Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages.

J Clin Invest

“Dysregulated adipocyte physiology leads to imbalanced energy storage, obesity, and associated diseases, imposing a costly burden on current health care.

Cannabinoid receptor type-1 (CB1) plays a crucial role in controlling energy metabolism through central and peripheral mechanisms.

In this work, adipocyte-specific inducible deletion of the CB1 gene (Ati-CB1-KO) was sufficient to protect adult mice from diet-induced obesity and associated metabolic alterations and to reverse the phenotype in already obese mice. Compared with controls, Ati-CB1-KO mice showed decreased body weight, reduced total adiposity, improved insulin sensitivity, enhanced energy expenditure, and fat depot-specific cellular remodeling toward lowered energy storage capacity and browning of white adipocytes. These changes were associated with an increase in alternatively activated macrophages concomitant with enhanced sympathetic tone in adipose tissue.

Remarkably, these alterations preceded the appearance of differences in body weight, highlighting the causal relation between the loss of CB1 and the triggering of metabolic reprogramming in adipose tissues. Finally, the lean phenotype of Ati-CB1-KO mice and the increase in alternatively activated macrophages in adipose tissue were also present at thermoneutral conditions.

Our data provide compelling evidence for a crosstalk among adipocytes, immune cells, and the sympathetic nervous system (SNS), wherein CB1 plays a key regulatory role.”

https://www.ncbi.nlm.nih.gov/pubmed/29035280

https://www.jci.org/articles/view/83626

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Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling.

Molecular Metabolism

“In visceral obesity, an overactive endocannabinoid/CB1 receptor (CB1R) system promotes increased caloric intake and decreases energy expenditure, which are mitigated by global or peripheral CB1R blockade. In mice with diet-induced obesity (DIO), inhibition of food intake by the peripherally restricted CB1R antagonist JD5037 could be attributed to endogenous leptin due to the rapid reversal of hyperleptinemia that maintains leptin resistance, but the signaling pathway engaged by leptin has remained to be determined.

METHODS:

We analyzed the hypothalamic circuitry targeted by leptin following chronic treatment of DIO mice with JD5037.

RESULTS:

Leptin treatment or an increase in endogenous leptin following fasting/refeeding induced STAT3 phosphorylation in neurons in the arcuate nucleus (ARC) in lean and JD5037-treated DIO mice, but not in vehicle-treated DIO animals. Co-localization of pSTAT3 in leptin-treated mice was significantly less common with NPY+ than with POMC+ ARC neurons. The hypophagic effect of JD5037 was absent in melanocortin-4 receptor (MC4R) deficient obese mice or DIO mice treated with a MC4R antagonist, but was maintained in NPY-/- mice kept on a high-fat diet.

CONCLUSIONS:

Peripheral CB1R blockade in DIO restores sensitivity to endogenous leptin, which elicits hypophagia via the re-activation of melanocortin signaling in the ARC.”

https://www.ncbi.nlm.nih.gov/pubmed/29031713

http://www.molmetab.com/article/S2212-8778(17)30327-7/fulltext

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Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy.

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“Altered glucose reabsorption via the facilitative glucose transporter 2 (GLUT2) during diabetes may lead to renal proximal tubule cell (RPTC) injury, inflammation, and interstitial fibrosis. These pathologies are also triggered by activating the cannabinoid-1 receptor (CB1R), which contributes to the development of diabetic nephropathy (DN). However, the link between CB1R and GLUT2 remains to be determined. Here, we show that chronic peripheral CB1R blockade or genetically inactivating CB1Rs in the RPTCs ameliorated diabetes-induced renal structural and functional changes, kidney inflammation, and tubulointerstitial fibrosis in mice. Inhibition of CB1R also downregulated GLUT2 expression, affected the dynamic translocation of GLUT2 to the brush border membrane of RPTCs, and reduced glucose reabsorption. Thus, targeting peripheral CB1R or inhibiting GLUT2 dynamics in RPTCs has the potential to treat and ameliorate DN. These findings may support the rationale for the clinical testing of peripherally restricted CB1R antagonists or the development of novel renal-specific GLUT2 inhibitors against DN.”

https://www.ncbi.nlm.nih.gov/pubmed/29030466

http://jasn.asnjournals.org/content/early/2017/10/12/ASN.2017040371

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Re-visiting the Endocannabinoid System and Its Therapeutic Potential in Obesity and Associated Diseases.

 Current Diabetes Reports

“The purpose of the review was to revisit the possibility of the endocannabinoid system being a therapeutic target for the treatment of obesity by focusing on the peripheral roles in regulating appetite and energy metabolism.

Previous studies with the global cannabinoid receptor blocker rimonabant, which has both central and peripheral properties, showed that this drug has beneficial effects on cardiometabolic function but severe adverse psychiatric side effects. Consequently, focus has shifted to peripherally restricted cannabinoid 1 (CB1) receptor blockers as possible therapeutic agents that mitigate or eliminate the untoward effects in the central nervous system.

Targeting the endocannabinoid system using novel peripheral CB1 receptor blockers with negligible penetrance across the blood-brain barrier may prove to be effective therapy for obesity and its co-morbidities.

Perhaps the future of blockers targeting CB1 receptors will be tissue-specific neutral antagonists (e.g., skeletal muscle specific to treat peripheral insulin resistance, adipocyte-specific to treat fat excess, liver-specific to treat fatty liver and hepatic insulin resistance).”

https://www.ncbi.nlm.nih.gov/pubmed/28913816

https://link.springer.com/article/10.1007%2Fs11892-017-0924-x

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The role of cannabinoid receptors in renal diseases.

