A Role for Peripheral Anandamide and 2-Arachidonoylglycerol in Short-Term Food Intake and Orexigenic Hypothalamic Responses in a Species with Continuous Nutrient Delivery.

The endocannabinoid system (ECS) plays a pivotal role in the complex control and regulation of food intake. Pharmacological ECS activation could improve health in energy-deficient stages by increasing food intake, at least in intermittent feeders. However, knowledge of the mechanism regulating appetite in species with continued nutrient delivery is incomplete. The objectives of this pilot study were to investigate the effect of the intraperitoneal (i.p.) administration of the endocannabinoids (ECs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG) on food intake, plasma EC concentrations and hypothalamic orexigenic signaling, and to study how the circulatory EC tone changes in response to short-term food deprivation in dairy cows, a species with continuous nutrient delivery. The administration of EC resulted in higher food intake during the first hour after treatment. Plasma AEA concentrations were significantly increased 2.5 h after AEA injection, whereas plasma 2-AG concentrations remained unchanged 2.5 h after 2-AG injection. The hypothalamic immunoreactivity of cannabinoid receptor 1, agouti-related protein, and orexin-A was not affected by either treatment; however, neuropeptide Y and agouti-related protein mRNA abundances were downregulated in the arcuate nucleus of AEA-treated animals. Short-term food deprivation increased plasma 2-AG, while plasma AEA remained unchanged. In conclusion, i.p.-administered 2-AG and AEA increase food intake in the short term, but only AEA accumulates in the circulation. However, plasma 2-AG concentrations are more responsive to food deprivation than AEA.

High plasma concentration of non-esterified polyunsaturated fatty acids is a specific feature of severe COVID-19 pneumonia.

COVID-19 pneumonia has specific features and outcomes that suggests a unique immunopathogenesis. Severe forms of COVID-19 appear to be more frequent in obese patients, but an association with metabolic disorders is not established. Here, we focused on lipoprotein metabolism in patients hospitalized for severe pneumonia, depending on COVID-19 status. Thirty-four non-COVID-19 and 27 COVID-19 patients with severe pneumonia were enrolled. Most of them required intensive care. Plasma lipid levels, lipoprotein metabolism, and clinical and biological (including plasma cytokines) features were assessed. Despite similar initial metabolic comorbidities and respiratory severity, COVID-19 patients displayed a lower acute phase response but higher plasmatic concentrations of non-esterified fatty acids (NEFAs). NEFA profiling was characterised by higher level of polyunsaturated NEFAs (mainly linoleic and arachidonic acids) in COVID-19 patients. Multivariable analysis showed that among severe pneumonia, COVID-19-associated pneumonia was associated with higher NEFAs, lower apolipoprotein E and lower high-density lipoprotein cholesterol concentrations, independently of body mass index, sequential organ failure (SOFA) score, and C-reactive protein levels. NEFAs and PUFAs concentrations were negatively correlated with the number of ventilator-free days. Among hospitalized patients with severe pneumonia, COVID-19 is independently associated with higher NEFAs (mainly linoleic and arachidonic acids) and lower apolipoprotein E and HDL concentrations. These features might act as mediators in COVID-19 pathogenesis and emerge as new therapeutic targets. Further investigations are required to define the role of NEFAs in the pathogenesis and the dysregulated immune response associated with COVID-19.Trial registration: NCT04435223.

Treatment of Primary Aldosteronism Increases Plasma Epoxyeicosatrienoic Acids.

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The associations of plasma phospholipid arachidonic acid with cardiovascular diseases: A Mendelian randomization study.

