Category Archives: Obesity

Cannabinoid-1 Receptor Antagonism Improves Glycemic Control and Increases Energy Expenditure via Sirt1/mTORC2 and AMPK Signaling.

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“Endocannabinoids promote energy conservation in obesity, whereas cannabinoid-1 receptor (CB1 R) blockade reverses body weight gain and insulin resistance and increases energy expenditure.

Here we investigated the molecular mechanisms of the catabolic effects of CB1 R blockade in the liver.

CONCLUSION: peripheral CB1 R blockade in obese mice improves glycemic control via the hepatic Sirt1/mTORC2/Akt pathway, whereas it increases fatty acid oxidation via LKB1/AMPK signaling.”

https://www.ncbi.nlm.nih.gov/pubmed/30506571

https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.30364

Cannabinoid receptor type-1 partially mediates metabolic endotoxemia-induced inflammation and insulin resistance.

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Physiology & Behavior

“Cannabinoid receptor type-1 partially mediates metabolic endotoxemia-induced inflammation and insulin resistance. Despite no significant differences in body weight among groups, chronic exposure to low-level LPS altered hepatic endocannabinoid signaling, increased inflammation, and impaired insulin sensitivity and insulin clearance. CB1 inhibition significantly attenuated LPS signaling, which attenuated LPS-induced metabolic alterations. Therefore, we concluded that CB1 contributes to LPS-mediated inflammation and insulin resistance, suggesting that blocking CB1 signaling may have therapeutic benefits in reducing inflammation-induced metabolic abnormalities.”

https://www.ncbi.nlm.nih.gov/pubmed/30502357

https://www.sciencedirect.com/science/article/abs/pii/S0031938418304190?via%3Dihub

Cannabinoids, Chemical Senses, and Regulation of Feeding Behavior.

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“The herb Cannabis sativa has been traditionally used in many cultures and all over the world for thousands of years as medicine and recreation.

However, because it was brought to the Western world in the late 19th century, its use has been a source of controversy with respect to its physiological effects as well as the generation of specific behaviors. In this regard, the CB1 receptor represents the most relevant target molecule of cannabinoid components on nervous system and whole-body energy homeostasis.

Thus, the promotion of CB1 signaling can increase appetite and stimulate feeding, whereas blockade of CB1 suppresses hunger and induces hypophagia.

Taste and flavor are sensory experiences involving the oral perception of food-derived chemicals and drive a primal sense of acceptable or unacceptable for what is sampled. Therefore, research within the last decades focused on deciphering the effect of cannabinoids on the chemical senses involved in food perception and consequently in the pattern of feeding.

In this review, we summarize the data on the effect of cannabinoids on chemical senses and their influences on food intake control and feeding behavior.”

https://www.ncbi.nlm.nih.gov/pubmed/30481264

Inhibition of Cannabinoid Receptor 1 Can Influence the Lipid Metabolism in Mice with Diet-Induced Obesity.

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“A growing number of evidences accumulated about critical metabolic role of cannabinoid type 1 receptor (CB1), carnitine palmitoyltransferase-1 (CPT1) and peroxisome proliferator-activated receptors (PPARs) in some peripheral tissues, including adipose tissue, liver, skeletal muscle and heart.

Taken together, these data indicate that the inhibition of CB1 could ameliorate lipid metabolism via the stimulation of the CPT1A and CPT1B expression in vivo. Simultaneously, the PPARα and PPARγ expression levels significantly differed compared to that of PPARβ in obesity and lipid metabolism-related disorders under blockade of CB1.

Both the mechanism of the influence of CB1 inhibition on lipid metabolism in the examined tissues and the specific mechanism of PPARα, PPARγ and PPARβ involvement in lipid exchange under these conditions remain to be further elucidated.”

https://www.ncbi.nlm.nih.gov/pubmed/30472964

https://link.springer.com/article/10.1134%2FS0006297918100127

The protective effects of Δ9 -tetrahydrocannabinol against inflammation and oxidative stress in rat liver with fructose-induced hyperinsulinemia.

