Tag Archives: Cannabinoids

Understanding metabolic homeostasis and imbalance: what is the role of the endocannabinoid system?

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Abstract

“Endogenous endocannabinoids (ECs) (anandamide and 2-arachidonoyl glycerol) are part of the leptin-regulated neural circuitry involved in appetite regulation. One of the sites of the orexigenic action of ECs involves activation of cannabinoid-1 (CB1) receptors in the lateral hypothalamus, from which neurons involved in mediating food reward project into the limbic system. In animal models of obesity, pharmacologic blockade or genetic ablation of CB1 receptors causes a transient reduction in food intake accompanied by sustained weight loss, reduced adiposity, and reversal of hormonal/metabolic changes, such as elevated levels of plasma leptin, insulin, glucose, and triglyceride, and reduced levels of plasma adiponectin (Acrp30). However, the beneficial effects of CB1 blockade on weight and metabolism cannot be explained by appetite suppression alone. Animal studies suggest that CB1 blockade exerts a direct peripheral as well as a central effect on fat metabolism. CB1 receptor blockade with rimonabant has been shown to not only reduce weight and adiposity but also to directly modulate fat metabolism at peripheral sites in skeletal muscle, adipose tissue, and the liver. Preclinical animal studies suggest that CB1 blockade acts on adipocytes to increase Acrp30 expression, on hepatocytes to decrease de novo lipogenesis and increase fatty acid oxidation, and on skeletal muscle to reduce blood glucose and insulin levels. Extrapolating from animal studies to the clinic, CB1 receptor blockade offers a promising strategy not only for reducing weight and abdominal adiposity but also for preventing and reversing its metabolic consequences.”

http://www.ncbi.nlm.nih.gov/pubmed/17720356

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

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

The Central Cannabinoid CB1 Receptor Is Required for Diet-Induced Obesity and Rimonabant’s Antiobesity Effects in Mice

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Abstract

“Cannabinoid receptor CB1 is expressed abundantly in the brain and presumably in the peripheral tissues responsible for energy metabolism. It is unclear if the antiobesity effects of rimonabant, a CB1 antagonist, are mediated through the central or the peripheral CB1 receptors. To address this question, we generated transgenic mice with central nervous system (CNS)-specific knockdown (KD) of CB1, by expressing an artificial microRNA (AMIR) under the control of the neuronal Thy1.2 promoter. In the mutant mice, CB1 expression was reduced in the brain and spinal cord, whereas no change was observed in the superior cervical ganglia (SCG), sympathetic trunk, enteric nervous system, and pancreatic ganglia. In contrast to the neuronal tissues, CB1 was undetectable in the brown adipose tissue (BAT) or the liver. Consistent with the selective loss of central CB1, agonist-induced hypothermia was attenuated in the mutant mice, but the agonist-induced delay of gastrointestinal transit (GIT), a primarily peripheral nervous system-mediated effect, was not. Compared to wild-type (WT) littermates, the mutant mice displayed reduced body weight (BW), adiposity, and feeding efficiency, and when fed a high-fat diet (HFD), showed decreased plasma insulin, leptin, cholesterol, and triglyceride levels, and elevated adiponectin levels. Furthermore, the therapeutic effects of rimonabant on food intake (FI), BW, and serum parameters were markedly reduced and correlated with the degree of CB1 KD. Thus, KD of CB1 in the CNS recapitulates the metabolic phenotype of CB1 knockout (KO) mice and diminishes rimonabant’s efficacy, indicating that blockade of central CB1 is required for rimonabant’s antiobesity actions.”

http://www.nature.com/oby/journal/v19/n10/full/oby2011250a.html

The future of weight loss: A ‘marijuana’ diet pill?

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“Limiting a brain compound that regulates metabolism allows genetically altered mice to stay skinny without exercising. Is a dream pill far behind?

If you find the prospect of staying thin while eating as much as you want appealing, scientists have news for you. New research from the University of California, Irvine — detailed in the March issue of Cell Metabolism — found that certain brain chemicals with characteristics similar to marijuana might help the body shed pounds without any exercise. A dream come true? Here’s a brief look at the promising discovery:

What chemical could have such power?
It’s an endocannabinoid compound called 2-AG. Endocannabinoids, as the name might suggest, share a similar molecular structure to the active ingredients in cannabis. Typically, high levels of 2-AG are found in the brains of mammals, and previous studies suggested that these compounds may make the body crave fat. Scientists think endocannabinoids play a key role in regulating the body’s metabolism, or the energy it makes from food.

How did scientists put the compound to the test?
Researchers genetically engineered brain cells in mice to exhibit low levels of 2-AG, on the theory that this would allow the rodents’ metabolic rates to “go crazy,” says Kristen Philipkoski at Gizmodo. And the hunch was right. These mice lived in a “hypermetabolic state,” burning fat calories far more efficiently than normal mice, study researcher Daniele Piomeli said in a statement. They were “resistant to obesity,” staying thin despite a high-fat diet without exercise. They even had normal blood pressure, and showed no increased risk of heart disease or diabetes. 

How could this discovery help humans?
“To produce the desired effects, we would need to create a drug that blocks 2-AG production in the brain,” says Piomeli, “something we’re not yet able to do.” 

So can we expect a miracle pill in the foreseeable future?
“Tweaking” human brain chemistry is no easy task, says Philipkoski. And preliminary estimates say it would take a decade and cost up to $2 billion to make the drug safe and effective enough for the FDA to to approve it. “So don’t cancel that gym membership just yet,” says Piomeli.”

http://news.yahoo.com/future-weight-loss-marijuana-diet-pill-071500947.html

Pot Smokers May Have Lower Risk of Obesity

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“Despite the tendency of marijuana users to experience the “munchies,” pot smokers may have a lower risk of obesity that those who don’t use the drug, a new study finds.