BACKGROUND: Arachidonic acid (AA), a major long-chain n-6 polyunsaturated fatty acid in animal foods, has been linked to inflammation, coagulation, and testosterone, which might relate to atherosclerotic cardiovascular diseases (ASCVD). We assessed the associations of genetically predicted plasma phospholipid AA with ASCVD and other CVD overall and by sex using Mendelian randomization (MR). METHODS: We conducted two-sample MR, applying eight genetic variants, independent of a highly pleiotropic variant (rs174547), strongly (p < 5 × 10-8) predicting AA, primarily to summary statistics of genetic associations with ASCVD, including ischaemic heart disease (IHD), ischaemic stroke, and peripheral artery disease (PAD) from CARDIoGRAMplusC4D 1000 Genomes (60,801 IHD cases, 123,504 controls), MEGASTROKE (34,217 ischaemic stroke cases, 406,111 controls), and Pan-UK Biobank (n=~420,531), and secondarily to genetic associations with other CVD from Pan-UK Biobank, Atrial Fibrillation Consortium, HERMES consortium, and FinnGen. We also assessed sex differences. FINDINGS: Genetically predicted AA was associated with ASCVD (odds ratio (OR) per % of total fatty acids increase 1.03, 95% confidence interval (CI) 1.01 to 1.05) and its subtypes IHD (OR 1.03, 95% CI 1.004 to 1.05), ischaemic stroke (OR 1.03, 95% CI 1.004 to 1.06) and possibly PAD (OR 1.08, 95% CI 1.00 to 1.17), possibly more strongly in men than women. AA was also associated with venous thromboembolism (OR 1.12, 95% CI 1.05 to 1.19). A similar pattern was observed when using rs174547 to genetically predict AA. INTERPRETATION: Our study suggests positive associations of AA with ASCVD and venous thromboembolism, with possibly stronger associations in men than women. FUNDING: No funding.

BIONOTE as an Innovative Biosensor for Measuring Endocannabinoid Levels.

In this study, a novel approach was developed to quantify endocannabinoids (eCBs), and was based on the liquid biosensor BIONOTE. This device is composed of a probe that can be immersed in a solution, and an electronic interface that can record a current related to the oxy-reductive reactions occurring in the sample. The two most representative members of eCBs have been analysed in vitro by BIONOTE: anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG). Bovine serum albumin was used to functionalize the probe and improve the sensibility of the whole analytical system. We show that BIONOTE is able to detect both AEA and 2-AG at concentrations in the low nanomolar range, and to discriminate between these eCBs and their moieties arachidonic acid, ethanolamine and glycerol. Notably, BIONOTE distinguished these five different molecules, and it was also able to quantify AEA in human plasma. Although this is just a proof-of-concept study, we suggest BIONOTE as a cheap and user-friendly prototype sensor for high throughput quantitation of eCB content in biological matrices, with an apparent diagnostic potential for tomorrow's medicine.

Endocannabinoids and related lipids in serum from patients with amyotrophic lateral sclerosis.

BACKGROUND: The goals of this study were to determine whether serum concentrations of endocannabinoids (eCB) and related lipids predict disease status in patients with amyotrophic lateral sclerosis (ALS) relative to healthy controls, and whether concentrations correlate with disease duration and severity. METHODS: Serum concentrations of the eCBs 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA), and related lipids palmitoylethanolamine (PEA), oleoylethanolamine (OEA), and 2-oleoylglycerol (2-OG), were measured in samples from 47 patients with ALS and 19 healthy adults. Hierarchical binary logistic and linear regression analyses assessed whether lipid concentrations predicted disease status (ALS or healthy control), duration, or severity. RESULTS: Binary logistic regression revealed that, after controlling for age and gender, 2-AG, 2-OG and AEA concentrations were unique predictors of the presence of ALS, demonstrating odds ratios of 0.86 (P = .039), 1.03 (P = .023), and 42.17 (P = .026), respectively. When all five lipids and covariates (age, sex, race, ethnicity, body mass index, presence of a feeding tube) were included, the resulting model had an overall classification accuracy of 92.9%. Hierarchical linear regression analyses indicated that in patients with ALS, AEA and OEA inversely correlated with disease duration (P = .030 and .031 respectively), while PEA demonstrated a positive relationship with disease duration (P = .013). None of the lipids examined predicted disease severity. CONCLUSIONS: These findings support previous studies indicating significant alterations in concentrations of circulating lipids in patients with ALS. They suggest that arachidonic and oleic acid containing small lipids may serve as biomarkers for identifying the presence and duration of this disease.

Plasma endocannabinoids and cannabimimetic fatty acid derivatives are altered in gastroparesis: A sex- and subtype-dependent observation.