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“A large amount of fructose is metabolized in the liver and causes hepatic functional damage. Δ9 -tetrahydrocannabinol (THC) is known as a therapeutic agent for clinical and experimental applications.

 

The study aims to investigate the effects of THC treatment on inflammation, lipid profiles and oxidative stress in rat liver with hyperinsulinemia.

 

According to the result, long-term and low-dose THC administration may reduce hyperinsulinemia and inflammation in rats to some extent.”

 

https://www.ncbi.nlm.nih.gov/pubmed/30427077

https://onlinelibrary.wiley.com/doi/abs/10.1111/jphp.13042

Identification of novel mouse and rat CB1R isoforms and in silico modeling of human CB1R for peripheral cannabinoid therapeutics.

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“Targeting peripheral CB1R is desirable for the treatment of metabolic syndromes without adverse neuropsychiatric effects.

We previously reported a human hCB1b isoform that is selectively enriched in pancreatic beta-cells and hepatocytes, providing a potential peripheral therapeutic hCB1R target. It is unknown whether there are peripherally enriched mouse and rat CB1R (mCB1 and rCB1, respectively) isoforms.

In this study, we found no evidence of peripherally enriched rodent CB1 isoforms; however, some mCB1R isoforms are absent in peripheral tissues. We show that the mouse Cnr1 gene contains six exons that are transcribed from a single promoter. We found that mCB1A is a spliced variant of extended exon 1 and protein-coding exon 6; mCB1B is a novel spliced variant containing unspliced exon 1, intron 1, and exon 2, which is then spliced to exon 6; and mCB1C is a spliced variant including all 6 exons.

Using RNAscope in situ hybridization, we show that the isoforms mCB1A and mCB1B are expressed at a cellular level and colocalized in GABAergic neurons in the hippocampus and cortex. RT-qPCR reveals that mCB1A and mCB1B are enriched in the brain, while mCB1B is not expressed in the pancreas or the liver. Rat rCB1R isoforms are differentially expressed in primary cultured neurons, astrocytes, and microglia.

We also investigated modulation of Cnr1 expression by insulin in vivo and carried out in silico modeling of CB1R with JD5037, a peripherally restricted CB1R inverse agonist, using the published crystal structure of hCB1R.

The results provide models for future CB1R peripheral targeting.”

 https://www.ncbi.nlm.nih.gov/pubmed/30202012
https://www.nature.com/articles/s41401-018-0152-1

Role of Cannabinoids in Obesity.

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“Obesity is an increasing health problem worldwide. Its related comorbidities imply a high cost for the National Health System and diminish a patient’s life quality.

Adipose tissue is composed of three types of cells. White adipocytes are involved in fat storage and secretion of hormones. Brown adipocytes are involved in thermogenesis and caloric expenditure. Beige adipocytes are transitional adipocytes that in response to various stimuli can turn from white to brown and could be protective against the obesity, enhancing energy expenditure.

The conversion of white in beige adipose tissue is a potential new therapeutic target for obesity.

Cannabinoid receptors (CB) regulate thermogenesis, food intake and inflammation. CB1 ablation or inhibition helps reducing body weight and food intake. Stimulation of CB2 limits inflammation and promotes anti-obesity effects by reducing food intake and weight gain. Its genetic ablation results in adiposity development.

CB receptors are also responsible for transforming white adipose tissue towards beige or brown adipocytes, therefore their modulation can be considered potential anti-obesity target. CB1 principal localization in central nervous system represents an important limit. Stimulation of CB2, principally localized on peripheral cells instead, should facilitate the anti-obesity effects without exerting remarkable psychotropic activity.”

https://www.ncbi.nlm.nih.gov/pubmed/30201891

http://www.mdpi.com/1422-0067/19/9/2690

Endocannabinoids in Body Weight Control.

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“Maintenance of body weight is fundamental to maintain one’s health and to promote longevity. Nevertheless, it appears that the global obesity epidemic is still constantly increasing.