The results show the prevalence of obesity is lower among people who frequently smoke pot compared with those who have never inhaled.

The researchers said they were surprised by their initial results, because they expected to find the opposite. So they examined a second sample of people, and found exactly the same result. Together, the two samples studied more than 50,000 people.

The reason behind the link is not clear. It could be that people who use cannabis also engage in other behaviors that lower their obesity risk. Or it may be that pot smokers exercise more or have a specific diet that keeps them thin, said study researcher Yann Le Strat, a psychiatrist at Louis Mourier Hospital in France.

“On a personal point of view, I would be surprised that cannabis use is associated with a higher rate of physical activity, but this cannot be ruled out,” Le Strat told MyHealthNewsDaily.

Another possibility is that components of cannabis may help people lose weight. If this turns out to be the case, researchers should investigate which components these might be and try to put them into drug form, Le Strat said.”

Read more: http://www.foxnews.com/health/2011/09/06/pot-smokers-may-have-lower-risk-obesity/#ixzz29gdL3zlB

Marijuana Slims? Why Pot Smokers Are Less Obese

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“If cannabis causes the munchies, how is it possible that pot smokers are thinner than nonsmokers?

A new study published in the American Journal of Epidemiology finds an intriguing connection between marijuana use and body weight, showing that rates of obesity are lower by roughly a third in people who smoke pot at least three times a week, compared with those who don’t use marijuana at all.

Researchers analyzed data from two large national surveys of the American population, which together included some 52,000 participants. In the first survey, they found that 22% of those who did not smoke marijuana were obese, compared with just 14% of the regular marijuana smokers. The second survey found that 25% of nonsmokers were obese, compared with 17% of regular cannabis users.”

Read more: http://healthland.time.com/2011/09/08/marijuana-slims-pot-smoking-linked-to-lower-body-weight/#ixzz29gb31XKW

Cannabis drug could help fight obesity

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“Apparently scientists have discovered that a natural component of cannabis suppresses the appetite and that discovery may lead to a new class of drugs for treating obesity.

Scientist professor Roger Pertwee, a neuropharmacologist at Aberdeen University, says it was already well known that cannabis stimulated the appetite, but not widely known that the plant also contained substances that produced the opposite effect.

That substance is apparently called THCV and is chemically similar to another cannabis chemical, or cannabinoid, called THC that stimulates the appetite.

As drugs based on THC are already being used to increase the appetite of AIDS patients, the focus is now on developing THCV for use as an anti-obesity drug, said Professor Pertwee.

Pertwee says that cannabis is rich in substances that can mimic the natural or endogenous cannabinoids in the brain, that act as chemical messengers in the nervous pathways, involved in such activities as appetite control or pain relief.

These endogenous cannabinoids seem to act on the reward pathways to the brain, to increase the reward you get when you take food, but can have harmful effects.

By increasing appetite they can increase fat, which can give rise to obesity or overweight.

Drugs are apparently now being developed that can increase the levels of these chemicals in our brains by slowing down the rate at which they disappear once they have been released,says Pertwee.

Professor Pertwee has also found a method of potentially boosting the signals in the brain that are generated by these endogenous cannabinoids.”

http://www.news-medical.net/news/2005/09/10/13067.aspx

Marijuana May Deflect Obesity

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“Cannabis seems to have many different allures. It can produce a “high.” It can give the feeling of munchies. Now, it can possibly help combat obesity. Scientists recently revealed that they found two compounds from cannabis leaves that could up the total energy that the body burns.

Previous studies of two specific compounds demonstrated that they could be used to treat type-two diabetes. The compounds were also discovered to have the ability to reduce cholesterol levels in the blood stream and decrease fat in important organs such as the liver. With the aim of treating patients who have “metabolic syndrome,” the researchers are currently conducting clinical trials in 200 patients with the drug. With “metabolic syndrome,” diabetes, high blood pressure, and obesity combine to heighten the risk of heart disease and stroke in patients.

“We are conducting four Phase 2a clinical trials and we expect some results later this year,” commented Dr. Steph Wright, director of research and development at GW Pharmaceuticals, in a Telegraph article. “The results in animal models have been very encouraging. We are interested in how these drugs effect the fat distribution and utilization in the body as a treatment for metabolic diseases… Humans have been using these plants for thousands of years so we have quite a lot of experience of the chemicals in the plants.”

GW Pharmaceuticals was given a license to grow cannabis in greenhouses that were specially constructed for project. The company produces cannabis plants that have a number of cannabinoids, which are varied compounds of cannabis. They are already working on creating drugs that can assist in treating epilepsy and multiple sclerosis. Interesting enough, when the scientists studied two specific compounds, THCV and cannabioidol, they found that they had the ability to suppress appetite but the effect lasted for a short amount of time. Upon further examination, the investigators discovered that the compounds could influence the fat level in the body as well as its effects to the hormone insulin.

Likewise, the studies of the compounds in mice showed that they increased the metabolism of the animals, causing decreased levels of fat in livers and minimized levels of cholesterol in the blood stream. In particular, THCV showed the ability of boosting the animals’ sensitivity to insulin but also shielding the insulin-producing cells. With these actions, the cells were able to work at a longer and more durable pace.

The researchers hope that the findings will help in the development of treatments for obesity-related illnesses and type-two diabetes.”

http://www.redorbit.com/news/health/1112653330/research-finds-marijuana-may-deflect-obesity/
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