BACKGROUND: Gastroparesis (GP) is a motility disorder of the stomach presenting with upper gastrointestinal symptoms in the setting of delayed gastric emptying. Endocannabinoids are involved in the regulation of GI function including motility. However, their role in the pathophysiology of GP has not been sufficiently investigated. Our goal was to compare the circulating levels of endocannabinoids and cannabimimetic fatty acid derivatives in GP versus control subjects. METHODS: The study compared plasma concentrations of endocannabinoids and their lipoamine and 2-acyl glycerol congeners, measured by high-pressure liquid chromatography/tandem mass spectrometry (HPLC-MS-MS), in adult patients with diabetic gastroparesis (DM-GP; n = 24; n = 16 female), idiopathic gastroparesis (ID-GP; n = 19; n = 11 female), diabetic patients without GP (DM; n = 19; n = 10 female), and healthy controls (HC; n = 18; n = 10 female). Data, presented as mean ± SEM, were analyzed with ANOVA (Sidak post hoc). KEY RESULTS: Endocannabinoids anandamide (AEA: 0.5 ± 0.1 nMol/L) and 2-arachidonoyl glycerol (2-AG: 2.6 ± 0.7 nMol/L) were significantly lower in female DM-GP patients vs. DM females (AEA: 2.5 ± 0.7 nMol/L and 2-AG: 9.4 ± 3.3 nMol/L). Other monoacylglycerols including 2-palmitoyl glycerol and 2-oleoyl glycerol were also lower in female DM-GP patients compared to DM females. No changes were observed in men. CONCLUSIONS & INFERENCES: Endocannabinoids and other fatty acid derivatives with cannabimimetic properties are reduced in female DM-GP patients. Since GP, particularly with diabetic etiology, is more prevalent among women and since cannabinoids are antiemetic, this decrease in levels may contribute to symptom development in these subjects. Targeting the endocannabinoid system may be a future therapeutic option in DM-GP patients.

Comparison of endocannabinoids levels, FAAH gene polymorphisms, and appetite regulatory substances in women with and without binge eating disorder: a cross- sectional study.

Binge eating disorder (BED) is known as the most common eating disorder with both psychosocial and biological factors involved. In this regard, there is a need to recognize probable disturbances in substances involved in food intake regulation in BED. In this study, we hypothesized that the levels of endocannabinoids, fatty acid amid hydrolase (FAAH) gene polymorphisms, and appetite regulatory substances are different in overweight and obese women with and without BED. A Binge Eating Scale was used to estimate the prevalence of BED in 180 women classified as overweight or obese. The levels of anandamide (AEA), 2-arachidonoylglycerol (2-AG), leptin, insulin, and orexin-A were measured by enzyme-linked immunosorbent assay kits. The subjects were genotyped for polymorphisms of FAAH gene using amplification refractory mutation system-polymerase chain reaction. Data were analyzed using SPSS software. About 41.6% (n = 75) of the subjects were diagnosed with BED. Women with BED exhibited significantly higher levels of AEA, 2-AG, leptin, and insulin compared to non-BED women (P < .05). Binary logistic regression analysis also showed that AEA, leptin, and insulin were the predictors of having BED after adjusting for body mass index (P < .05). In addition, the frequency of A allele of FAAH gene was higher in women with BED compared to women without BED; however, there were no significant differences between these 2 groups (P = .08). These results supported our hypothesis in the cases of AEA, 2-AG, leptin, and insulin but not orexin and FAAH gene polymorphisms. The findings of the current study provide further evidence concerning the role of these substances in BED.

Dietary fatty acid intake and gut microbiota determine circulating endocannabinoidome signaling beyond the effect of body fat.

