Category Archives: Obesity

Association Between Use of Cannabis in Adolescence and Weight Change into Midlife.

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“Cannabis use has been found to stimulate appetite and potentially promote weight gain via activation of the endocannabinoid system.

Despite the fact that the onset of cannabis use is typically during adolescence, the association between adolescence cannabis use and long-term change in body weight is generally unknown.

This study aims to examine the association between adolescence cannabis use and weight change to midlife, while accounting for the use of other substances.

In conclusion, this study does not provide evidence of an association between adolescence cannabis use and weight change from adolescence to midlife.”

 https://www.ncbi.nlm.nih.gov/pubmed/28060830

Dietary olive oil induces cannabinoid CB2 receptor expression in adipose tissue of ApcMin/+ transgenic mice.

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“Cannabinoid– 2 (CB2) receptor is known for its anti-obesity effects silencing the activated immune cells that are key drivers of metabolic syndrome and inflammation.

Nutritional interventions in experimental models of carcinogenesis have been demonstrated to modulate tissue inflammation state and proliferation.

OBJECTIVE: Aim of this study was to test, in ApcMin/+ mice, whether a diet enriched with olive oil, omega- 3 and omega-6- PUFAs affects the adipose tissue inflammation status.

RESULTS: The diet enriched with olive oil significantly induced CB2 receptor expression and it was able to control inflammatory and proliferative activity of mice adipose tissue.

CONCLUSIONS: The present findings open opportunities for developing novel nutritional strategies considering olive oil a key ingredient of a healthy dietary pattern.”

 https://www.ncbi.nlm.nih.gov/pubmed/28035344

Cannabinoid 2 Receptor Agonist Improves Systemic Sensitivity to Insulin in High-Fat Diet/Streptozotocin-Induced Diabetic Mice.

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“The endocannabinoid signalling (ECS) system has been known to regulate glucose homeostasis.

Previous studies have suggested that the cannabinoid 2 (CB2) receptor may play a regulatory role on insulin secretion, immune modulation and insulin resistance.

Given that diabetes and insulin resistance are attributable to elevated inflammatory tone, we investigated the role of CB2 receptor on glucose tolerance and insulin sensitivity in high-fat diet (HFD)/streptozotocin (STZ)-induced mice.

Our data suggest a lipolytic role of SER601 in HFD/STZ-induced diabetic mice, which results in significant improvement of systemic insulin sensitivity.

Thus, the CB2 receptor may be considered a promising target for therapeutic development against insulin resistance and obesity-related diabetes.”

https://www.ncbi.nlm.nih.gov/pubmed/27960161

Fetal Syndrome of Endocannabinoid Deficiency (FSECD) In Maternal Obesity.

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“The theory of a fetal origin of adult diseases links many pathological conditions to very early life events and is known as a “developmental programming” phenomenon. The mechanisms of this phenomenon are not quite understood and have been explained by inflammation, stress, etc. In particular the epidemic of obesity, with more than 64% of women being overweight or obese, has been associated with conditions in later life such as mental disorders, diabetes, asthma, and irritable bowel syndrome.

Interestingly, these diseases were classified a decade ago as Clinical Syndrome of Endocannabinoid Deficiency (CECD), which was first described by Russo in 2004.

Cannabinoids have been used for the treatment of chronic pain for millenniums and act through the mechanism of “kick-starting” the components of the endogenous cannabinoid system (ECS).

ECS is a pharmacological target for the treatment of obesity, inflammation, cardiovascular and neuronal damage, and pain.

We hypothesize that the deteriorating effect of maternal obesity on offspring health is explained by the mechanism of Fetal Syndrome of Endocannabinoid Deficiency (FSECD), which accompanies maternal obesity. Here we provide support for this hypothesis.”

https://www.ncbi.nlm.nih.gov/pubmed/27959272

Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome.

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“Extreme obesity is a core phenotypic feature of Prader-Willi syndrome (PWS).

Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R) blockade reverses obesity both in animals and humans.

The first-in-class CB1R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects.

CONCLUSIONS:

Dysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS.”

https://www.ncbi.nlm.nih.gov/pubmed/27900261

Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance.

