Category Archives: Obesity

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

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 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

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

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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

Proximal Tubular Cannabinoid-1 Receptor Regulates Obesity-Induced CKD.

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“Obesity-related structural and functional changes in the kidney develop early in the course of obesity and occur independently of hypertension, diabetes, and dyslipidemia. Activating the renal cannabinoid-1 receptor (CB1R) induces nephropathy, whereas CB1R blockade improves kidney function. Whether these effects are mediated via a specific cell type within the kidney remains unknown. Here, we show that specific deletion of CB1R in the renal proximal tubule cells did not protect the mice from obesity, but markedly attenuated the obesity-induced lipid accumulation in the kidney and renal dysfunction, injury, inflammation, and fibrosis. These effects associated with increased activation of liver kinase B1 and the energy sensor AMP-activated protein kinase, as well as enhanced fatty acid β-oxidation. Collectively, these findings indicate that renal proximal tubule cell CB1R contributes to the pathogenesis of obesity-induced renal lipotoxicity and nephropathy by regulating the liver kinase B1/AMP-activated protein kinase signaling pathway.”

https://www.ncbi.nlm.nih.gov/pubmed/28860163

http://jasn.asnjournals.org/content/early/2017/08/30/ASN.2016101085

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

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“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

Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities.

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“Cannabinoid pharmacology has been intensely studied because of cannabis’ pervasive medicinal and non-medicinal uses as well as for the therapeutic potential of cannabinoid-based drugs for the treatment of pain, anxiety, substance abuse, obesity, cancer and neurodegenerative disorders. The identification of allosteric modulators of the cannabinoid receptor 1 (CB1) has given a new direction to the development of cannabinoid-based therapeutics due to the many advantages offered by targeting allosteric site(s). Allosteric receptor modulators hold potential to develop subtype-specific and pathway-specific therapeutics. Here we briefly discuss the first-generation of allosteric modulators of CB1 receptor, their structure-activity relationships, signaling pathways and the allosteric binding site(s) on the CB1 receptor.”

https://www.ncbi.nlm.nih.gov/pubmed/28527758

http://www.sciencedirect.com/science/article/pii/S0028390817302307

GPR55 and the regulation of glucose homeostasis.

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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

Cannabinoid type 1 receptor-containing axons innervate NPY/AgRP neurons in the mouse arcuate nucleus.

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“Phytocannabinoids, such as THC and endocannabinoids, are well known to promote feeding behavior and to control energy metabolism through cannabinoid type 1 receptors (CB1R). However, the underlying mechanisms are not fully understood.

Generally, cannabinoid-conducted retrograde dis-inhibition of hunger-promoting neurons has been suggested to promote food intake, but so far it has not been demonstrated due to technical limitations.

Our immunohistochemical and ultrastructural study demonstrates the morphological substrate for cannabinoid-conducted feeding behavior via retrograde dis-inhibition of hunger-promoting AgRP/NPY neurons.”

https://www.ncbi.nlm.nih.gov/pubmed/28377876

Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats.

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“Weight gain is an important side effect of most atypical antipsychotic drugs such as olanzapine. Moreover, although many animal models with metabolic side effects have been well defined, the interaction with other pathways has to be considered.

The endocannabinoid system and the CB1 receptor (CB1R) are among the most promising central and peripheral targets involved in weight and energy balance.

In this study we developed a rat model based 15-days treatment with olanzapine that shows weight gain and an alteration of the blood parameters involved in the regulation of energy balance and glucose metabolism. Consequently, we analysed whether, and by which mechanism, a co-treatment with the novel CB1R neutral antagonist NESS06SM, could attenuate the adverse metabolic effects of olanzapine compared to the reference CB1R inverse agonist rimonabant.

Our results showed alterations of the cannabinoid markers in the nucleus accumbens and of orexigenic/anorexigenic markers in the hypothalamus of female rats treated with olanzapine. These molecular modifications could explain the excessive food intake and the resulting weight gain. Moreover, we confirmed that a co-treatment with CB1R antagonist/inverse agonist compounds decreased food intake and weight increment and restored all blood parameters, without altering the positive effects of olanzapine on behaviour. Furthermore, rimonabant and NESS06SM restored the metabolic enzymes in the liver and fat tissue altered by olanzapine.

Therefore, CB1 receptor antagonist/inverse agonist compounds could be good candidate agents for the treatment of weight gain induced by olanzapine.”

https://www.ncbi.nlm.nih.gov/pubmed/28377074

The CB1 Receptor as the Cornerstone of Exostasis.

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“The type-1 cannabinoid receptor (CB1) is the main effector of the endocannabinoid system (ECS), which is involved in most brain and body functions. In this Perspective, we provide evidence indicating that CB1 receptor functions are key determinants of bodily coordinated exostatic processes. First, we will introduce the concepts of endostasis and exostasis as compensation or accumulation for immediate or future energy needs and discuss how exostasis has been necessary for the survival of species during evolution. Then, we will argue how different specific biological functions of the CB1 receptor in the body converge to provide physiological exostatic processes. Finally, we will introduce the concept of proactive evolution-induced diseases (PEIDs), which helps explain the seeming paradox that an evolutionary-selected physiological function can become the cause of epidemic pathological conditions, such as obesity. We propose here a possible unifying theory of CB1 receptor functions that can be tested by future experimental studies.”

https://www.ncbi.nlm.nih.gov/pubmed/28334603

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

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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