The endocannabinoidome encompasses several fatty acid (FA)-derived mediators, including the endocannabinoid anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), which served as targets for anti-obesity drug development, and their congener N-acyl-ethanolamines (NAEs) and 2-monoacyl-glycerols (2­MAGs), which are involved in food intake and energy metabolism. Body weight and fat distribution have been suggested as determinants of peripheral endocannabinoid levels. We aimed at investigating factors, beyond body fat composition, that are associated with circulating NAE and 2-MAG levels in a heterogeneous human population. Plasma NAEs and 2-MAGs were measured using LC-MS/MS in a cross-sectional sample of healthy men and women (n = 195) covering a wide range of BMI and individuals before and after a 2-day Mediterranean diet (n = 21). Circulating levels of all 2-MAGs and NAEs, other than N-oleoyl-ethanolamine (OEA), correlated with body fat mass and visceral adipose tissue (0.26 < r < 0.54). NAE levels were elevated in individuals with elevated fat mass, while 2-MAGs were increased in individuals with predominantly visceral body fat distribution. Dietary intakes of specific FAs were associated with 2-AG and omega-3-FA-derived NAEs or 2-MAGs, irrespective of the body fat distribution. Some gut bacterial families (e.g. Veillonellaceae, Peptostreptococcaceae and Akkermansiaceae) were associated with variations in most NAEs or omega-3-FA-derived 2­MAGs, independently of fat mass and dietary FA intake. Finally, a 2-day Mediterranean diet intervention increased circulating levels of NAEs and 2-MAGs in agreement with changes in FA intake (p < 0.01). Self-reported intake and short-term dietary intervention increased in oleic acid and EPA and DHA intake as well as certain gut microbiota taxa are associated to circulating NAEs and 2­MAGs independently of adiposity measures, thus highlighting the potential importance of these variables in determining endocannabinoidome signaling in humans.

Effect of acute physical exercise on motor sequence memory.

Acute physical exercise improves memory functions by increasing neural plasticity in the hippocampus. In animals, a single session of physical exercise has been shown to boost anandamide (AEA), an endocannabinoid known to promote hippocampal plasticity. Hippocampal neuronal networks encode episodic memory representations, including the temporal organization of elements, and can thus benefit motor sequence learning. While previous work established that acute physical exercise has positive effects on declarative memory linked to hippocampal plasticity mechanisms, its influence on memory for motor sequences, and especially on neural mechanisms underlying possible effects, has been less investigated. Here we studied the impact of acute physical exercise on motor sequence learning, and its underlying neurophysiological mechanisms in humans, using a cross-over randomized within-subjects design. We measured behavior, fMRI activity, and circulating AEA levels in fifteen healthy participants while they performed a serial reaction time task before and after a short period of exercise (moderate or high intensity) or rest. We show that exercise enhanced motor sequence memory, significantly for high intensity exercise and tending towards significance for moderate intensity exercise. This enhancement correlated with AEA increase, and dovetailed with local increases in caudate nucleus and hippocampus activity. These findings demonstrate that acute physical exercise promotes sequence learning, thus attesting the overarching benefit of exercise to hippocampus-related memory functions.

Whey protein supplementation reducing fasting levels of anandamide and 2-AG without weight loss in pre-menopausal women with obesity on a weight-loss diet.

BACKGROUND: Despite the importance of dairy proteins in modifying of metabolic abnormalities, no attention has been given to their effects on endocannabinoids. METHODS: A total number of 60 obese women were recruited in a 2-month randomized clinical trial. Following random allocation, they were assigned to one of the two groups: control (n = 30) and intervention (n = 30). Then, all the subjects followed a hypocaloric diet of 800 kcal below estimated energy needs. The intervention group received isocaloric weight-loss diet and whey protein powders (30 g/day). Baseline and 2-month fasting anthropometric, blood glucose, serum insulin, insulin resistance, lipid profile, AEA, and 2-AG were measured. RESULTS: The study groups were homogenous in terms of baseline characteristics (p > 0.05) except for MUFA intake (p = 0.021). There were no significant differences in energy and macronutrient intakes in the intervention group compared to the control group at the end of the study (p > 0.05). The results of the ANCOVA did not show significant reductions in body weight and BMI of the intervention group compared to the control group (p > 0.05); however, WC, body fat, FBS, AEA, 2-AG, total cholesterol, and triglyceride decreased and HDL-c significantly increased in the intervention group compared to the control group (p < 0.05). CONCLUSIONS: In this study, the effects of simultaneous weight-loss diet and whey protein supplementation on the reduction of endocannabinoids were determined. TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT2017021410181N8 . Registered on March 2017.

