Category Archives: Obesity

Role of the endocannabinoid system in energy balance regulation and obesity.

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Abstract

“The endogenous cannabinoid system (ECS) is a neuromodulatory system recently recognized to have a role in the regulation of various aspects of eating behavior and energy balance through central and peripheral mechanisms. In the central nervous system, cannabinoid type 1 receptors and their endogenous ligands, the endocannabinoids, are involved in modulating food intake and motivation to consume palatable food. Moreover, the ECS is present in peripheral organs, such as liver, white adipose tissue, muscle, and pancreas, where it seems to be involved in the regulation of lipid and glucose homeostasis. Dysregulation of the ECS has been associated with the development of obesity and its sequelae, such as dyslipidemia and diabetes. Conversely, recent clinical trials have shown that cannabinoid type 1 receptor blockade may ameliorate these metabolic abnormalities. Although further investigation is needed to better define the actual mechanisms of action, pharmacologic approaches targeting the ECS may provide a novel, effective option for the management of obesity, type 2 diabetes and cardiovascular disease.”

http://www.ncbi.nlm.nih.gov/pubmed/18230900

The role of the endocannabinoid system in skeletal muscle and metabolic adaptations to exercise: potential implications for the treatment of obesity.

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“The results of recent studies add the endocannabinoid system, and more specifically CB1 receptor signalling, to the complex mechanisms that negatively modulate insulin sensitivity and substrate oxidation in skeletal muscle. CB1 receptors might become overactive in the skeletal muscle during obesity due to increased levels of endocannabinoids. However, quite surprisingly, one of the most studied endocannabinoids, anandamide, when administered in a sufficient dose, was shown to improve muscle glucose uptake and activate some key molecules of insulin signalling and mitochondrial biogenesis. This is probably because anandamide is only a partial agonist at CB1 receptors and interacts with other receptors (PPARĪ³, TRPV1), which may trigger positive metabolic effects. This putative beneficial role of anandamide is worth considering because increased plasma anandamide levels were recently reported after intense exercise. Whether the endocannabinoid system is involved in the positive exercise effects on mitochondrial biogenesis and glucose fatty acid oxidation remains to be confirmed. Noteworthy, when exercise becomes chronic, a decrease in CB1 receptor expression in obese metabolically deregulated tissues occurs. It is then tempting to hypothesize that physical activity would represent a complementary alternative approach for the clinical management of endocannabinoid system deregulation in obesity, without the side effects occurring with CB1 receptor antagonists.”

http://www.ncbi.nlm.nih.gov/pubmed/22943701

Investigations of the endocannabinoid system in adipose tissue: effects of obesity/ weight loss and treatment options.

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Abstract

“Obesity is a world wide epidemic; it is becoming more usual to be overweight or obese than to be normal weight. Obesity increases the risk of an extensive range of diseases such as cardiovascular disease, diabetes mellitus type 2, hypertension, depression and some types of cancer. Adipose tissue is more than a storage organ for surplus energy – it is also a setting for complex metabolic processes and adipose tissue releases substances that interact with other parts of the body to influence several systems including food intake and energy metabolism. The endocannabinoid system (ECS) is one of the signalling systems that control feeding behaviour. The ECS is implicated in many functions, such as pain, memory, addiction, inflammation, and feeding, and could be considered a stress recovery system. It also seems to integrate nutrient intake, metabolism and storage maintaining homeostatic balance. The ECS is a recently discovered system, and research indicates hyperactivity in obesity. The aim of this thesis is to elaborate on the relationships of this widespread system and its elements in adipose tissue in obesity. Study I is a 4 weeks rat intervention study to investigate whether weight independent effect of Rimonabant treatment exists. We found that food intake-tolerance development could be circumvented by cyclic administration of Rimonabant and implications of weight independent effects of treatment. Study II is a cross-sectional study to establish the expression of cannabinoid receptor 1 from various adipose tissue depots of lean and obese persons. In this study we conclude, that the subcutaneous adipose tissue express more CBR1 than the visceral depot in lean, but comparable levels in obese. Study III is a 10 weeks human intervention study to asses the effects on the ECS of 10% weight loss. We found reduction in the ECS in obesity that normalised with weight loss. Our results clearly show the presence of all the components of the ECS in human adipose tissue, and suggest that the ECS is reduced in adipose tissue in obesity. Our results do not support the hypothesis of hyperactivity of the ECS in human obesity. Possible future treatment of obesity with CBR1 antagonist could involve cyclic treatment of specific peripheral compounds.”

http://www.ncbi.nlm.nih.gov/pubmed/21466769

Biomarkers of Endocannabinoid System Activation in Severe Obesity

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BACKGROUND:

“Obesity is a worldwide epidemic, and severe obesity is a risk factor for many diseases, including diabetes, heart disease, stroke, and some cancers. Endocannabinoid system (ECS) signaling in the brain and peripheral tissues is activated in obesity and plays a role in the regulation of body weight. The main research question here was whether quantitative measurement of plasma endocannabinoids, anandamide, and related N-acylethanolamines (NAEs), combined with genotyping for mutations in fatty acid amide hydrolase (FAAH) would identify circulating biomarkers of ECS activation in severe obesity.”

