• Arachidonic acid
• Endocannabinoids
• LC-MS/MS
• NAFLD
• Stearic acid

• Cannabis sativa L.
• EU-GMP
• LD50
• acute oral toxicity
• cannabidiol
• delta-9-tetrahydrocannabinol
• pharmacokinetic profile
• rats

• PN-III-P4-ID-PCE-2020-1247 This work was supported by a grant of the Ministry of Research, Innovation and Digitization, CNCS/CCCDI - UEFISCDI, project number PN-III-P4-ID-PCE-2020-1247, within PNCDI III

• CB2 receptor
• curcumin
• diabetes
• myocardial infarction
• oxidative stress

• EMR/2016/005106 Science and Engineering Research Board
• University Program for Advanced Research (UPAR) United Arab Emirates University

Rapidly increasing worldwide prevalence of obesity and related pathologies encompassing coronary heart disease, hypertension, metabolic syndrome, or type 2 diabetes constitute serious threats to global health and are associated with a significantly elevated risk of premature death. Considering the enormous burden of these pathologies, novel therapeutic and preventive patterns are indispensable. Dysregulation of one of the most complex biological systems in the human body namely, the endocannabinoid system (ECS) may result in metabolic imbalance and development of insulin resistance, type 2 diabetes, or non-alcoholic fatty liver disease. Furthermore, many studies showed that physical exercises, depending on their type, intensity, and frequency, exert various alterations within the ECS. Emerging evidence suggests that targeting the ECS via physical activity may produce robust beneficial effects on the course of metabolic pathologies. However, the data showing a direct correlation between the ECS and physical activity in the aspect of metabolic health are very scarce. Therefore, the aim of this review was to provide the most up-to-date state of knowledge about the interplay between the ECS activity and physical exercises in the novel therapeutic and preventive approach toward metabolic pathologies. We believe that this paper, at least in part, will fulfill the existing gap in knowledge and encourage researchers to further explore this very complex yet interesting link between the ECS, its action in physical activity, and subsequent positive outcomes for metabolic health.

•

Intracerebroventricular N-arachidonylethanolamide (AEA) injection increases short-term feed intake of cows.

Among the endocannabinoids, N-arachidonylethanolamide (AEA; anandamide) plays a key role in regulating energy homeostasis and energy intake. Recent studies suggest the existence of a peripheral mechanism by which AEA increases feed intake in the short term and modulates whole-body energy metabolism in dairy cows. Here, we aimed to test the hypothesis that AEA has a long-lasting central effect in increasing feed intake that leads to an increase in milk yield of dairy cows. In the present pilot study, 3 nonpregnant Holstein dairy cows were equipped with an intracerebroventricular (i.c.v.) catheter. Cows were deprived from feed for 2 h and received either no injection or an i.c.v. injection of either 12 μg of AEA or DMSO (control), followed by measurement of feed intake for 10 h and milk yield. Administration of AEA increased 10-h dry matter intake (DMI) by between 1.13 and 2.06 kg, whereas 22-h DMI was only marginally altered. However, compared with the control treatment, AEA reduced daily milk yield by 0.3 to 1.4 L/d in all 3 cows. The results demonstrate that i.c.v. administration of 12 µg of AEA increased 10-h DMI but decreased daily milk yield by a central mechanism.