Circulating endocannabinoid concentrations in grieving adults.

Bereavement is one of the most intense, distressing, and traumatic events an elderly person will experience. The symptom responses to bereavement vary, particularly during the first year. However, the neurobiology underlying the symptom variance in grief is poorly understood. The endocannabinoid signaling (ECS) system is stress-responsive; mounting evidence implicates the central ECS in psychopathology. The current study aimed to investigate the hypothesis that the ECS is abnormal in grief, using circulating eCB concentrations as a biomarker of central ECS. A predominantly older sample of grief participants, within 13 months following the death of a loved one, and healthy comparison (HC) participants were studied. Associations of circulating eCBs with symptom variance in grievers were also examined. A total of 61 (grief: n = 44; HC: n = 17) adults completed cross-sectional clinical assessments and a fasting blood draw. Assessments included the Inventory of Complicated Grief scale; the 17-item Hamilton Depression Rating Scale; and the Hamilton Anxiety scale. Serum eCB concentrations (i.e., N-arachidonoylethanolamine [AEA] and 2-arachidonoylglycerol [2-AG]) were quantified using isotope dilution, liquid chromatography-mass spectrometry. Relative to HC participants, grievers had significantly elevated serum AEA but similar 2-AG concentrations. In grievers, serum AEA concentrations were positively associated with depressive and anxiety symptoms, but only in those with low grief symptoms. These novel findings indicate that elevated circulating eCB concentrations are found following bereavement. The eCB signaling response varies based on the degree of grief severity. Circulating eCB measures may have the potential to serve as biomarkers of prolonged grief disorder.

The association of dietary patterns with endocannabinoids levels in overweight and obese women.

BACKGROUND: Higher levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG), the main arachidonic acid-derived endocannabinoids, are frequently reported in overweight and obese individuals. Recently, endocannabinoids have become a research interest in obesity area regarding their role in food intake. The relationship between dietary patterns and endocannabinoids is poorly understood; therefore, this study evaluated the association of the dietary patterns with AEA and 2-AG levels in overweight and obese women. METHODS: In this cross sectional study, 183 overweight and obese females from Tabriz, Iran who aged between 19 and 50 years old and with mean BMI = 32.44 ± 3.79 kg/m2 were interviewed. The AEA and 2-AG levels were measured, and the dietary patterns were assessed using food frequency questionnaire. To extract the dietary patterns, factor analysis was applied. The association between AEA and 2-AG levels and dietary patterns was analyzed by linear regression. RESULTS: Three major dietary patterns including "Western", "healthy", and "traditional" were extracted. After adjusting for age, physical activity, BMI, waist circumference, and fat mass, higher levels of AEA and 2-AG were observed in participants who were in the highest quintile of the Western pattern (P <  0.05). Also, in both unadjusted and adjusted models, significantly lower levels of AEA and 2-AG were detected in the women of the highest quintile of the healthy pattern (P <  0.01). Moreover, there was no significant association between "traditional" pattern and AEA and 2- AG levels in both unadjusted and adjusted models (P > 0.05). CONCLUSION: In regard with the lower levels of endocannabinoids in healthy dietary pattern, adherence to healthy pattern might have promising results in regulating endocannabinoids levels.

Disease-Specific Derangement of Circulating Endocannabinoids and N-Acylethanolamines in Myeloproliferative Neoplasms.

Growing evidence highlights the endocannabinoid (EC) system involvement in cancer progression. Lipid mediators of this system are secreted by hematopoietic cells, including the ECs 2-arachidonoyl-glycerol (2AG) and arachidonoyl-ethanolamide (AEA), the 2AG metabolite 1AG, and members of N-acylethanolamine (NAE) family-palmitoyl-ethanolamide (PEA) and oleoyl-ethanolamide (OEA). However, the relevance of the EC system in myeloproliferative neoplasms (MPN) was never investigated. We explored the EC plasma profile in 55 MPN patients, including myelofibrosis (MF; n = 41), polycythemia vera (PV; n = 9), and essential thrombocythemia (ET; n = 5) subclasses and in 10 healthy controls (HC). AEA, PEA, OEA, 2AG, and 1AG plasma levels were measured by LC-MS/MS. Overall considered, MPN patients displayed similar EC and NAE levels compared to HC. Nonetheless, AEA levels in MPN were directly associated with the platelet count. MF patients showed higher levels of the sum of 2AG and 1AG compared to ET and PV patients, higher OEA/AEA ratios compared to HC and ET patients, and higher OEA/PEA ratios compared to HC. Furthermore, the sum of 2AG and 1AG positively correlated with JAK2V617F variant allele frequency and splenomegaly in MF and was elevated in high-risk PV patients compared to in low-risk PV patients. In conclusion, our work revealed specific alterations of ECs and NAE plasma profile in MPN subclasses and potentially relevant associations with disease severity.

