Cannabinoid receptors, metabolism, inflammation, and obesity

Metabolism, obesity, and inflammation… genetic connections through the endocannabinoid system

Cannabis and marijuana may be the first thing that comes to mind when learning about the body’s cannabinoid receptors.  And yes, cannabis acts upon the receptors, activating them and causing the pleasant effects on mood as well as the increase in appetite.  But there is a lot more to this system’s role in our body than the effects of marijuana.

This article looks at the role of cannabinoid receptors in the body, focusing on the role that endocannabinoids and their receptors play in metabolism, inflammation, and obesity.

The endocannabinoid system consists of endogenous (made in our body) cannabinoid receptors in the body and also the endogenous agonists of those receptors.  This system is involved in a variety of your body’s processes including regulating appetite, immune system functions, and pain management.  The two main cannabinoid receptors in humans are cannabinoid receptor 1 and 2 (CB1 and CB2).  CB1 is coded for by the gene CNR1, and CB2 is coded for by CNR2.   There are variants of these genes that alter a person’s cannabinoid receptor levels.

Effect on Metabolism and Obesity:

A 2008 study in the Journal of Neuroendocrinology summarized that:

In the hypothalamus, CB1 receptors and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control several metabolic functions by acting on peripheral tissues such as adipocytes, hepatocytes, the gastrointestinal tract, the skeletal muscles and the endocrine pancreas. The relevance of the system is further strengthened by the notion that visceral obesity seems to be a condition in which an overactivation of the endocannabinoid system occurs, and therefore drugs interfering with this overactivation by blocking CB1 receptors are considered as potentially valuable candidates for the treatment of obesity and related cardiometabolic risk factors.

A 2011 study in the Journal of Inflammation gives great background information on the endocannabinoid system:

“The endocannabinoid system is said to be usually silent and to become transiently activated in stressful conditions. After ligand binding, signalling cascades of cannabinoid receptors can occur through several mechanisms that can act via G protein-dependent and independent pathways. Consequently, according to the signalling pathway activated, multiple biological effects are attributed to the endocannabinoid system which has been found to regulate appetite and energy expenditure, insulin sensitivity, as well as glucose and lipid metabolism ([8] for review). Moreover, it seems that the endocannabinoid system exerts many anti-inflammatory actions ([9] for review). Several recent data obtained from studies carried out on animals or humans have demonstrated a close association between obesity and the endocannabinoid system dysregulation, illustrated either by an overproduction of endocannabinoids or by an upregulation of CB1 expression in tissues involved in energy homeostasis ([8] for review). Interest in blocking stimulation of this pathway to aid weight loss and reduce cardiometabolic risk factor development is an area of interest and research”

That whole study is interesting to read and looks at inflammation in fat cells when stimulated by lipopolysaccharides and the effects of a CB1 antagonist on reducing the inflammatory response.

Endogenous agonists:

The CB1 and CB2 receptors have endogenous agonists, which is to say that there are substances made in the body that activate the receptors.  Anandamide and 2-arachidonoylglycerol (2-AG) are the two main agonists produced by the body.

Anandamide, a neurotransmitter, is made from arachidonic acid which comes from omega-6 polyunsaturated fatty acids (PUFA).  It acts on the CB1 receptors in the central nervous system and on the CB2 receptors mainly in the peripheral nervous system.  It is also important for implantation of an embryo, and levels of anandamide rise at ovulation.

So the body synthesizes anandamide from arachidonic acid through a variety of pathways. It is fairly quickly broken down again by the fatty acid amide hydrolase (FAAH) enzyme.  The FAAH enzyme is encoded by the FAAH gene, which has several polymorphisms researched in conjunction with obesity and with drug use.

Mouse studies of FAAH-/- mice have shown that the absence of the FAAH enzyme has significant effects on weight.  While all FAAH-/- mice showed increased body weight with the same amount of feed as normal mice on a standard diet, the weight increase was even more dramatic on a high-fat diet.  [ref]  Another mouse study goes into details on the lipid changes in FAAH-/- mice. [ref]

2-AG (2-arachidonoylglycerol) is the second main agonist for the CB1 receptor.  It is also formed from arachidonic acid (omega-6).

Gastrointestinal system:

The endocannabinoid system is also involved in the gastrointestinal system.  Activation of the CB1 receptors reduces nausea.  Additionally, CB1 receptor activation work in inhibiting relaxation of the LES (lower esophageal sphincter) and inhibiting gastric acid secretion. [ref]  So blocking CB1 receptors can cause nausea and possibly heartburn.

CNR1 gene variants:

CNR1 is the gene that codes for the CB1 receptors.  There are several variants that have been well studied.  Quite a few of the studies look at the effects of cannabis on the receptors, so if you are interested in addiction studies, look up these variants on for more information.

rs1049353 (risk allele is T) (v.4 and v.5 )

  • In a study of visceral fat mass in young men, the common allele was found to be associated with higher fat mass and higher serum triglycerides.  [ref]
  • The opposite was found in a 2007 study where the AA genotype was associated with increased abdominal adiposity in obese men.  [ref]
  • A Feb. 2016 study found that in obese subjects with AA and AG  (TT and CT for 23andme), HDL cholesterol was higher and triglycerides were lower.
  • Another Feb. 2016 study of 896 females also found the A carriers to have higher HDL cholesterol.

rs806368 (risk allele is C ) (v.4 and v.5)

  • The 2015 PCOS study found that the CC genotype of rs806368 had an 8x risk of PCOS.  [ref]
  • A 2016 study of adolescents found that “among individuals with cannabis abuse/dependence the presence of one or both copies of the rs806368 A > G minor allele conferred a 5.4-fold increase (P = 0.003) in the likelihood that they would be in the frequent and persistent use group rather than the declining use group” [ref]

rs12720071 (risk allele is C) (v.4 only)

  • A 2015 study looked at the association of CNR1 variants with polycystic ovary syndrome.  PCOS is associated with insulin resistance, abdominal obesity, and hyperandrogenism.  The study found that for rs12720071 the GG (CC) genotype had a 3x higher risk of PCOS.   [ref]

rs806380 (risk allele is G) (v.4 and v.5)

  • The minor allele is associated with a decreased risk of marijuana and cocaine dependence.

FAAH variants:

rs324420 (risk allele is A ) (v.4 and v.5)

  • According to a 2015 study, this fairly common variant leads to a reduction of FAAH protein levels and thus, an increase in anandamine levels.  The A allele also showed reduced anxiety levels.  It is an interesting study using both mice and humans. [ref]
  • Another 2015 study found that: “The homozygous genotype AA for the variant 385C>A in FAAH was associated with higher levels of AEA versus the wild homozygous CC and heterozygotes combined. In the obese group, the homozygous genotype AA was also associated with higher levels of OEA and lower levels of HMW adiponectin” [ref]
  • A 2005 study showed that the impact of this variant may depend on ancestry.  In this study the rs324420 AA genotype was associated with overweight and obesity in black and white subjects, but not in those of Asian descent.  [ref]

Pharmaceutical intervention:
The drug rimonabant is a CB1 antagonist that was approved in the EU in 2006 for obesity.  It was never approved by the FDA and has since been discontinued in the EU due to the risk of psychiatric disorders including suicide.  [ref]

Inverse Agonists:
An inverse agonist is “an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist.” [ref]

Falcarinol was found to be an inverse agonist of CB1 [ref].  Falcarinol occurs naturally in carrots, red ginseng, and ivy, and acts as a natural pesticide in those plants.  It is sensitive to light and heat, so raw carrots may be your best source.  [ref]

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