB1 receptors are present in the liver, skeletal muscle, and adipose tissue, where they affect insulin signalling. Excessive stimulation of these CB1 receptors and overactivity of the endocannabinoid system can inhibit insulin signalling and reduce tissue sensitivity to insulin.

Conversely, insulin action can also affect activity within the endocannabinoid system. For example, one of the effects of insulin is to suppress appetite. This appetite-suppressing (or ‘anorectic’) effect is thought to partly result from insulin’s interaction with endocannabinoids in the brain’s neural reward system, where insulin reduces the rewarding value of food.  

In adipose tissue and the pancreas, high levels of insulin are associated with increased production of endocannabinoids. This may lead to overactivity of the endocannabinoid system, which, in turn, promotes compulsive eating.

Given these interactions, poor sensitivity to insulin (or ‘insulin resistance’) and associated high levels of insulin also increase your risk of compulsive eating. In line with this, your Compulsive Overeating (FAAH) trait analyses data from your Lifestyle Survey to assess whether you have lifestyle variables suggestive of poor insulin sensitivity. Such data include:

• Fasting blood glucose levels
• Waist circumference
• Body composition

Therefore, if you have lifestyle factors suggestive of poor insulin sensitivity, you will be at an increased risk of compulsive eating regardless of what FAAH gene variants you carry.

Leptin

Leptin is a hormone secreted by fat cells that acts in the brain to suppress appetite and food intake. You can read more about leptin in the Leptin Resistance trait blog.

Part of leptin’s appetite suppressant effects result from its interaction with the endocannabinoid system. For example, leptin inhibits the action of anandamide in the hypothalamic brain circuits that control food intake and satiety.

Furthermore, leptin has been shown to increase FAAH enzyme activity, thereby lowering levels of anandamide and limiting endocannabinoid system activity.

Resistance to the effects of leptin, as is often found in overweight and obese people, can therefore lead to weaker suppression of endocannabinoid system activity. The resultant overactivity of the endocannabinoid system can then increase the risk of compulsive eating.

Given this effect, your Compulsive Overeating (FAAH) trait also analyses data from your Leptin Resistance trait, which includes lifestyle data such as your BMI, body composition and waist circumference.

If you have lifestyle and genetic data suggestive of leptin resistance, you will be at an increased risk of compulsive eating regardless of what FAAH gene variants you carry.

 

KEY POINTS

• Poor insulin sensitivity can lead to endocannabinoid system overactivity and an increased risk of compulsive overeating.
• Leptin resistance can lead to endocannabinoid system overactivity and an increased risk of compulsive overeating.
• Lifestyle variables linked to poor insulin sensitivity and leptin resistance include: high blood glucose levels, increased waist circumference, high BMI and a higher body fat percentage.
• Your Compulsive Overeating (FAAH) trait uses lifestyle data from your Lifestyle Survey when calculating your result.

 

Your Compulsive Overeating (FAAH) trait

Your Compulsive Overeating (FAAH) trait analyses variants of your FAAH gene as well as your Lifestyle Survey responses to assess your risk of compulsive overeating.

You will be classified into one of 4 groups:

• Increased risk of compulsive overeating: you carry the risk ‘A’ allele of the FAAH gene.
  
  
• Increased compulsive overeating due to lifestyle (insulin): you do not carry the risk ‘A’ allele of the FAAH gene, but have lifestyle factors linked to poor insulin sensitivity.
  
  
• Increased compulsive overeating due to lifestyle (leptin): you do not carry the risk ‘A’ allele of the FAAH gene, but have lifestyle factors linked to poor insulin sensitivity.
  
  
• Reduced risk of compulsive overeating: you do not carry the risk ‘A’ allele of the FAAH gene and do not have lifestyle data suggestive of poor insulin sensivitiy or leptin resistance.

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