Tag Archives: endocannabinoid system

Expression of the cannabinoid system in muscle: effects of a high-fat diet and CB1 receptor blockade

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Abstract

“The ECS (endocannabinoid system) plays an important role in the onset of obesity and metabolic disorders, implicating central and peripheral mechanisms predominantly via CB1 (cannabinoid type 1) receptors. CB1 receptor antagonist/inverse agonist treatment improves cardiometabolic risk factors and insulin resistance. However, the relative contribution of peripheral organs to the net beneficial metabolic effects remains unclear. In the present study, we have identified the presence of the endocannabinoid signalling machinery in skeletal muscle and also investigated the impact of an HFD (high-fat diet) on lipid-metabolism-related genes and endocannabinoid-related proteins. Finally, we tested whether administration of the CB1 inverse agonist AM251 restored the alterations induced by the HFD. Rats were fed on either an STD (standard/low-fat diet) or an HFD for 10 weeks and then treated with AM251 (3 mg/kg of body weight per day) for 14 days. The accumulated caloric intake was progressively higher in rats fed on the HFD than the STD, resulting in a divergence in body weight gain. AM251 treatment reduced accumulated food/caloric intake and body weight gain, being more marked in rats fed on the HFD. CB2 (cannabinoid type 2) receptor and PPARα (peroxisome-proliferator-activated receptor α) gene expression was decreased in HFD-fed rats, whereas MAGL (monoglyceride lipase) gene expression was up-regulated. These data suggest an altered endocannabinoid signalling as a result of the HFD. AM251 treatment reduced CB2 receptor, PPARγ and AdipoR1 (adiponectin receptor 1) gene expression in STD-fed rats, but only partially normalized the CB2 receptor in HFD-fed rats. Protein levels corroborated gene expression results, but also showed a decrease in DAGL (diacylglycerol) β and DAGLα after AM251 treatment in STD- and HFD-fed rats respectively. In conclusion, the results of the present study indicate a diet-sensitive ECS in skeletal muscle, suggesting that blockade of C1 receptors could work towards restoration of the metabolic adaption imposed by diet.”

“In the present study, we focused on skeletal muscles, which are an important tissue for glucose and fat oxidation, being an important site for insulin action [27]. However, despite the fact that AEA can modify the pathways regulating fatty acid oxidation in the skeletal muscle, probably via CB1 receptors, suggesting that CB1 receptor antagonism would have an important role in oxidative metabolism and energy regulation [28,29], there is still a general lack of clarity regarding the physiological functions and molecular mechanism implicated. In fact, there are almost no studies demonstrating the presence of endocannabinoid signalling proteins and their sensitivity to HFDs (high-fat diets). Therefore, in the present study, we have (i) investigated the presence of the endocannabinoid signalling machinery in skeletal muscle, (ii) analysed the impact of an HFD on lipid and glucose metabolism and endocannabinoid-related genes, and (iii) monitored the effects of the CB1 receptor inverse agonist AM251 during an STD (standard/low-fat diet) and HFD on the endocannabinoid machinery and the genes related to lipid oxidative metabolism in skeletal muscle of rats. Among the many molecules involved in lipid metabolism of skeletal muscle, we evaluated changes in the gene and protein expression of relevant components of the ECS, such as the CB1 and CB2 receptors and some of the enzymes responsible for their synthesis.

The presence of the ECS in skeletal muscle

As a final note, the regulatory mechanisms may be different at rest and during exercise, may change as the exercise intensity increases, and this could be influential in endocannabinoid production [31,49]. It would be interesting to repeat this type of experiment combining exercise and diet in its original design. Regulation of skeletal muscle fat and glucose metabolism is clearly multifactorial, and different mechanisms may dominate in different conditions; besides, potential variations may exist between individuals in response to stimulating or blocking CB1 receptors. This could cause differences in response to treatment with CB1 receptor antagonists between different obese states. In conclusion, we have provided findings identifying important relevant players involved in the signalling pathways of CB1 receptor antagonism in skeletal muscle and determined the extent of changes in this system associated with either an HFD or CB1 receptor blockade.”

http://www.biochemj.org/bj/433/0175/bj4330175.htm

Obesity, the Endocannabinoid System, and Bias Arising from Pharmaceutical Sponsorship

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“Previous research has shown that academic physicians conflicted by funding from the pharmaceutical industry have corrupted evidence based medicine and helped enlarge the market for drugs. Physicians made pharmaceutical-friendly statements, engaged in disease mongering, and signed biased review articles ghost-authored by corporate employees.

 This paper tested the hypothesis that bias affects review articles regarding rimonabant, an anti-obesity drug that blocks the central cannabinoid receptor.

