Tag Archives: treatment

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

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Abstract

“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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Abstract

“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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Abstract

“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

The challenge of treating obesity: the endocannabinoid system as a potential target.

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Abstract

“Obesity and cardiometabolic risk, or the metabolic syndrome, continue to be major public health concerns. To date, treatment with lifestyle and pharmacotherapy interventions has resulted in limited efficacy in reversing the upward trend in this present-day health crisis. Research reveals that a modest 5% to 10% weight loss results in substantial improvement in health. While obtaining modest weight loss is often achievable, maintaining lost weight is challenging. Research has recently improved our understanding of several endogenous pathways that influence body weight regulation and disease risk. The endocannabinoid system has been found to regulate appetite and energy expenditure, as well as lipid and glucose metabolism. Interest in blocking stimulation of this pathway to aid weight loss and reduce cardiometabolic risk factor development is an area of interest and research. This article reviews the mechanisms by which the endocannabinoid system is believed to influence body weight regulation and cardiometabolic risk factors, as well as the results of clinical trials investigating the safety and efficacy of a selective cannabinoid-1 receptor antagonist (rimonabant). Clinical trials investigating rimonabant treatment resulted in substantial reductions in body weight and markers for cardiometabolic risk in study participants. However, increases in adverse events were reported in the drug-treated group. Data regarding long-term benefit and adverse events from rimonabant treatment are being collected in several ongoing clinical trials. Rimonabant is currently available in 42 countries, but has not received United States Food and Drug Administration approval. Food and nutrition professionals play a pivotal role in tackling the current obesity crisis; it is essential that they understand the many physiological mechanisms regulating body weight. Emerging research data reveals pathways that influence appetite and energy metabolism, and this knowledge may form the foundation for new clinical treatment options for obese individuals.”

http://www.ncbi.nlm.nih.gov/pubmed/18442506

The endocannabinoid system: its roles in energy balance and potential as a target for obesity treatment.

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Abstract

“Obesity and cardiometabolic risk continue to be major public health concerns. A better understanding of the physiopathological mechanisms leading to obesity may help to identify novel therapeutic targets. The endocannabinoid system discovered in the early 1990s is believed to influence body weight regulation and cardiometabolic risk factors. This article aims to review the literature on the endocannabinoid system including the biological roles of its major components, namely, the cannabinoid receptors, their endogenous ligands the endocannabinoids and the ligand-metabolising enzymes. The review also discusses evidence that the endocannabinoid system constitutes a new physiological pathway occurring in the central nervous system and peripheral tissues that has a key role in the control of food intake and energy expenditure, insulin sensitivity, as well as glucose and lipid metabolism. Based on the important finding that there is a close association between obesity and the hyperactivity of the endocannabinoid system, interest in blocking stimulation of this pathway to aid weight loss and reduce cardiometabolic risk factor development has become an important area of research. Among the pharmacological strategies proposed, the antagonism of the cannabinoid receptors has been particularly investigated and several clinical trials have been conducted. One challenging pharmacological task will be to target the endocannabinoid system in a more selective, and hence, safe way. As the management of obesity also requires lifestyle modifications in terms of healthy eating and physical activity, the targeting of the endocannabinoid system may represent a novel approach for a multifactorial therapeutic strategy.”

http://www.ncbi.nlm.nih.gov/pubmed/20541029

The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis

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“The therapeutic potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis, was explored in murine collagen-induced arthritis (CIA).

CBD was administered after onset of clinical symptoms, and in both models of arthritis the treatment effectively blocked progression of arthritis. CBD was equally effective when administered i.p. or orally.

Clinical improvement was associated with protection of the joints against severe damage.

Taken together, these data show that CBD, through its combined immunosuppressive and anti-inflammatory actions, has a potent anti-arthritic effect in CIA.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC16904/

“In the present study, we report that CBD has a beneficial therapeutic action on established CIA, and we explore its mode of action.”   http://www.pnas.org/content/97/17/9561.long

Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma

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“Because cannabinoid receptor agonists are capable of reducing proliferation and inducing apoptosis (cell death) in diverse cancer cells such as glioma, breast cancer, and melanoma, we evaluated whether CB1 is a potential drug target in rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children…

 Our study shows that treatment with the cannabinoid receptor agonists HU210 (cloned THC from Hebrew University) and Delta(9)-tetrahydrocannabinol (THC from cannabis) lowers the viability of translocation-positive rhabdomyosarcoma cells through the induction of apoptosis…

These results support the notion that cannabinoid receptor agonists could represent a novel targeted approach for treatment of translocation-positive rhabdomyosarcoma.”

Full text: http://mct.aacrjournals.org/content/8/7/1838.long

The effects of hempseed meal intake and linoleic acid on Drosophila models of neurodegenerative diseases and hypercholesterolemia

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Molecules and Cells

“Hemp seed is rich in polyunsaturated fatty acids (PUFAs), which have potential as therapeutic compounds for the treatment of neurodegenerative and cardiovascular disease.

In this study, we assessed the effects of the intake of  hempseed meal (HSM) and PUFAs on oxidative stress, cytotoxicity and neurological phenotypes, and cholesterol uptake, using Drosophila models.

HSM intake was shown to reduce H(2)O(2) toxicity markedly, indicating that HSM exerts a profound antioxidant effect.

Meanwhile, intake of HSM, as well as linoleic or linolenic acids (major PUFA components of HSM) was shown to ameliorate Aβ42-induced eye degeneration, thus suggesting that these compounds exert a protective effect against Aβ42 cytotoxicity.

Additionally, intake of HSM or linoleic acid was shown to reduce cholesterol uptake significantly.

Moreover, linoleic acid intake has been shown to delay pupariation, and cholesterol feeding rescued the linoleic acid-induced larval growth delay, thereby indicating that linoleic acid acts antagonistically with cholesterol during larval growth.

In conclusion, our results indicate that HSM and linoleic acid exert inhibitory effects on both Aβ42 cytotoxicity and cholesterol uptake, and are potential candidates for the treatment of Alzheimer’s disease and cardiovascular disease.”

http://www.ncbi.nlm.nih.gov/pubmed/21331775 

“A number of previous studies have shown that polyunsaturated fatty acids (PUFAs) and phytosterols are critically important for human health. Hempseed is a rich source of plant oil, which contains more than 80% PUFAs and 3922-6719 mg/kg of phytosterols (e.g., sitosterol and campesterol). The fatty acids in hempseed oil include a variety of essential fatty acids, including linoleic acid ”

https://link.springer.com/article/10.1007%2Fs10059-011-0042-6

Anti-tumoral Action of Cannabinoids

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“Delta9-Tetrahydrocannabinol, the main active component of marijuana… Here, we show that intratumoral administration of Delta9-tetrahydrocannabinol… induced a considerable regression of malignant gliomas… Cannabinoid treatment did not produce any substantial neurotoxic effect… cannabinoids signal apoptosis (cell death/suicide) by a pathway involving cannabinoid receptors… These results may provide the basis for a new therapeutic approach for the treatment of malignant gliomas.”

‎”Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death…”

http://www.ncbi.nlm.nih.gov/pubmed/10700234