Endocannabinoids (eCBs) are lipid messengers that are involved in overall body weight control by interfering with manifold central and peripheral regulatory circuits that orchestrate energy homeostasis.

Initially, blocking of eCB signaling by first generation cannabinoid type 1 receptor (CB1) inverse agonists such as rimonabant revealed body weight-reducing effects in laboratory animals and men. Unfortunately, rimonabant also induced severe psychiatric side effects.

At this point, it became clear that future cannabinoid research has to decipher more precisely the underlying central and peripheral mechanisms behind eCB-driven control of feeding behavior and whole body energy metabolism.

Here, we will summarize the most recent advances in understanding how central eCBs interfere with circuits in the brain that control food intake and energy expenditure. Next, we will focus on how peripheral eCBs affect food digestion, nutrient transformation and energy expenditure by interfering with signaling cascades in the gastrointestinal tract, liver, pancreas, fat depots and endocrine glands.

To finally outline the safe future potential of cannabinoids as medicines, our overall goal is to address the molecular, cellular and pharmacological logic behind central and peripheral eCB-mediated body weight control, and to figure out how these precise mechanistic insights are currently transferred into the development of next generation cannabinoid medicines displaying clearly improved safety profiles, such as significantly reduced side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/29849009

http://www.mdpi.com/1424-8247/11/2/55

Computational investigation on the binding modes of Rimonabant analogues with CB1 and CB2.

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“The human cannabinoid G protein coupled receptor 1 (CB1) is highly expressed in central nervous system. CB1-selective antagonists show therapeutic promise in a wide range of disorders, such as obesity-related metabolic disorders, dyslipidemia, drug abuse and type 2 diabetes.

Rimonabant (SR141716A), MJ08 and MJ15 are selective CB1 antagonists with selectivity >1000 folds over CB2 despite of 42% sequence identity between CB1 and CB2. The integration of homology modeling, automated molecular docking and molecular dynamics simulation were used to investigate the binding modes of these selective inverse agonists/antagonists with CB1 and CB2 and their selectivity.

Our analyses showed that the hydrophobic interactions between ligands and hydrophobic pockets of CB1 account for the main binding affinity. In addition, instead of interacting with ligands directly as previously reported, the Lys1923.28in CB1 was engaged in indirect interactions with ligands to keep inactive-state CB1 stable by forming the salt bridge with Asp1762.63 . Lastly, our analyses indicated that the selectivity of these antagonists came from the difference in geometry shapes of binding pockets of CB1 and CB2.

The present study could guide future experimental works on these receptors and has the guiding significance for the design of functionally selective drugs targeting CB1 or CB2 receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/29797785

https://onlinelibrary.wiley.com/doi/abs/10.1111/cbdd.13337

Endocannabinoid system and pathophysiology of adipogenesis: current management of obesity.

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“The endocannabinoids are now known as novel and important regulators of energy metabolism and homeostasis.

The endocrine functions of white adipose are chiefly involved in the control of whole-body metabolism, insulin sensitivity and food intake. Adipocytes produce hormones, such as leptin and adiponectin, that can improve insulin resistance or peptides, such as TNF-α, that elicit insulin resistance. Adipocytes express specific receptors, such as peroxisome proliferator-activated receptor (PPAR)-γ, which serve as adipocyte targets for insulin sensitizers such as thiazolidinediones.

Recently, endocannabinoids and related compounds were identified in human fat cells.

The endocannabinoid system consists primarily of two receptors, cannabinoid (CB)1 and CB2, their endogenous ligands termed endocannabinoids and the enzymes responsible for ligand biosynthesis and degradation.

The endocannabinoids 2-arachidonylglycerol and anandamide or N-arachidonoylethanolamine increase food intake and promote weight gain in animals. Rimonabant, a selective CB1 blocker, reduces food intake and body weight in animals and humans.”

 https://www.ncbi.nlm.nih.gov/pubmed/29788669
https://www.futuremedicine.com/doi/10.2217/17410541.4.3.307