The feeding value and impact of hemp stubble in the diet of ruminants is unknown. Fifteen Merino castrated male sheep were maintained in individual pens and fed one of three pelletized experimental inclusion diets, as a 0% (Control), 28% (Hemp 1), and 56% (Hemp 2) pellet that delivered a diet meeting the nutrient requirements of the animals. Inclusion of hemp stubble had no effect (P > 0.05) on either DM intake, live weight gain or the feed to gain ratio but positively impacted (P < 0.05) on nutrient digestibility. Hemp stubble inclusion increased the concentration (but not molar proportions) of acetic and butyric acids and increased both the concentrations and molar proportions of iso-butyric, iso-valeric, hexanoic and heptanoic acids, possibly due to increased protein digestibility and/or changes in the composition of rumen cellulolytic bacteria. Tetrahydrocannabinolic acid (THCA) was the only cannabinoid found in plasma in the sheep fed the hemp-containing diets, and this was found at very low concentrations (<16 μg/L). The psychoactive cannabinoid delta-9-tetrahydrocannabinol (Δ ⁹-THC) was not detected in any plasma samples. THCA was detected in the liver of two sheep fed the Hemp 1 pellets and two sheep fed the Hemp 2 pellets. Cannabidiol (CBD) was detected in the liver of one sheep fed the Hemp 2 pellets (but no liver THCA was detected in this sheep). Δ ⁹-THC was detected in both the kidney fat and subcutaneous fat of all sheep fed hemp stubble, with the concentrations being higher (P < 0.05) in the sheep fed the Hemp 1 pellets. THCA was also detected in the subcutaneous fat of one of the sheep fed the Hemp 1 pellets. Four of the five sheep fed the Hemp 1 pellet and one of the five sheep fed Hemp 2 pellet had detectable levels of Δ ⁹-THC in the meat (loin). No other cannabinoids were detected in the meat. Current food standards regulations in Australia prohibit presence of any cannabinoid residues in commercial meat products; thus, determination of a withholding period is required to enable the safe feeding of hemp-stubble to sheep. Further research is also required to gain a greater understanding of the rumen metabolism of cannabinoids.

• hemp
• novel forage
• summer crops
• tetrahydrocannabinol

The endocannabinoid system has emerged as a key regulatory signaling pathway in the pathophysiology of alcohol-associated liver disease (ALD). More than 30 years of research have established different roles of endocannabinoids and their receptors in various aspects of liver diseases, such as steatosis, inflammation, and fibrosis. However, pharmacological applications of the endocannabinoid system for the treatment of ALD have not been successful because of psychoactive side effects, despite some beneficial effects. Thus, a more delicate and detailed elucidation of the mechanism linking the endocannabinoid system and ALD may be of paramount significance in efforts to apply the system to the treatment of ALD.

Three electronic databases (PubMed, MEDLINE, and Cochrane Library) were used for literature search from November 1988 to April 2021. Major keywords used for literature searches were “cannabinoid,” “cannabinoid receptor,” “ALD,” “steatosis,” and “fibrosis.”

According to the inclusion and exclusion criteria, the authors selected 47 eligible full-text articles out of 2,691 searched initially. Studies in the past 3 decades revealed the opposite effects of cannabinoid receptors CB1R and CB2R on steatosis, inflammation, and fibrosis in ALD.

This review summarizes the endocannabinoid signaling in the general physiology of the liver, the pathogenesis of ALD, and some of the potential therapeutic implications of cannabinoid-based treatments for ALD.

• CB1R
• CB2R
• alcohol
• cell communication
• endocannabinoid
• fatty liver
• metabotropic glutamate receptor 5
• xCT

• Adipose tissue
• Diabetes
• Endocannabinoids
• Lipid signaling
• Liver
• Microbiome
• Obesity

• Lean
• Metabolic syndrome
• Non-alcoholic fatty liver disease
• Nonalcoholic Steatohepatitis
• Nonobese
• Nonoverweight

• Body Mass Index
• Humans
• Non-alcoholic Fatty Liver Disease/diagnosis
• Non-alcoholic Fatty Liver Disease/epidemiology
• Obesity/epidemiology
• Prevalence
• Risk Factors

• K24 HL145076 NHLBI NIH HHS
• P30 DK036836 NIDDK NIH HHS
• P30 DK116073 NIDDK NIH HHS

• Cannabidiol
• dietary supplements
• regulations

General obesity has been linked to dysregulation of the endocannabinoid system in humans. However, there is a lack of studies on the relationship between cannabis use and specific abdominal fat phenotypes. The aim was to investigate the associations between cannabis use and magnetic resonance imaging-derived fat phenotypes, as well as indices of insulin sensitivity and insulin secretion.