CONCLUSIONS:

The findings are characteristic of bias that arises from financial conflicts of interest, and suggestive of ghostwriting by a common author. Resolutions for this scenario are proposed.

In summary, financial conflicts permeate the system and are by no means limited to corporations referenced in this article, such as Merck, Parke-Davis, Pfizer, Sanofi-Aventis, and Wyeth-Ayerst. On balance, pharmaceutical corporations do good work and aid in humanitarian efforts. For example Sanofi-Aventis provides artemisinin at cost to malaria-endemic countries. Nevertheless, ghost authorship and the corrupting effects of covert financial support must cease. Only three of eight rimonabant review articles disclosed corporate sponsorship; two authors specifically denied conflicts. Lack of disclosure prevents readers from judging the credibility of an author. Medical journals should require stronger author disclosure procedures, and universities should discipline academics who sign ghostwritten articles. This behavior should be regarded as unethical misconduct. More broadly, researchers with conflicts of interest should not be allowed to sit on guideline committees and regulatory boards. Corporate funding of CME programs and review articles should be abolished.

While this paper was under review, Merck halted taranabant RCTs, and Sanofi-Aventis removed rimonabant from the European market. The FDA rejected rimonabant after data submitted by Sanofi-Aventis revealed adverse effects in RIO trials that went unreported in RIO publications [86], including one death in a rimonabant-treated subject (ruled a suicide by the FDA, [86]) that did not appear in the pertinent publication [7]. Although the risk-benefit ratio of cannabinoid receptor blockade may preclude its use for chronic conditions such as obesity and drug or alcohol dependence, cannabinoid receptor blockade could serve in the treatment of acute endocannabinoid dysregulation, such as hepatic cirrhosis, hemorrhagic or endotoxic shock, cardiac reperfusion injury, and doxorubicin-induced cardiotoxicity.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659447/

 

Rimonabant: an antagonist drug of the endocannabinoid system for the treatment of obesity.

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Abstract

“Obesity, an ever-increasing problem in the industrialized world, has long been a target of research for a cure or, at least, control of its expansion. In the search for treatment, the recently discovered endocannabinoid system has emerged as a new target for controlling obesity and its associated conditions. The endocannabinoid system plays an important role in controlling weight and energy balance in humans. This system is activated to a greater extent in obese patients, and the specific blockage of its receptors is the aim of rimonabant, one of the most recent drugs created for the treatment of obesity. This drug acts as a blockade for endocannabinoid receptors found in the brain and peripheral organs that play an important role on carbohydrate and fat metabolism. Clinical studies have confirmed that, when used in combination with a low calorie diet, rimonabant promotes loss in body weight, loss in abdominal circumference, and improvements in dyslipidemia. Rimonabant is also being tested as a potential anti-smoking treatment since endocannabinoids are related to the pleasurable effect of nicotine. Thus, rimonabant constitutes a new therapeutic approach to obesity and cardiovascular risk factors. Studies show effectiveness in weight loss; however, side effects such as psychiatric alterations have been reported, including depression and anxiety. These side effects have led the FDA (Food and Drug Administration) to not approve this drug in the United States. For a more complete evaluation on the safety of this drug, additional studies are in progress.”

http://www.ncbi.nlm.nih.gov/pubmed/19443932

The endocannabinoid system and rimonabant: a new drug with a novel mechanism of action involving cannabinoid CB1 receptor antagonism–or inverse agonism–as potential obesity treatment and other therapeutic use.

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Abstract

“There is considerable evidence that the endocannabinoid (endogenous cannabinoid) system plays a significant role in appetitive drive and associated behaviours. It is therefore reasonable to hypothesize that the attenuation of the activity of this system would have therapeutic benefit in treating disorders that might have a component of excess appetitive drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders. Towards this end, antagonists of cannabinoid receptors have been designed through rational drug discovery efforts. Devoid of the abuse concerns that confound and impede the use of cannabinoid receptor agonists for legitimate medical purposes, investigation of the use of cannabinoid receptor antagonists as possible pharmacotherapeutic agents is currently being actively investigated. The compound furthest along this pathway is rimonabant, a selective CB(1) (cannabinoid receptor subtype 1) antagonist, or inverse agonist, approved in the European Union and under regulatory review in the United States for the treatment of obesity. This article summarizes the basic science of the endocannabinoid system and the therapeutic potential of cannabinoid receptor antagonists, with emphasis on the treatment of obesity.”

http://www.ncbi.nlm.nih.gov/pubmed/17489873

Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis.