CONCLUSIONS/SIGNIFICANCE:

“Significantly increased levels of the endocannabinoid anandamide and related NAEs were found in carriers of the FAAH 385 A mutant alleles compared with wild-type FAAH controls. This evidence supports endocannabinoid system activation due to the effect of FAAH 385 mutant A genotype on plasma AEA and related NAE analogs. This is the first study to document that FAAH 385 A mutant alleles have a direct effect on elevated plasma levels of anandamide and related NAEs in humans. These biomarkers may indicate risk for severe obesity and may suggest novel ECS obesity treatment strategies.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808340/

Activation of the peripheral endocannabinoid system in human obesity.

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Abstract

“Obesity is the main risk factor for the development of type 2 diabetes. Activation of the central endocannabinoid system increases food intake and promotes weight gain. Blockade of the cannabinoid type 1 (CB-1) receptor reduces body weight in animals by central and peripheral actions; the role of the peripheral endocannabinoid system in human obesity is now being extensively investigated. We measured circulating endocannabinoid concentrations and studied the expression of CB-1 and the main degrading enzyme, fatty acid amide hydrolase (FAAH), in adipose tissue of lean (n = 20) and obese (n = 20) women and after a 5% weight loss in a second group of women (n = 17). Circulating levels of anandamide and 1/2-arachidonoylglycerol were increased by 35 and 52% in obese compared with lean women (P < 0.05). Adipose tissue mRNA levels were reduced by -34% for CB-1 and -59% for FAAH in obese subjects (P < 0.05). A strong negative correlation was found between FAAH expression in adipose tissue and circulating endocannabinoids. Circulating endocannabinoids and CB-1 or FAAH expression were not affected by 5% weight loss. The expression of CB-1 and FAAH was increased in mature human adipocytes compared with in preadipocytes and was found in several human tissues. Our findings support the presence of a peripheral endocannabinoid system that is upregulated in human obesity.”

“We demonstrated that the CB-1 receptor is expressed in organs relevant to the pathogenesis of obesity in humans, so that results from mechanistic studies in animals may also be applicable to patients. Furthermore, the peripheral endocannabinoid system is activated in human obesity. The observation that endocannabinoid activation is not reversible with a 5% weight loss may suggest that this activation is a cause rather than a consequence of obesity. The physiology and pathophysiology of the peripheral adipose tissue endocannabinoid system warrant further studies.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2228268/

[A role for the endocannabinoid system in obesity].

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Abstract

“Endocannabinoids are the endogenous ligands for the cannabinoid receptors type 1 and 2. These membrane receptors are responsible for the psychotropic effects of Cannabis Sativa, when bound to its active component known as (-)-Delta(9)-tetrahydro-cannabinol. Cannabinoid receptors, endocannabinoids and the enzymes catalyzing their biosynthesis and degradation, constitute the endocannabinoid system (ECS), which has a remarkable role controlling energy balance, both at central nervous system and peripheral tissues. The ECS regulates food ingestion by stimulating a network of orexigenic neurons present in the hypothalamus and reinforcing motivation and reward to food consumption in the nucleus accumbens. Regarding peripheral tissues, this system controls lipid and glucose metabolism at different levels, reduces energy expenditure and leads energy balance to fat storage. Metabolic alterations, including excessive accumulation of abdominal fat, dyslipidaemia and hyperglicaemia, are suggested to be associated to a hyperactivated ECS. Since obesity is one of the major health problems in modern societies, in this review we discuss the role of the endocannabinoid system in metabolic pathways associated to control mechanisms of energy balance and its involvement in overweight and obesity. In addition, we also discuss therapeutic possibilities and emergent problems due to cannabinoid receptor type 1 antagonism utilized as treatment for such alterations.”

http://www.ncbi.nlm.nih.gov/pubmed/20668819

Dysregulation of the Peripheral and Adipose Tissue Endocannabinoid System in Human Abdominal Obesity

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“The endocannabinoid system has been suspected to contribute to the association of visceral fat accumulation with metabolic diseases. We determined whether circulating endocannabinoids are related to visceral adipose tissue mass in lean, subcutaneous obese, and visceral obese subjects (10 men and 10 women in each group). We further measured expression of the cannabinoid type 1 (CB(1)) receptor and fatty acid amide hydrolase (FAAH) genes in paired samples of subcutaneous and visceral adipose tissue in all 60 subjects. Circulating 2-arachidonoyl glycerol (2-AG) was significantly correlated with body fat (r = 0.45, P = 0.03), visceral fat mass (r = 0.44, P = 0.003), and fasting plasma insulin concentrations (r = 0.41, P = 0.001) but negatively correlated to glucose infusion rate during clamp (r = 0.39, P = 0.009). In visceral adipose tissue, CB(1) mRNA expression was negatively correlated with visceral fat mass (r = 0.32, P = 0.01), fasting insulin (r = 0.48, P < 0.001), and circulating 2-AG (r = 0.5, P < 0.001), whereas FAAH gene expression was negatively correlated with visceral fat mass (r = 0.39, P = 0.01) and circulating 2-AG (r = 0.77, P < 0.001). Our findings suggest that abdominal fat accumulation is a critical correlate of the dysregulation of the peripheral endocannabinoid system in human obesity. Thus, the endocannabinoid system may represent a primary target for the treatment of abdominal obesity and associated metabolic changes.”

