GPR55 and the regulation of glucose homeostasis.

Posted on May 2, 2017 by David

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“Pathophysiological conditions such as obesity and type 2 diabetes (T2D) are reportedly associated to over-activation of the endocannabinoid system (ECS). Therefore, modulation of the ECS offers potential therapeutic benefits on those diseases. GPR55, the receptor for L-α-lysophosphatidylinositol (LPI) that has also affinity for various cannabinoid ligands, is distributed at the central and peripheral level and it is involved in several physiological processes. This review summarizes the localization and role of GPR55 in tissues that are crucial for the regulation of glucose metabolism, and provides an update on its contribution in obesity and insulin resistance. The therapeutic potential of targeting the GPR55 receptor is also discussed.”

https://www.ncbi.nlm.nih.gov/pubmed/28457969

Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy.

Posted on April 8, 2017 by David

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“The endocannabinoid system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effect of combined therapy with AM6545, a ‘peripherally’ restricted cannabinoid receptor type 1 (CB1R) neutral antagonist, and AM1241, a cannabinoid receptor type 2 (CB2R) agonist, in experimental DN.

RESULTS.:

Single treatment with either AM6545 or AM1241 alone reduced diabetes-induced albuminuria and prevented nephrin loss both in vivo and in vitro in podocytes exposed to glycated albumin. Dual therapy performed better than monotherapies, as it abolished albuminuria, inflammation, tubular injury and markedly reduced renal fibrosis. Converging anti-inflammatory mechanisms provide an explanation for this greater efficacy as dual therapy abolished diabetes-induced renal monocyte infiltration and M1/M2 macrophage imbalance in vivo and abrogated the profibrotic effect of M1 macrophage-conditioned media on cultured mesangial cells.

CONCLUSION.:

‘Peripheral’ CB1R blockade is beneficial in experimental DN and this effect is synergically magnified by CB2R activation.”

https://www.ncbi.nlm.nih.gov/pubmed/28387811

Overactivation of the endocannabinoid system alters the anti-lipolytic action of insulin in mouse adipose tissue.

Posted on March 23, 2017 by David

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“Evidence has accumulated that obesity-related metabolic dysregulation is associated with overactivation of the endocannabinoid system (ECS), which involves cannabinoid receptor 1 (CB1R), in peripheral tissues, including adipose tissue (AT).

The functional consequences of CB1R activation on AT metabolism remain unclear. Since excess fat mobilization is considered an important primary event contributing to the onset of insulin resistance, we combined in vivo and in vitro experiments to investigate whether activation of ECS could alter the lipolytic rate.

For this purpose, the appearance of plasma glycerol was measured in wild-type and CB1R^-/- mice after acute anandamide administration or inhibition of endocannabinoid degradation by JZL195. Additional experiments were conducted on rat AT explants to evaluate the direct consequences of ECS activation on glycerol release and signaling pathways.

Treatments stimulated glycerol release in mice fasted for 6 h and injected with glucose but not in 24-h fasted mice or in CB1R^-/-suggesting that the effect was dependent on plasma insulin levels and mediated by CB1R. We concomitantly observed that Akt cascade activity was decreased, indicating an alteration of the anti-lipolytic action of insulin.

Similar results were obtained with tissue explants exposed to anandamide, thus identifying CB1R of AT as a major target.

This study indicates the existence of a functional interaction between CB1R and lipolysis regulation in AT. Further investigation is needed to test whether the elevation of ECS tone encountered in obesity is associated with excess fat mobilization contributing to ectopic fat deposition and related metabolic disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/28325733

Antidiabetic, antidyslipidemic and toxicity profile of ENV-2: A potent pyrazole derivative against diabetes and related diseases.

Posted on March 23, 2017 by David

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“Diabetes is a major health problem and a predisposition factor for further degenerative complications and, therefore, novel therapies are urgently needed. Currently, cannabinoid receptor 1 (CB₁ receptor) antagonists have been considered as promissory entities for metabolic disorders treatment.

Accordingly, the purpose of this work was the evaluation of the sub-acute antidiabetic, anti-hyperglycemic, antidyslipidemic and toxicological profile of ENV-2, a potent hypoglycemic and antioxidant CB₁ receptor antagonist.

In this study, ENV-2 showed a pronounced anti-hyperglycemic effect even at a dose of 5mg/kg (P< 0.001) in a glucose tolerance test on normoglycemic rats. Moreover, after administration of ENV-2 (16mg/kg) to diabetic rats, a prominent antidiabetic activity was observed (P< 0.001), which was higher than glibenclamide.

