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Peripheral effects of Rimonabant  
Overactive Endocannabinoid System and Obesity  
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The Endocannabinoid System in Appetite Regulation

It has been known for centuries that smoking cannabis is a potent stimulator of appetite, indeed because of this property it is often prescribed for medicinal purposes to stimulate eating.  How cannabis causes this was not understood until the discovery of the receptor that the active ingredient, tetrahydrocannibinol (THC), was acting upon. This receptors is part of the endocannabinoid system and is called CB1.  The first natural ligand for the CB1 receptor, anandamide, was identified in 1992 which, like THC, is a member of the endocannabinoid (EC) family.  Both of these substances activate the EC system and act to enhance appetite and so can cause weight gain.  The role of the EC system in appetite regulation was not fully explored until 1994 following the discovery of a CB1 selective antagonist, Rimonabant, (Rinaldi-Carmona et al, 1994). Antagonism of the CB1 receptor was found to have significant appetite reducing and weight reduction effects.  This factor, coupled to the appetite enhancing affects of anandamide and THC and because the CB1 receptor and endocannabinoids are expressed in brain regions associated with appetite regulation (Cota et al, 2003), really provided the impetus for the drive in research centered around how the EC system was implicated in appetite regulation.

Studies involving rodents confirmed the role of the EC system and the CB1 receptor in appetite regulation;  Mice lacking the CB1 receptor reduce their food intake, even after fasting, and lose weight compared to wild type mice and when wild type mice receive a dose of the CB1 antagonist Rimonabant, food intake is also decreased (Di Marzo et al, 2001).  These results imply that the CB1 receptor is responsible for the changes observed in food intake.  This has resulted in the release of the CB1 antagonist, Rimonabant, trade name Acomplia, as an anti-obesity drug.

Acomplia – The Anti-Obesity Drug

Acomplia was licensed to be prescribed for obesity in 2006 in countries within the EU.  It was produced by the French pharmaceutical company, Sanofi.  This release of an anti-obesity drug is highly significant as it is the first anti-obesity drug to be prescribed since the 1970’s.  So the emergence of Acomplia onto the market is a breakthrough for the treatment of obesity and results so far have proved encouraging. For all current information on Acomplia visit www.acompliareport.com

The anti-obesity actions of Acomplia involve a short term reduction in appetite accompanied by a long term decrease in body fat.  Human testing of Acomplia began in 2000 where results were very encouraging with obese individuals losing around 3 – 4kg over 4 months, compared to control patients who only lost approximately 1kg.  A second trial investigating its short term effects found significant decreases in food intake, particularly of foods with high calorie and fat content.  A larger phase III trial, using over 6000 patients and conducted over 2 years, began in 2001, with obese patients being treated either with Acomplia or a placebo.  After one year Acomplia caused ≥5% weight loss in 62% of patients and ≥ 10% in 32% of patients, significantly more than patients receiving a placebo (Pagotto et al, 2005 & Di Marzo et al, 2005).

Central effects of Rimonabant

The endocannabinoids and the CB1 receptor are expressed in brain regions implicated in the control of appetite and so it was thought likely that the effects on appetite were mediated in the brain.  This was supported by the emergence that the endocannabinoids appear to be under negative control by leptin.  Administration of leptin decreases the levels of orexigenic endocannabinoids in hypothalamic brain areas and when leptin signalling is defective, as in the ob/ob and db/db mice, hypothalamic concentrations of orexigenic endocannabinoids increase.  It appears, at least in those models, that chronic activation of the EC system is linked to obesity and leptin and endocannabinoid pathways may interact.  This is supported by the fact that both leptin and the EC system have roles in other physiological functions as well such as the stress response and reproduction. 

The central affects of the endocannabinoids on appetite stimulation appears to be independent from the orexigenic effects of the arcuate nucleus NPY neurones as when a CB1 antagonist is applied to rodents with functional and defective NPY neurones, the reduction in food intake is comparable between the groups. The EC system also interacts with the mesolymbic dopaminergic system which is involved in the motivation to search for food and it seems that the endocannabinoids interact with this system to promote food searching (Pagotto et al, 2005) so endocannabinoids may influence appetite through interactions with this system. This pathway is thought to be strongly involved in addictive behaviours, indeed it is also thought to be involved in gambling and alcohol addictions. Ultimately, where the endocannabinoids are synthesised, and how they interact with the various signalling pathways in the hypothalamus, remains to be discovered.