“In conclusion, extending previous observations that the peripheral endocannabinoid system may be activated in human obesity (21), we demonstrate here that visceral fat accumulation is an important correlate of an activated peripheral endocannabinoid system. In addition, strong expression of CB1 receptors in visceral adipose tissue could represent a primary target for the beneficial effects of CB1 blockade on different components of the metabolic syndrome.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2228260/

Dysregulation of the endocannabinoid system in obesity.

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“An activation of the endocannabinoid system (ECS) in obesity with increased concentrations of endocannabinoids in several tissues and in the circulation is described in this review. This increased availability of endocannabinoids might stimulate cannabinoid receptors in a pathophysiological manner. The successful use of the cannabinoid receptor CB(1) inverse agonists rimonabant and taranabant for weight loss and the treatment of obesity-associated metabolic disorders might well be through blocking this overstimulation of cannabinoid receptors. At present, no single mechanism has been identified that explains the increased bioavailability of endocannabinoids in obesity. Both increased synthesis and decreased degradation appear to operate in a species- and tissue-dependent manner, but many pieces of the puzzle still need to be collected. For example, most data show decreased fatty acid amide hydrolase (FAAH) expression and/or activity as a result of obesity or high-fat intake, but the endocannabinoid predominantly increased in tissues is 2-arachidonoylglycerol (2-AG), which is not degraded by FAAH in vivo. Furthermore, the influence of dietary fatty acids on the synthesis of endocannabinoids needs to be studied in much more detail. Although weight loss does not seem to influence activation of the endocannabinoid system (ECS) in human obesity, suggesting an underlying mechanisms independent of body weight, no such mechanism at the genetic level has yet been identified either. Thus, activation of the ECS is a hallmark of abdominal obesity, and explains the success of pharmacological CB(1) blockade, but serious attempts have to be made to clarify the underlying mechanisms of this activation.”

http://www.ncbi.nlm.nih.gov/pubmed/18426509

The endocannabinoid system as a target for obesity treatment.

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Abstract

“Overweight and obesity are major factors contributing to the development of type 2 diabetes mellitus (DM) and cardiovascular disease (CVD). In addition to the many physical and metabolic consequences of obesity, there are also mental health consequences, in particular, the risk for depression. Depression can lead to poor self-care, poor treatment compliance, and possible increased morbidity and mortality from such illnesses as type 2 DM and CVD. Lifestyle modification for the treatment of overweight and obesity is rarely successful over the long term, and use of surgery is limited by eligibility criteria; therefore, researchers and clinicians continue to explore pharmacotherapy, with intense efforts being directed toward the development of agents that, optimally, will reduce weight and simultaneously reduce or eliminate modifiable cardiovascular and metabolic risk factors. Among the promising new agents are the CB(1) receptor antagonists. These agents target receptors of the endocannabinoid system, a neuromodulatory system recently found to influence energy balance, eating behavior, and metabolic homeostasis via central and peripheral mechanisms. In animal and clinical studies, antagonism of CB(1) receptors has resulted in meaningful weight loss and improvement of lipid and glycemic profiles. Thus, these agents may provide a rational and effective approach for the management of not only overweight and obesity but also their metabolic and cardiovascular sequelae.”

http://www.ncbi.nlm.nih.gov/pubmed/19046740

 

The endocannabinoid system as a novel approach for managing obesity.

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“The recent discovery of the endocannabinoid system has led to the development of promising treatments for patients with obesity and associated cardiometabolic risk factors. Basic research has demonstrated that the endocannabinoid system plays an integral role in the regulation of food intake, metabolism, and storage. Research with the endocannabinoid receptor antagonist rimonabant has demonstrated statistically significant improvements in body weight, fasting insulin levels, glucose tolerance, high-density lipoprotein cholesterol levels, serum triglyceride levels, and waist circumference, compared with placebo. Rimonabant has also produced statistically significant improvements in inflammatory markers. Research with rimonabant has demonstrated sustained efficacy for as long as 2 years when used in conjunction with a reduced-calorie diet and moderate physical activity. Rimonabant is the first cannabinoid receptor 1 antagonist to be marketed in Europe and the first to file an New Drug Application in the United States. It may provide a novel therapeutic strategy for the treatment of patients with obesity and associated cardiometabolic risk factors.”

http://www.ncbi.nlm.nih.gov/pubmed/17784530