In this cross-sectional study, magnetic resonance imaging was used to quantify subcutaneous fat volume (SFV), visceral fat volume (VFV), intra-hepatic fat deposition (IHFD), intra-pancreatic fat deposition (IPFD) and skeletal muscle fat deposition (SMFD) by two independent observers. Insulin sensitivity was determined based on HOMA-IS, Raynaud index and Matsuda index, whereas insulin secretion was determined based on HOMA-β, insulinogenic index 30’ and insulinogenic index 60’. A validated questionnaire was used to ascertain participants’ cannabis use. Linear regression models were constructed, adjusting for demographics, glycated hemoglobin, physical activity, tobacco smoking and alcohol consumption.

A total of 120 individuals were included. Cannabis use explained 9.2% of variance in IHFD, 4.4% in SMFD, 3.4% in VFV, 0.4% in SFV and 0.2% in IPFD. Regular cannabis users had significantly greater IHFD compared with never users, in both the unadjusted (P = 0.002) and all adjusted (P = 0.002; P = 0.008) analyses. The other fat phenotypes did not differ significantly between either regular or non-regular users compared with never users. Regular cannabis users had significantly greater insulin secretion (as defined by the insulinogenic index 60’) compared with never users, in both the unadjusted (P = 0.049) and all adjusted (P = 0.003; P = 0.004) analyses. Cannabis use explained 20.3% of variance in the insulinogenic index 60’, but was not significantly associated with the other indices of insulin secretion. There were no significant differences in indices of insulin sensitivity in either regular or non-regular cannabis users compared with never users.

Regular cannabis use may be a risk factor for non-alcoholic fatty liver disease (but not IPFD) and may alter the neuromodulation of insulin secretion. Further investigations are now warranted to elucidate the mechanisms underlying these associations.

• Cannabis use
• Insulin traits
• Intra-hepatic fat
• Intra-pancreatic fat
• Magnetic resonance imaging
• Skeletal muscle fat
• Subcutaneous fat
• Visceral fat

• NAEs
• NAPE-PLD
• bile acids
• bioactive lipids
• inflammation
• liver
• obesity

• Animals
• Diet, High-Fat
• Gene Deletion
• Hepatocytes/enzymology
• Inflammation/enzymology
• Inflammation/pathology
• Lipid Metabolism
• Liver/enzymology
• Liver/metabolism
• Mice, Inbred C57BL
• Mice, Obese
• Organ Specificity
• Phenotype
• Phospholipase D/genetics
• Phospholipase D/metabolism
• RNA, Messenger/genetics
• RNA, Messenger/metabolism

• Lipogenesis
• Mitochondrial dysfunction
• Non-alcoholic fatty liver disease
• Omega fatty acids
• Oxidative stress
• Reactive oxygen species

• NAFLD
• NASH
• cannabinoids
• cannabis
• endocannabinoid
• endocannabinoid system
• exocannabinoid
• marijuana
• nonalcoholic fatty liver disease
• nonalcoholic steatohepatitis

The cannabinoid receptor 2 (CB2) plays a pleiotropic role in the innate immunity and is considered a crucial mediator of liver disease. Cannabinoid CB2 receptor activation has been reported to attenuate liver fibrosis in CCl4 exposed mice and also plays a potential role in liver regeneration in a mouse model of I/R and protection against alcohol-induced liver injury.

In this study, we investigated the impact of CB2 receptors on the antifibrotic and regenerative process associated with cholestatic liver injury.

Twenty-six rats had bile duct ligation co-treated with silymarin and AM1241 for 3 consecutive weeks. Serum hepatotoxicity markers were determined, and histopathological evaluation was performed.

Following bile duct ligation (BDL) for 3 weeks, there was increased aminotransferase levels, marked inflammatory infiltration and hepatocyte apoptosis with induced oxidative stress, as reflected by increased lipid peroxidation. Conversely, following treatment with the CB2 agonist, AM-1241, BDL rats displayed a reduction in liver injury and attenuation of fibrosis as reflected by expression of hydroxyproline and α-smooth muscle actin. AM1241 treatment also significantly attenuated lipid peroxidation end-products, p53-dependent apoptosis and also attenuated inflammatory process by stimulating IL-10 production. Moreover, AM1241 treated rats were associated with significant expression of hepatic progenitor/oval cell markers.