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“We recently showed that the peripheral cannabinoid receptor type 1 (CNR1) gene is upregulated by the synthetic glucocorticoid dexamethasone.

CNR1 is highly expressed in the central nervous system and has been a drug target for the treatment of obesity.

Here we explore the role of peripheral CNR1 in states of insulin resistance in human adipose tissue.

CNR1 is upregulated in states of type 2 diabetes and insulin resistance.

Furthermore, CNR1 is involved in glucocorticoid-regulated lipolysis.

Peripheral CNR1 could be an interesting drug target in type 2 diabetes and dyslipidemia.”

https://www.ncbi.nlm.nih.gov/pubmed/27858284

Crystal Structure of the Human Cannabinoid Receptor CB1.

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“Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use.

CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders.

Here, we present the 2.8 Å crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study.

The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding.

In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids.

This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.”

https://www.ncbi.nlm.nih.gov/pubmed/27768894

Dendritic Cell Regulation by Cannabinoid-Based Drugs.

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“Cannabinoid pharmacology has made important advances in recent years after the cannabinoid system was discovered.

Studies in experimental models and in humans have produced promising results using cannabinoid-based drugs for the treatment of obesity and cancer, as well as neuroinflammatory and chronic inflammatory diseases.

Moreover, as we discuss here, additional studies also indicates that these drugs have immunosuppressive and anti-inflammatory properties including modulation of immune cell function.

Thus, manipulation of the endocannabinoid system in vivo may provide novel therapeutic strategies against inflammatory disorders.

At least two types of cannabinoid receptors, cannabinoid 1 and cannabinoid 2 receptors are expressed on immune cells such as dendritic cells (DC). Dendritic cells are recognized for their critical role in initiating and maintaining immune responses.

Therefore, DC are potential targets for cannabinoid-mediated modulation.

Here, we review the effects of cannabinoids on DC and provide some perspective concerning the therapeutic potential of cannabinoids for the treatment of human diseases involving aberrant inflammatory processes.”

https://www.ncbi.nlm.nih.gov/pubmed/27713374

Tetrahydropyrazolo[4,3-c]pyridine derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists.

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“Peripherally restricted CB1 receptor inverse agonists hold potential as useful therapeutics to treat obesity and related metabolic diseases without causing undesired CNS-mediated adverse effects. We identified a series of tetrahydropyrazolo[4,3-c]pyridine derivatives as potent and highly peripherally selective CB1 receptor inverse agonists. This discovery was achieved by introducing polar functional groups into the molecule, which increase the topological polar surface area and reduce its brain-penetrating ability.”

https://www.ncbi.nlm.nih.gov/pubmed/27671499

“Tetrahydroindazole derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists. A series of potent and receptor-selective cannabinoid-1 (CB1) receptor inverse agonists has been discovered. Peripheral selectivity of the compounds was assessed by a mouse tissue distribution study, in which the concentrations of a test compound in both plasma and brain were measured. A number of peripherally selective compounds have been identified through this process. Compound 2p was further evaluated in a 3-week efficacy study in the diet-induced obesity (DIO) mouse model. Beneficial effects on plasma glucose were observed from the compound-treated mice.”  https://www.ncbi.nlm.nih.gov/pubmed/27671496

The syntheses of isotopically labelled CB-1 antagonists for the treatment of obesity.

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“BMS-725519, BMS-811064, and BMS-812204 are potent and selective central cannabinoid receptor antagonists that have been investigated for the treatment of human obesity. To further understand their biotransformation profiles, radiolabelled and stable-labelled products were required. This paper describes the utility of [14 C]1,1-carbonyldiimidazole as a radiolabelling reagent for the syntheses of carbonyl-labelled [14 C]BMS-725519, [14 C]BMS-811064, and [14 C]BMS-812204. The syntheses of stable-labelled [13 C6 ]BMS-725519 and [13 CD3 13 CD2 ]BMS-812204 synthesized from of [13 C6 ]4-chloroacetophenone and [13 CD3 13 CD2 ]iodoethane, respectively, are also described.”

http://www.ncbi.nlm.nih.gov/pubmed/27624665