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Abstract

“The endogenous cannabinoid (CB) (endocannabinoid) signaling system is involved in a variety of (patho)physiological processes, primarily by virtue of natural, arachidonic acid-derived lipids (endocannabinoids) that activate G protein-coupled CB1 and CB2 receptors. A hyperactive endocannabinoid system appears to contribute to the etiology of several disease states that constitute significant global threats to human health. Consequently, mounting interest surrounds the design and profiling of receptor-targeted CB antagonists as pharmacotherapeutics that attenuate endocannabinoid transmission for salutary gain. Experimental and clinical evidence supports the therapeutic potential of CB1 receptor antagonists to treat overweight/obesity, obesity-related cardiometabolic disorders, and substance abuse. Laboratory data suggest that CB2 receptor antagonists might be effective immunomodulatory and, perhaps, anti-inflammatory drugs. One CB1 receptor antagonist/inverse agonist, rimonabant, has emerged as the first-in-class drug approved outside the United States for weight control. Select follow-on agents (taranabant, otenabant, surinabant, rosonabant, SLV-319, AVE1625, V24343) have also been studied in the clinic. However, rimonabant’s market withdrawal in the European Union and suspension of rimonabant’s, taranabant’s, and otenabant’s ongoing development programs have highlighted some adverse clinical side effects (especially nausea and psychiatric disturbances) of CB1 receptor antagonists/inverse agonists. Novel CB1 receptor ligands that are peripherally directed and/or exhibit neutral antagonism (the latter not affecting constitutive CB1 receptor signaling) may optimize the benefits of CB1 receptor antagonists while minimizing any risk. Indeed, CB1 receptor-neutral antagonists appear from preclinical data to offer efficacy comparable to or better than that of prototype CB1 receptor antagonists/inverse agonists, with less propensity to induce nausea. Continued pharmacological profiling, as the prelude to first-in-man testing of CB1 receptor antagonists with unique modes of targeting/pharmacological action, represents an exciting translational frontier in the critical path to CB receptor blockers as medicines.”

http://www.ncbi.nlm.nih.gov/pubmed/19249987

Inverse agonism and neutral antagonism at cannabinoid CB1 receptors.

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Abstract

“There are at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled. CB1 receptors are expressed predominantly at nerve terminals and mediate inhibition of transmitter release whereas CB2 receptors are found mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous cannabinoid receptor agonists also exist and these “endocannabinoids” together with their receptors constitute the “endocannabinoid system”. These discoveries were followed by the development of a number of CB1- and CB2-selective antagonists that in some CB1 or CB2 receptor-containing systems also produce “inverse cannabimimetic effects”, effects opposite in direction from those produced by cannabinoid receptor agonists. This review focuses on the CB1-selective antagonists, SR141716A, AM251, AM281 and LY320135, and discusses possible mechanisms by which these ligands produce their inverse effects: (1) competitive surmountable antagonism at CB1 receptors of endogenously released endocannabinoids, (2) inverse agonism resulting from negative, possibly allosteric, modulation of the constitutive activity of CB1 receptors in which CB1 receptors are shifted from a constitutively active “on” state to one or more constitutively inactive “off” states and (3) CB1 receptor-independent mechanisms, for example antagonism of endogenously released adenosine at A1 receptors. Recently developed neutral competitive CB1 receptor antagonists, which are expected to produce inverse effects through antagonism of endogenously released endocannabinoids but not by modulating CB1 receptor constitutive activity, are also discussed. So too are possible clinical consequences of the production of inverse cannabimimetic effects, there being convincing evidence that released endocannabinoids can have “autoprotective” roles.”

http://www.ncbi.nlm.nih.gov/pubmed/15670612

Cannabinoid 1 G protein-coupled receptor (periphero-)neutral antagonists: emerging therapeutics for treating obesity-driven metabolic disease and reducing cardiovascular risk.