In conclusion, this study points out that CB2 receptors reduce liver injury and promote liver regeneration via distinct mechanisms including IL-10 dependent inhibition of inflammation, reduction of p53-reliant apoptosis and through stimulation of oval/progenitor cells. These results suggest that CB2 agonists display potent hepatoregenrative properties, in addition to their antifibrogenic effects.

• AM1241
• Bile duct ligation
• CD34
• Cannabinoid receptor 2
• Hepatic progenitor cells
• IL-10
• Liver fibrosis
• p53

• Endocannabinoid
• FABP1
• Gene ablation
• High fat diet
• Liver
• Mouse

• Cannabis
• body mass index
• obesity
• omega-6 fatty acid
• theory

• Cannabis
• Gastroenterological disorders
• Hepatic disorders
• Position statement

Our aim is to review the efficacy of various herbs and supplements as a possible therapeutic option in the treatment and/or prevention of nonalcoholic fatty liver disease (NAFLD). We performed a systematic review of medical literature using the PubMed Database by searching the chemical names of many common herbs and supplements with “AND (NAFLD or NASH)”. Studies and medical literature that discussed the roles and usage of herbs and supplements in NAFLD and nonalcoholic steatohepatitis (NASH) from inception until 20 June 2018 were reviewed. Many studies have claimed that the use of various herbs and supplements may improve disease endpoints and outcomes related to NAFLD and/or NASH. Improvement in liver function tests were noted. Amelioration or reduction of lobular inflammation, hepatic steatosis, and fibrosis were also noted. However, well-designed studies demonstrating improved clinical outcomes are lacking. Furthermore, experts remain concerned about the lack of regulation of herbs/supplements and the need for further research on potential adverse effects and herb–drug interactions. In conclusion, preliminary data on several herbs have demonstrated promising antioxidant, anti-inflammatory, anti-apoptotic, and anti-adipogenic properties that may help curtail the progression of NAFLD/NASH. Clinical trials testing the safety and efficacy must be completed before widespread use can be recommended.

• Ginkgo biloba
• NAFLD
• NASH
• cannabinoids
• coffee
• fish oil
• garlic
• green tea
• herb
• nonalcoholic fatty liver disease
• resveratrol
• silymarin
• turmeric

This study aimed to analyze the effect of exercise and/or dietary change on improvement of non-alcoholic fatty liver disease (NAFLD) in chronic high-fat diet (HFD)-induced obese mice.

Forty male C57BL/6 (8 weeks old) mice were divided into normal diet (CO, n = 8) and high-fat diet (HF, n = 32) groups. The HF group was fed with 60% fat chow for 16 weeks to induce obesity. After the obesity induction period, the HF group was subdivided into HFD + sedentary (n = 8), HFD + training (HFT, n = 8), dietary change to normal-diet + sedentary (HFND, n = 8), and dietary change to normal-diet + training (HFNDT, n = 8) groups, and the mice in the training groups underwent treadmill training for 8 weeks, 5 times per week, 40 min per day.

A 24-week HFD induced increase of cannabinoid-1 receptor (CB1), fatty acid synthase (FAS), and AMP-activated protein kinase (AMPK) protein expressions (p < 0.05) and decrease of p-AMPK and carnitine palmitoyltransferase1 (CPT1) protein expressions (P < 0.05), resulting in increased liver fat accumulation. Treatment of exercise with dietary change and dietary change alone decreased CB1 and AMPK protein expressions with increased p-AMPK and CPT1 protein expressions (P < 0.05), leading to decreased body weight and liver fat (P < 0.05). The CB1 and FAS protein expressions in the HFT group were still higher than those in the CO group (P < 0.05), but the p-AMPK and CPT1 protein expressions were higher than those in the HF group (P < 0.05). Moreover, improved glucose tolerance and decreased liver fat were confirmed, although treatment of exercise alone had no effect on weight loss compared to pre-exercise.

Even in the case of obesity induced by chronic HFD, exercise and/or dietary interventions have preventive and therapeutic effects on fat accumulation in the liver, resulting from upregulations of lipolytic factors. Therefore, the results of this study suggested that treatment of exercise alone without dietary change also leads to improvement of NAFLD and glucose tolerance without weight loss benefits.

