Tag Archives: Cannabinoids

The endocannabinoid system, eating behavior and energy homeostasis: the end or a new beginning?

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Abstract

“The endocannabinoid system (ECS) consists of two receptors (CB(1) and CB(2)), several endogenous ligands (primarily anandamide and 2-AG), and over a dozen ligand-metabolizing enzymes. The ECS regulates many aspects of embryological development and homeostasis, including neuroprotection and neural plasticity, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and the focus of this review: hunger, feeding, and metabolism. This mini-review summarizes the main findings that supported the clinical use of CB1 antagonists/inverse agonists, the clinical concerns that have emerged, and the possible future of cannabinoid-based therapy of obesity and related diseases. The ECS controls energy balance and lipid metabolism centrally (in the hypothalamus and mesolimbic pathways) and peripherally (in adipocytes, liver, skeletal muscle and pancreatic islet cells), acting through numerous anorexigenic and orexigenic pathways. Obese people seem to display an increased endocannabinoid tone, driving CB(1) receptor in a feed-forward dysfunction. Several CB(1) antagonists/inverse agonists have been developed for the treatment of obesity. Although these drugs were found to be efficacious at reducing food intake as well as abdominal adiposity and cardiometabolic risk factors, they resulted in adverse psychiatric effects that limited their use and finally led to the end of the clinical use of systemic CB(1) ligands with significant inverse agonist activity for complicated obesity. However, the existence of alternatives such as CB(1) partial agonists, neutral antagonists, antagonists restricted to the periphery, allosteric modulators and other potential targets within the ECS indicate that a cannabinoid-based therapy for the management of obesity and its associated cardiometabolic sequelae should remain open for consideration.”

http://www.ncbi.nlm.nih.gov/pubmed/20347862

Cannabinoid receptors as therapeutic targets for obesity and metabolic diseases.

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Abstract

“One of the most interesting pharmacological targets proposed in the past ten years for fighting obesity and related metabolic disorders is the endocannabinoid system. The role of the endocannabinoid system is crucial in regulating the rewarding properties of food, in controlling energy balance by acting at the hypothalamic circuitries involved in food intake, and in peripheral metabolism by influencing adipocytes, hepatocytes, myocytes and pancreatic endocrine cells. Obesity seems to be a condition associated with a pathological overactivation of the endocannabinoid system; therefore, restoring a normal endocannabinoid tone by antagonizing the cannabinoid receptor type 1 (CB(1)) could help arrest both the development and the maintenance of obesity.”

http://www.ncbi.nlm.nih.gov/pubmed/17027338

The Emerging Role of the Endocannabinoid System in Endocrine Regulation and Energy Balance

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Abstract

“During the last few years, the endocannabinoid system has emerged as a highly relevant topic in the scientific community. Many different regulatory actions have been attributed to endocannabinoids, and their involvement in several pathophysiological conditions is under intense scrutiny. Cannabinoid receptors, named CB1 receptor and CB2 receptor, first discovered as the molecular targets of the psychotropic component of the plant Cannabis sativa, participate in the physiological modulation of many central and peripheral functions. CB2 receptor is mainly expressed in immune cells, whereas CB1 receptor is the most abundant G protein-coupled receptor expressed in the brain. CB1 receptor is expressed in the hypothalamus and the pituitary gland, and its activation is known to modulate all the endocrine hypothalamic-peripheral endocrine axes. An increasing amount of data highlights the role of the system in the stress response by influencing the hypothalamic-pituitary-adrenal axis and in the control of reproduction by modifying gonadotropin release, fertility, and sexual behavior. The ability of the endocannabinoid system to control appetite, food intake, and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptor and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the gastrointestinal tract, and, possibly, skeletal muscle. The relevance of the system is further strenghtened by the notion that drugs interfering with the activity of the endocannabinoid system are considered as promising candidates for the treatment of various diseases, including obesity.”

I. Introduction

“THE FIRST STEPS in the discovery of the endocannabinoid system date back almost 4000 yr, when the therapeutic and psychotropic actions of the plant Cannabis sativa were first documented in India (1). Over the last 40 yr, after Gaoni and Mechoulam (2) purified the psychoactive component from hemp, a stunning amount of research has revealed the endocannabinoid system as a central modulatory system in animal physiology.

Elements of the endocannabinoid system comprise the cannabinoid receptors, the endogenous lipid ligands (endocannabinoids), and the machinery for their biosynthesis and metabolism (3, 4). Despite public concern related to the abuse of marijuana and its derivatives, the research on the endocannabinoid system has recently aroused enormous interest not only for the physiological functions, but also for the promising therapeutic potentials of drugs interfering with the activity of cannabinoid receptors. This review aims to provide an overview on the pivotal role of the endocannabinoid system in the modulation of the neuroendocrine and peripheral endocrine systems. Moreover, in the context of the recently proposed therapeutic applications of cannabinoid receptor antagonists in the treatment of obesity, the key role of the endocannabinoid system in the control of eating behavior, food intake, and energy metabolism will be discussed in the light of the recent data obtained from human and animal studies.”

http://edrv.endojournals.org/content/27/1/73.long

How many sites of action for endocannabinoids to control energy metabolism?

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Abstract

“The promising results obtained by clinical trials using Rimonabant to tackle visceral obesity and related disorders recently promoted a remarkable impulse to carry out detailed investigations into the mechanisms of action of endocannabinoids in regulating food intake and energy metabolism. The endocannabinoid system has been known for many years to play an important role in the modulation of the neuronal pathways mediating the rewarding properties of food. However, in the last few years, with the advanced understanding of the crucial role of the hypothalamic neuronal network in the regulation of appetite, several studies have also directed attention to the orexigenic role of the endocannabinoid system, substantiating the well known appetite stimulating properties of derivatives of Cannabis sativa. Furthermore, the last 2 years have seen a number of relevant publications emphasizing the role of endocannabinoids as significant players in various peripheral metabolic processes. To date, the roles of the endocannabinoid system in influencing energy metabolism have proved to be more complex than was formerly believed. However, the diverse ability to modulate both central and peripheral processes highlights the pivotal involvement of the endocannabinoid system in the control of metabolic processes. This review describes the roles of endocannabinoids and the cannabinoid type 1 receptor (CB1) in the control of energy balance.”

http://www.ncbi.nlm.nih.gov/pubmed/16570104

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