Sub-acute treatment (10 days) of ENV-2 resulted in a significant reduction of plasma glucose (P< 0.001). Also, the levels of peripheral lipids were improved; blood triacylglycerols (TG) and cholesterol (CHOL) were diminished (P< 0.001). In addition, it was found that ENV-2 reduced IL-1β and IL-18 mRNA expression in adipose tissue (P< 0.05). Due to the satisfactory outcomes, we were interested in evaluating the toxicity of ENV-2 in both acute and sub-chronic approaches. Regarding the acute administration, the compound resulted to be non-toxic and was grouped in category 5 according to OECD. It was also found that sub-chronic administration did not increase the size of the studied organs, while no structural damage was observed in heart, lung, liver and kidney tissues. Finally, neither AST nor ALT damage hepatic markers were augmented.”

https://www.ncbi.nlm.nih.gov/pubmed/28322830

2-Arachidonoylglycerol ameliorates inflammatory stress-induced insulin resistance in cardiomyocytes.

Posted on March 23, 2017 by David

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“Several studies have linked impaired glucose uptake and insulin resistance (IR) to functional impairment of the heart. Recently, endocannabinoids have been implicated in cardiovascular disease. However, the mechanisms involving endocannabinoid signaling, glucose uptake and IR in cardiomyocytes are understudied.

Here, we report the endocannabinoid 2-Arachidonoylglycerol (2-AG) via stimulation of cannabinoid type-1 (CB1) receptor and Ca2+/Calmodulin-dependent protein kinase β (CaMKKβ) activates AMPK leading to increased glucose uptake. Interestingly, we have observed that the mRNA expression of CB1 and CB2 receptors was decreased in diabetic mice, indicating reduced endocannabinoid signaling in diabetic heart. We further establish that TNFα induces IR in cardiomyocytes.

Treatment with 2-AG suppresses TNFα-induced pro-inflammatory markers, and improves IR and glucose uptake. Conversely, pharmacological inhibition or knockdown of AMPK attenuates the anti-inflammatory effect and reversal of IR elicited by 2-AG. Additionally, in human embryonic stem cell-derived cardiomyocytes challenged with TNFα or free fatty acid (FFA), we demonstrate that 2-AG improves insulin sensitivity and glucose uptake.

In conclusion, 2-AG abates inflammatory responses, increases glucose uptake and overcomes IR in an AMPK-dependent manner in cardiomyocytes.”

https://www.ncbi.nlm.nih.gov/pubmed/28320859

MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future.

Posted on March 2, 2017 by David

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“The endocannabinoid system (ECS), including cannabinoid type 1 and type 2 receptors (CB1R and CB2R), endogenous ligands called endocannabinoids and their related enzymatic machinery, is known to have a role in the regulation of energy balance.

Past information generated on the ECS, mainly focused on the involvement of this system in the central nervous system regulation of food intake, while at the same time clinical studies pointed out the therapeutic efficacy of brain-penetrant CB1R antagonists like rimonabant for obesity and metabolic disorders.

Rimonabant was removed from the market in 2009 and its obituary written due to its psychiatric side effects. However, in the meanwhile a number of investigations had started to highlight the roles of the peripheral ECS in the regulation of metabolism, bringing up new hope that the ECS might still represent target for treatment.

Accordingly, peripherally-restricted CB1R antagonists or inverse agonists have shown to effectively reduce body weight, adiposity, insulin resistance and dyslipidemia in obese animal models.

Very recent investigations have further expanded the possible toolbox for the modulation of the ECS, by demonstrating the existence of endogenous allosteric inhibitors of CB1R, the characterization of the structure of the human CB1R, and the likely involvement of CB2R in metabolic disorders. Here we give an overview of these findings, discussing what the future may hold in the context of strategies targeting the ECS in metabolic disease.”

https://www.ncbi.nlm.nih.gov/pubmed/28246151

Effects of tetrahydrocannabinol on glucose uptake in the rat brain.

Posted on February 22, 2017 by David

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“Δ⁹-Tetrahydrocannabinol (THC) is the psychoactive component of the plant Cannabis sativa and acts as a partial agonist at cannabinoid type 1 and type 2 receptors in the brain.

The goal of this study was to assess the effect of THC on the cerebral glucose uptake in the rat brain.