• AMPK
• CB1 receptor
• CPT1
• FAS
• NAFLD
• Training

• Appetite
• BPA
• Endocannabinoid
• Liver
• Zebrafish

• Animals
• Benzhydryl Compounds/pharmacology
• Brain/drug effects
• Brain/metabolism
• Endocannabinoids/metabolism
• Endocrine Disruptors/pharmacology
• Female
• Free Radical Scavengers/pharmacology
• Lipid Metabolism/drug effects
• Liver/drug effects
• Liver/metabolism
• Phenols/pharmacology
• Zebrafish/metabolism

• alcohol
• cannabis
• drug abuse
• liver disease

• Cannabinoid receptor
• ERRγ
• Fibrinogen
• GSK5182
• High-fat diet
• Hyperfibrinogenemia

• Endocannabinoid
• FABP1
• Gene ablation
• High fat diet
• Liver
• Mouse

• Animals
• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• Diet, High-Fat
• Dietary Fats/metabolism
• Endocannabinoids/metabolism
• Fatty Acid-Binding Proteins/genetics
• Fatty Acid-Binding Proteins/metabolism
• Female
• Gene Deletion
• Liver/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout

• P30 GM103329 NIGMS NIH HHS
• R01 DK041402 NIDDK NIH HHS
• T35 OD010991 NIH HHS

• cannabinoid-based preparations
• functional liver impairments
• genotoxicity
• hepatocytes
• liver to body weight ratio
• oxidative stress

• Administration, Oral
• Animals
• Antineoplastic Agents, Phytogenic/pharmacology
• Biomarkers/metabolism
• Body Weight/drug effects
• Camptothecin/analogs & derivatives
• Camptothecin/pharmacology
• DNA Damage
• Dose-Response Relationship, Drug
• Dronabinol/pharmacology
• Irinotecan
• Liver/drug effects
• Liver/physiopathology
• Liver Function Tests
• Male
• Mutagenicity Tests
• Organ Size/drug effects
• Oxidative Stress/drug effects
• Rats, Wistar

• NAFLD
• NASH
• cannabinoids
• endocannabinoid
• endocannabinoid system
• exocannabinoid
• nonalcoholic fatty liver disease
• nonalcoholic steatohepatitis

Impairment of hepatic fatty acid metabolism can lead to liver steatosis and injury. Testing drugs for interference with hepatic fatty acid metabolism is therefore important. To find out whether HepG2 cells are suitable for this purpose, we investigated the effect of three established fatty acid metabolism inhibitors and of three test compounds on triglyceride accumulation, palmitate metabolism, the acylcarnitine pool and dicarboxylic acid accumulation in the cell supernatant and on ApoB-100 excretion in HepG2 cells. The three established inhibitors [etomoxir, methylenecyclopropylacetic acid (MCPA), and 4-bromocrotonic acid (4-BCA)] depleted mitochondrial ATP at lower concentrations than cytotoxicity occurred, suggesting mitochondrial toxicity. They inhibited palmitate metabolism at similar or lower concentrations than ATP depletion, and 4-BCA was associated with cellular fat accumulation. They caused specific changes in the acylcarnitine pattern and etomoxir an increase of thapsic (C18 dicarboxylic) acid in the cell supernatant, and did not interfere with ApoB-100 excretion (marker of VLDL export). The three test compounds (amiodarone, tamoxifen, and the cannabinoid WIN 55,212-2) depleted the cellular ATP content at lower concentrations than cytotoxicity occurred. They all caused cellular fat accumulation and inhibited palmitate metabolism at similar or higher concentrations than ATP depletion. They suppressed medium-chain acylcarnitines in the cell supernatant and amiodarone and tamoxifen impaired thapsic acid production. Tamoxifen and WIN 55,212-2 decreased cellular ApoB-100 excretion. In conclusion, the established inhibitors of fatty acid metabolism caused the expected effects in HepG2 cells. HepG cells proved to be useful for the detection of drug-associated toxicities on hepatocellular fatty acid metabolism.