A Plasma Protein Network Regulates PM20D1 and N-Acyl Amino Acid Bioactivity.

N-acyl amino acids are a family of cold-inducible circulating lipids that stimulate thermogenesis. Their biosynthesis is mediated by a secreted enzyme called PM20D1. The extracellular mechanisms that regulate PM20D1 or N-acyl amino acid activity in the complex environment of blood plasma remains unknown. Using quantitative proteomics, here we show that PM20D1 circulates in tight association with both low- and high-density lipoproteins. Lipoprotein particles are powerful co-activators of PM20D1 activity in vitro and N-acyl amino acid biosynthesis in vivo. We also identify serum albumin as a physiologic N-acyl amino acid carrier, which spatially segregates N-acyl amino acids away from their sites of production, confers resistance to hydrolytic degradation, and establishes an equilibrium between thermogenic "free" versus inactive "bound" fractions. These data establish lipoprotein particles as principal extracellular sites of N-acyl amino acid biosynthesis and identify a lipoprotein-albumin network that regulates the activity of a circulating thermogenic lipid family.

Role of Endocannabinoids in Energy-Balance Regulation in Participants in the Postobese State-a PREVIEW Study.

CONTEXT: Endocannabinoids are suggested to play a role in energy balance regulation. OBJECTIVE: We aimed to investigate associations of endocannabinoid concentrations during the day with energy balance and adiposity and interactions with 2 diets differing in protein content in participants in the postobese phase with prediabetes. DESIGN AND PARTICIPANTS: Participants (n = 38) were individually fed in energy balance with a medium protein (MP: 15:55:30% of energy from protein:carbohydrate:fat) or high-protein diet (HP: 25:45:30% energy from P:C:F) for 48 hours in a respiration chamber. MAIN OUTCOME MEASURES: Associations between energy balance, energy expenditure, respiratory quotient, and endocannabinoid concentrations during the day were assessed. RESULTS: Plasma-concentrations of anandamide (AEA), oleoylethanolamide (OEA), palmitoyethanolamide (PEA), and pregnenolone (PREG) significantly decreased during the day. This decrease was inversely related to body mass index (AEA) or body fat (%) (PEA; OEA). The lowest RQ value, before lunch, was inversely associated with concentrations of AEA and PEA before lunch. Area under the curve (AUC) of concentrations of AEA, 2-AG, PEA, and OEA were positively related to body fat% (P < .05).The HP and MP groups showed no differences in concentrations of AEA, OEA, PEA, and PREG, but the AUC of 2-arachidonoylglycerol (2-AG) was significantly higher in the HP vs the MP group. CONCLUSIONS: In energy balance, only the endocannabinoid 2-AG changed in relation to protein level of the diet, whereas the endocannabinoid AEA and endocannabinoid-related compounds OEA and PEA reflected the gradual energy intake matching energy expenditure during the day.

Endocannabinoid system and cardiometabolic risk factors: A comprehensive systematic review insight into the mechanistic effects of omega-3 fatty acids.