Low blood THC levels of <1 ng/ml corresponded to an increased glucose uptake while blood THC levels > 10 ng/ml coincided with a decreased glucose uptake. The effective concentration in this region was estimated 2.4 ng/ml.

This glucose PET study showed that stimulation of CB1 receptors by THC affects the glucose uptake in the rat brain, whereby the effect of THC is regionally different and dependent on dose – an effect that may be of relevance in behavioural studies.”

https://www.ncbi.nlm.nih.gov/pubmed/28219717

GPR55: a new promising target for metabolism?

Posted on February 16, 2017 by David

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“GPR55 is a G-protein coupled receptor (GPCR) that has been identified as a new cannabinoid receptor. Given the wide localization of GPR55 in brain and peripheral tissues, this receptor has emerged as a regulator of multiple biological actions. Lysophosphatidylinositol (LPI) is generally accepted as the endogenous ligand of GPR55. In this review, we will focus on the role of GPR55 in energy balance and glucose metabolism. We will summarize its actions on feeding, nutrient partitioning, gastrointestinal motility and insulin secretion in preclinical models and the scarce data available in humans. The potential of GPR55 to become a new pharmaceutical target to treat obesity and type 2 diabetes, as well as the foreseeing difficulties are also discussed.” https://www.ncbi.nlm.nih.gov/pubmed/28196832

“GPR55 – a putative “type 3” cannabinoid receptor in inflammation.” https://www.ncbi.nlm.nih.gov/pubmed/26669245

http://www.thctotalhealthcare.com/tag/gpr55/

The endocannabinoid system: no longer anonymous in the control of nitrergic signalling?

Posted on January 29, 2017 by David

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“The endocannabinoid system (ECS) is a key cellular signalling system that has been implicated in the regulation of diverse cellular functions. Importantly, growing evidence suggests that the biological actions of the ECS may, in part, be mediated through its ability to regulate the production and/or release of nitric oxide, a ubiquitous bioactive molecule, which functions as a versatile signalling intermediate. Herein, we review and discuss evidence pertaining to ECS-mediated regulation of nitric oxide production, as well as the involvement of reactive nitrogen species in regulating ECS-induced signal transduction by highlighting emerging work supporting nitrergic modulation of ECS function. Importantly, the studies outlined reveal that interactions between the ECS and nitrergic signalling systems can be both stimulatory and inhibitory in nature, depending on cellular context. Moreover, such crosstalk may act to maintain proper cell function, whereas abnormalities in either system can undermine cellular homoeostasis and contribute to various pathologies associated with their dysregulation. Consequently, future studies targeting these signalling systems may provide new insights into the potential role of the ECS -: nitric oxide signalling axis in disease development and/or lead to the identification of novel therapeutic targets for the treatment of nitrosative stress-related neurological, cardiovascular, and metabolic disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/28130308

Developmental Role of Macrophage Cannabinoid-1 Receptor Signaling in Type-2 Diabetes.

Posted on January 14, 2017 by David

“Islet inflammation promotes β-cell loss and type-2 diabetes (T2D), a process replicated in Zucker Diabetic Fatty (ZDF) rats in which β-cell loss has been linked to cannabinoid-1 receptor (CB₁R)-induced pro-inflammatory signaling in macrophages infiltrating pancreatic islets.

Here, we analyzed CB₁R signaling in macrophages and its developmental role in T2Dα. ZDF rats with global deletion of CB₁R are protected from β-cell loss, hyperglycemia and nephropathy present in ZDF littermates.

Adoptive transfer of CB₁R^-/- bone marrow to ZDF rats also prevents β-cell loss and hyperglycemia, but not nephropathy. ZDF islets contain elevated levels of CB₁R, IL-1β, TNF-α, the chemokine CCL2 and interferon regulatory factor-5 (IRF5), a marker of M1 inflammatory macrophage polarization.

In primary cultured rodent and human macrophages, CB₁R activation increased Irf5 expression, whereas knockdown of Irf5 blunted CB₁R-induced secretion of inflammatory cytokines without affecting CCL2 expression, which was p38MAPKα-dependent. Macrophage-specific in vivo knockdown of Irf5 protected ZDF rats from β-cell loss and hyperglycemia.

Thus, IRF5 is a crucial downstream mediator of diabetogenic CB₁R signaling in macrophages and a potential therapeutic target.”

https://www.ncbi.nlm.nih.gov/pubmed/28082458