• ApoB-100
• acylcarnitines
• biomarkers
• dicarboxylic acids
• fatty acids
• liver steatosis

• 2-arachidonoylglycerol
• N-arachidonoylethanolamide
• binding
• fatty acid binding protein-1
• metabolism
• structure

• Animals
• Dronabinol/adverse effects
• Dronabinol/pharmacology
• Endocannabinoids/metabolism
• Fatty Acid-Binding Proteins/deficiency
• Fatty Acid-Binding Proteins/genetics
• Fatty Acid-Binding Proteins/metabolism
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout

• Texas AgriLife Research

• gene ablation
• liver
• mouse

• Fatty acid binding protein (FABP1)
• Liver
• Triglyceride

• Animals
• Body Mass Index
• Brain/metabolism
• Cerebral Infarction/etiology
• Cerebral Infarction/genetics
• Dyslipidemias/genetics
• Dyslipidemias/metabolism
• Endocannabinoids/metabolism
• Fatty Acid-Binding Proteins/chemistry
• Fatty Acid-Binding Proteins/genetics
• Humans
• Liver/metabolism
• Mice
• Non-alcoholic Fatty Liver Disease/genetics
• PPAR alpha/metabolism
• Polymorphism, Single Nucleotide
• Protein Structure, Secondary
• Rats
• Species Specificity

• R25 OD016574 NIH HHS
• R01 DA035923 NIDA NIH HHS
• T35 OD010991 NIH HHS
• R21 DA032232 NIDA NIH HHS
• R01 DA035949 NIDA NIH HHS

• Amides
• Animals
• Arachidonic Acids/metabolism
• Benzhydryl Compounds
• Cell Line
• Endocannabinoids/metabolism
• Endocrine Disruptors
• Ethanolamines/metabolism
• Fatty Liver/chemically induced
• Fatty Liver/metabolism
• Feedback, Physiological/drug effects
• Glycerides/metabolism
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Humans
• Liver/drug effects
• Liver/metabolism
• Palmitic Acids/metabolism
• Phenols
• Polyunsaturated Alkamides/metabolism
• Receptor, Cannabinoid, CB1/metabolism
• Triglycerides/metabolism
• Zebrafish
• Zebrafish Proteins/metabolism

• R01 ES008314 NIEHS NIH HHS

The primary aim of the present study was to determine the expression levels of cannabinoid receptor type 1 (CB1) in steatotic rat livers. The secondary aim was to clarify whether steatosis and inflammation are more marked in areas with increased CB1 overexpression. For ethical and economic reasons, the present study investigated tissue from archived liver blocks, which were obtained from 38 rats that had been euthanized during the course of previous research at the Karolinska Institute of the Karolinska University Hospital (Stockholm, Sweden) and Lund University (Malmö, Sweden). Liver tissue fixed in formalin and embedded in paraffin was used that had been sourced from 36 male Sprague Dawley rats (age, 7 weeks) and 2 rats (age, 180 days) lacking normal leptin receptors. The rat liver tissue was stained with antibodies against CB1 and counterstained with hematoxylin. The expression of CB1 and the number of cells overexpressing CB1 were determined. Steatosis was scored according to the Dixon scoring system. CB1 overexpression and steatosis were detected in hepatocytes from all 38 livers sampled. The expression of CB1 was more marked in hepatocytes localized next to portal triads. Near the central veins, the expression was significantly weaker. Steatosis was more marked in areas of increased CB1 overexpression. Lymphocyte infiltration was more commonly observed in areas of increased CB1 overexpression. Therefore, the present results indicate that CB1 receptors are overexpressed in areas with steatosis, and indicate that CB1 in hepatocytes contributes to the formation of steatosis in rats, even prior to its progression to steatohepatitis. These results are consistent with publications reporting that CB1 in hepatocytes increases lipogenesis and contributes to inflammation.

• cannabinoid receptor 1
• fatty liver
• immunohistochemistry
• rats

• CBD
• THC
• cannabidiol
• cannabinoids
• cannabis
• delta-9-tetrahydrocannabinol
• headache
• hemp
• medical marijuana

• cannabinoid 1 receptor
• diabetes
• fatty liver
• hepatic energy state
• non-alcoholic steatohepatitis
• obesity

• cannabinoid receptors type 1
• cannabinoid receptors type 2
• endocannabinoids
• endocannabinoids system
• fatty liver disease