Increased levels of endocannabinoids, 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA) have a pathophysiological role in the setting of cardiometabolic diseases. This systematic review was carried out to appraise the effect of omega-3 on cardiometabolic risk factors by highlighting the mediating effect of endocannabinoids. SCOPUS, PubMed, Embase, Google Scholar and ProQuest databases were searched until January 2020. All published English-language animal studies and clinical trials that evaluated the effects of omega-3 on cardiometabolic diseases with a focus on endocannabinoids were included. Of 1407 studies, 16 animal studies and three clinical trials were included for analysis. Eleven animal studies and two human studies showed a marked reduction in 2-AG and AEA levels following intake of omega-3 which correlated with decreased adiposity, weight gain and improved glucose homeostasis. Moreover, endocannabinoids were elevated in three studies that replaced omega-3 with omega-6. Omega-3 showed anti-inflammatory properties due to reduced levels of inflammatory cytokines, regulation of T-cells function and increased levels of eicosapentaenoyl ethanolamide, docosahexaenoyl ethanolamide and oxylipins; however, a limited number of studies examined a correlation between inflammatory cytokines and endocannabinoids following omega-3 administration. In conclusion, omega-3 modulates endocannabinoid tone, which subsequently attenuates inflammation and cardiometabolic risk factors. However, further randomized clinical trials are needed before any recommendations are made to target the ECS using omega-3 as an alternative therapy to drugs for cardiometabolic disease improvement.

Increased Anandamide and Decreased Pain and Depression after Exercise in Fibromyalgia.

PURPOSE: Physical exercise is increasingly being promoted by health care for chronic pain conditions with beneficial outcomes, such as pain and fatigue reduction, and increased quality of life. Nevertheless, knowledge about biochemical consequences of physical exercise in chronic pain is still relatively poor. The endocannabinoid system has been suggested to play a role for acute exercise-induced reward and pain inhibition. The aim of this study is to investigate the chronic outcomes of resistance exercise on levels of endocannabinoids and related lipids in fibromyalgia (FM). METHODS: This study examine the outcomes of a 15-wk person-centered resistance exercise program on plasma levels of the lipid mediators; anandamide, 2-arachidonoylglycerol (2-AG), oleoylethanolamide, palmitoylethanolamide, and stearoylethanolamide (SEA) sampled from 37 women with FM and 33 healthy controls. The associations between clinical scorings of pain, depression, anxiety, fatigue, and muscle strength with levels of these lipid mediators before and after the exercise program are also analyzed. RESULTS: After the 15-wk exercise program, anandamide levels were significantly increased, and SEA levels significantly decreased in FM. Pain intensity and depression scorings decreased and muscle strength increased, and in a multivariate context, muscle strength was positively associated with 2-AG levels after the resistance exercise program in FM. CONCLUSIONS: The increased anandamide and decreased SEA in women with FM after the 15-wk program might point to a chronic effect of resistance exercise. Pain and depression scorings decreased in the FM group after the program, but no associations between pain, depression, and lipid level changes were assured.

5-Lipooxygenase Derivatives as Serum Biomarkers of a Successful Dietary Intervention in Patients with NonAlcoholic Fatty Liver Disease.

Background: It was previously shown that a bodyweight reduction among patients with nonalcoholic fatty liver (NAFLD) was connected to the lower concentration of arachidonic and linoleic acid derivatives in their blood. We hypothesized that the concentration of these lipids was correlated with the extent of their body mass reduction and, thus, liver steatosis. Methods: We analyzed 68 individuals who completed the dietary intervention. Patients were divided into two groups depending on their body mass reduction (more or less than 7%). Before and after the dietary intervention, all patients had the following measurements recorded: body mass, waist circumference, stage of steatosis, fatty liver index, liver enzymes, lipid parameters, insulin and glucose. Concentrations of lipoxins A4 (LTX A4), hydroxyeicosatetraenoic fatty acids (5(S)-HETE, 12(S)-HETE and 16(S)-HETE), hydroxyoctadecaenoic acids (9(S)-HODE and 13(S)-HODE) and 5-oxo-eicosatetraenoic acid (5-oxo-ETE) were measured in serum samples collected before and after the dietetic intervention using high-performance liquid chromatography (HPLC). Results: Patients who reduced their body mass by more than 7% revealed a significant improvement in their steatosis stage, waist circumference, fatty liver index, triglycerides and cholesterol. Conclusion: A reduction in body mass by more than 7% but not by less than 7% revealed a significant improvement in steatosis stage; waist circumference; fatty liver index; and levels of triglycerides, cholesterol, 5-oxo-ETE and LTXA-4.