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Abstract

“Introduction: Obesity and related cardiometabolic derangements are spiraling global health problems urgently in need of safe, effective and durable pharmacotherapy. Areas covered: As an orexigenic and anabolic biosignaling network, the endocannabinoid system interacts with other information-transducing pathways to help ensure metabolic homeostasis. Hyperphagia stimulates reinforcing neuronal circuits favoring energy intake and conservation, inviting overweight/obesity and cardiometabolic risk factors (‘metabolic syndrome’). Associated increases in cannabinoid 1 G protein-coupled receptor (CB1R) activity/expression further exacerbate food consumption and the metabolic shift toward fat production and accumulation. The role of CB1R activity in hyperphagia and weight gain spurred the development of rimonabant (SR141716; Acomplia), the first-in-class CB1R antagonist/inverse agonist weight-loss drug. Rimonabant and similar CB1R inverse agonists also exert pleiotropic actions in addition to weight-loss effects that help correct obesity-related metabolic derangements and reduce cardiovascular risk in humans. The medicinal utility of these agents was crippled by clinically significant central and peripheral adverse effects that appear to reflect CB1R inverse agonists as a class. Consequently, increased attention is being given to CB1R neutral antagonists, CB1R blockers with intrinsically weak, if any, functional potency to elicit the negative-efficacy responses associated with inverse agonists. Laboratory studies demonstrate that CB1R neutral antagonists – whether readily accessible to the central nervous system or not (i.e., ‘periphero-neutral’ antagonists) – retain the salient therapeutic effects of CB1R inverse agonists on hyperphagia, weight-gain, and obesity-driven metabolic abnormalities with the distinct advantage of being associated with significantly less preclinical adverse events than are conventional CB1R inverse agonists such as rimonabant. Expert opinion: CB1R (periphero-)neutral antagonists merit continued analysis of their molecular pharmacology and evaluation of their therapeutic significance and translational potential as new-generation medicines for obesity-related derangements, including nonalcoholic fatty liver disease and type 2 diabetes, if not obesity itself.”

http://www.ncbi.nlm.nih.gov/pubmed/22646861

Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

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Abstract

“Obesity and its metabolic consequences are a major public health concern worldwide. Obesity is associated with overactivity of the endocannabinoid system, which is involved in the regulation of appetite, lipogenesis, and insulin resistance. Cannabinoid-1 receptor (CB1R) antagonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity, but their therapeutic potential is limited by neuropsychiatric side effects. Here we have demonstrated that a CB1R neutral antagonist largely restricted to the periphery does not affect behavioral responses mediated by CB1R in the brains of mice with genetic or diet-induced obesity, but it does cause weight-independent improvements in glucose homeostasis, fatty liver, and plasma lipid profile. These effects were due to blockade of CB1R in peripheral tissues, including the liver, as verified through the use of CB1R-deficient mice with or without transgenic expression of CB1R in the liver. These results suggest that targeting peripheral CB1R has therapeutic potential for alleviating cardiometabolic risk in obese patients.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912197/

‘Cannabis’ receptor discovery may help understanding of obesity and pain

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“Aberdeen scientists believe that the findings—published in the —might help our understanding of these conditions and also be a step towards the development of personalised therapies to help treat them.

The team from the University’s Kosterlitz Centre for Therapeutics studied around the gene CNR1. This gene produces what are known as cannabinoid receptors, which are found in the brain, and which activate parts of the brain involved in memory, mood, appetite and pain.

activate these areas of the brain when they are triggered by chemicals produced naturally in our bodies called .

Chemicals found in the drug cannabis mimic the action of these endocannabinoids and there is growing evidence that cannabis has pain relieving and anti-inflammatory properties which can help treat diseases such as and arthritis. 

In order to understand more about these side effects and the which determine how people respond, the scientists studied genetic differences around the CNR1 gene.

Dr Alasdair MacKenzie, who helped lead the team, said: “We chose to look at one specific genetic difference in CNR1 because we know it is linked to and addiction. What we found was a mutation that caused a change in the genetic switch for the gene itself—a switch that is very ancient and has remained relatively unchanged in overthree hundred million years of evolution, since before the time of the dinosaurs.”

http://phys.org/news/2012-08-cannabis-receptor-discovery-obesity-pain.html

Fight obesity… with marijuana?

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“What did the study find?
Dr. Yann Le Strat, a psychiatrist at France’s Louis-Mourier Hospital, looked at data from two studies of U.S. adults from the early 2000s and noted the weight differences between those who used cannabis and those who didn’t. In both studies, cannabis users had relatively low rates of obesity: 14.3 and 17.2 percent. American adults who didn’t use cannabis had obesity rates of 22 and 25.3 percent.

Is this what researchers expected?
Nope. “Cannabis is supposed to increase appetite,” says Le Strat. “So we hypothesized that cannabis users would be more likely to have higher weight than non-users and be more likely to be obese.” Marijuana activist Michelle Aldrich isn’t all that surprised. “It’s true,” she says. “I don’t know too many fat marijuana smokers.”

What’s causing this phenomenon?
“There could be many other reasons why pot smokers have less obesity,” says dietitian Andrea Giancoli. “Maybe they’re inclined to exercise more, be outdoors more, eat more fruits and vegetables.” Aldrich thinks it could be related to the body’s endocannabinoid system — a group of receptors, primarily in the brain, that respond to compounds in marijuana. But the bottom line is that the exact mechanism responsible for this correlation remains a mystery — for now.”

http://news.yahoo.com/fight-obesity-marijuana-114000508.html