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“Chronic kidney disease (CKD) remains a major challenge for Public Health systems and corresponds to the replacement of renal functional tissue by extra-cellular matrix proteins such as collagens and fibronectin. There is no efficient treatment to date for CKD except nephroprotective strategies.

The cannabinoid system and more specifically the cannabinoid receptors 1 (CB1) and 2 (CB2) may represent a new therapeutic target in CKD.

Our review will first focus on the current state of knowledge regarding the cannabinoid system in normal renal physiology and in various experimental nephropathies, especially diabetes.  We will review the data obtained in models of diabetes and obesity as well as in nonmetabolic models of renal fibrosis and emphasizes the promising role of CB1 blockers and CB2 agonists in the development of renal disease and fibrosis. Next, we will review the current state of knowledge regarding the cellular pathways involved in renal fibrogenesis and renal injury.

Overall, this review will highlight the therapeutic potential of targeting the cannabinoid receptors in CKD and diabetes.”

https://www.ncbi.nlm.nih.gov/pubmed/28901271

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Polymorphism rs3123554 in the cannabinoid receptor gene type 2 (CNR2) reveals effects on body weight and insulin resistance in obese subjects.

Endocrinología, Diabetes y Nutrición

“Few studies assessing the relationship between single nucleotide polymorphisms in CNR2 and obesity or its related metabolic parameters are available.

OBJECTIVE:

To investigate the influence of polymorphism rs3123554 in the CNR2 receptor gene on obesity anthropometric parameters, insulin resistance, and adipokines in subjects with obesity.

DESIGN:

The study population consisted of 1027 obese subjects, who were performed bioelectrical impedance analyses, blood pressure measurements, serial assessments of dietary intake during three days, and biochemical tests.

RESULTS:

Genotypes GG, GA, and AA were found in 339 (33.0%), 467 (45.5%), and 221 (21.5%) respectively. Body mass index, weight, fat mass, waist circumference, insulin, HOMA-IR, and triglyceride and leptin levels were higher in A-allele carriers as compared to non A-allele carriers. No differences were seen in these parameters between the GA and AA genotypes. There were no statistical differences in dietary intake.

CONCLUSION:

The main study finding was the association of the minor allele of the SNP rs3123554 in the CNR2 gene with body weight and triglyceride, HOMA-IR, insulin, and leptin levels.”

https://www.ncbi.nlm.nih.gov/pubmed/28895540

http://www.sciencedirect.com/science/article/pii/S2530016417301799?via%3Dihub

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The cannabinoid ligand LH-21 reduces anxiety and improves glucose handling in diet-induced obese pre-diabetic mice.

“LH-21 is a triazol derivative that has been described as a low-permeant neutral CB1 antagonist, though its pharmacology is still unclear. It has been associated with anti-obesity actions in obese rats. However, its role in preventing type 2 diabetes (T2D) onset have not been studied yet. Given CB1 receptors remain as potential pharmacological targets to fight against obesity and T2D, we wanted to explore the metabolic impact of this compound in an animal model of obesity and pre-diabetes as well as the lack of relevant actions in related central processes such as anxiety. These results suggest that LH-21 can be a new candidate to fight against diabetes onset. Indeed, this compound shows potential in counteracting obesity-related anxiety.” https://www.ncbi.nlm.nih.gov/pubmed/28638091   https://www.nature.com/articles/s41598-017-03292-w

“Anti-obesity efficacy of LH-21, a cannabinoid CB(1) receptor antagonist with poor brain penetration, in diet-induced obese rats.”  https://www.ncbi.nlm.nih.gov/pubmed/21951309

“Antiobesity effects of the novel in vivo neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole–LH 21.”  https://www.ncbi.nlm.nih.gov/pubmed/16750544

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In Vivo Cannabidiol Treatment Improves Endothelium-Dependent Vasorelaxation in Mesenteric Arteries of Zucker Diabetic Fatty Rats.

 

 

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“We have shown that in vitro treatment with cannabidiol (CBD, 2 h) enhances endothelial function in arteries from Zucker diabetic fatty (ZDF) rats, partly due to a cyclooxygenase (COX)-mediated mechanism.

The aim of the present study was to determine whether treatment with CBD in vivo would also enhance endothelial function.

Conclusion and implications: Short-term in vivo treatment with CBD improves ex vivo endothelium-dependent vasorelaxation in mesenteric arteries from ZDF rats due to COX- or NO-mediated mechanisms, and leads to improvements in serum biomarkers.”  https://www.ncbi.nlm.nih.gov/pubmed/28572770

“In conclusion, this study has shown that a short in vivo treatment protocol with CBD was associated with improvements in endothelium-dependent vasorelaxation in mesenteric arteries, and an improvement in the profile of cardiovascular and metabolic parameters. The current study supports the growing evidence that CBD may be beneficial against a number of problems associated with diabetes including inflammation, endothelial dysfunction, cardiomyopathy, retinal function, and neuropathic pain.”  http://journal.frontiersin.org/article/10.3389/fphar.2017.00248/full
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GPR55 and the regulation of glucose homeostasis.

Image result for Int J Biochem Cell Biol.

“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

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Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy.

Image result for Nephrol Dial Transplant

“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

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