Peripheral effects of Rimonabant

So whilst it appears established that the endocannabinoids have a central mode of action in controlling appetite, evidence has now emerged that they may act peripherally as well.  Indeed, the CB1 receptor has been found expressed in the gastrointestinal tract on nerve terminals which are involved in satiety signalling in the gut (Gomez et al, 2002).  Food deprivation has been found to result in a significant increase in intestinal anandamide levels which are subsequently reduced upon refeeding.  The increase in anandamide is not observed in brain tissue and the cause of the rise is unknown but it may be that the rise in anandamide may act as a hunger signal to promote feeding.

Rimonabant acts short term to decrease food intake, but over the long term, fat mass is consistently decreased and there is an improvement in other metabolic parameters that are also typical of obesity, ie decreased plasma levels of insulin, fatty acids and cholesterol.  When CB1 null mice are pair fed on a normal diet with a wild type control mouse they have less fat mass and, after eating a high fat diet, the CB1 null mice do not become obese or insensitive to insulin or leptin, as wild type mice may, even though they consumed as much food.  This implies that CB1 antagonists not only act to decrease appetite at the central level, but act at the peripheral level by reversing endocannabinoids effects on fat accumulation and lipogenesis (Pagotto et al, 2005).  The peripheral effects of the endocannabinoids are supported by the discovery of CB1 receptors on white adipocytes where the endocannabinoids appear to activate the enzymes involved in lipogenesis and so by applying a CB1 antagonist, the hormone adiponectin, which is secreted from adipocytes, is upregulated. This hormone is essential for decreasing the expression of enzymes in lipogenesis (Di Marzo & Matias, 2005).

An Overactive Endocannabinoid System in Obesity

Obesity may result from an overactive endocannabinoid system (see Figure 1).  After a stressful event, endocannabinoid levels are increased, and this rise is thought to be a strategy that the organism employs to rebalance its homeostasis.  However activation of the EC system also causes metabolic problems like excessive eating and fat accumulation which can be reversed after application of a CB1 antagonist.  The chronic activation of the EC system may well contribute to the onset of obesity through its actions on tissues related to energy balance ie the white adipocytes.  This chronic activation may be caused by high fat diets, which can act as precursors for endocannabinoid biosynthesis.  So an overactive EC system in the pathogenesis of obesity is a distinct possibility.

Figure 1: Describes how a high fat diet or defective signalling systems may lead to an overactive endocannabinoid (EC) system, this then results in various metabolic disorders that contribute to obesity and its associated problems.

how a high fat diet or defective signalling systems may lead to an overactive endocannabinoid (EC) system, this then results in various metabolic disorders that contribute to obesity and its associated problems.

 

 

Acomplia is the first anti obesity drug to be released for many years, indeed very few have ever been released, which highlights the complexity of the various signalling pathways involved in the pathogenesis of obesity. As research is continuing into these mechanisims, more candidates for therapies are being discovered. The final section of this discussion involves a current hot topic in obesity research concerning a peripherally released signal. There is currently a hot debate regarding this peptide's use as a future anti obesity drug.

This peptide is released from the stomach and is called Peptide YY.

Key References

Rinaldi-Carmona et al. 1994. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Letters. 350. pp240-244 - The identification of the first CB1 selective antagonist

Di Marzo & Matias. 2005. Endocannabinoid Control of Food Intake and Energy Balance. Nature Neuroscience. 8 (5) pp585-589 - Very good overview of central and peripheral effects of Rimonabant

Pagotto et al. 2005. The Endocannabinoid System and the Treatment of Obesity. Annals of Medicine. 37 (4) pp270-275 - Another excellent paper on the endocannabinoid system and appetite, including results of the clinical trials

 
   
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