n-oleoylethanolamine and Weight-Loss

Nonalcoholic fatty liver disease (NAFLD) is one of the most common noncommunicable diseases worldwide. The present study aimed to investigate the effects of oleoylethanolamide (OEA) supplementation combined with calorie restriction on inflammation, body composition, and hepatic fibrosis among obese patients with NAFLD. In this 12-week randomized clinical trial, 76 obese patients newly diagnosed with NAFLD were randomly allocated into either OEA or placebo group. The weight-loss diet was also designed for both groups. Pre- and postintervention messenger RNA expression levels of the transcription factor nuclear factor-κB (NF-κB), interleukin-6 (IL-6) and IL-10, body composition, and NAFLD fibrosis score were assessed. At the end of the study, the OEA group showed lower NF-κB and IL-6 expression levels compared to the placebo (p < .01). However, IL-10 expression level was approximately twofold higher in the OEA group compared to the placebo group (p = .008). A significant reduction was observed in the fat mass of the OEA group compared to the placebo (p = .044) postintervention. In addition, OEA supplementation led to a significant increase in fat-free mass in the OEA group compared to the placebo (p = .032). A remarkable increase was observed in resting metabolic rate (RMR) in the OEA group (p = .009); however, it was not found in the placebo group. There were no significant between-group differences in RMR postintervention. In addition, no significant within-and between-group differences were observed in the NAFLD fibrosis score at the end of the trial. Treatment with OEA along with weight-loss intervention could significantly improve inflammation and body composition in patients with NAFLD.

Topics: Adult; Body Composition; Caloric Restriction; Dietary Supplements; Endocannabinoids; Female; Humans; Interleukin-10; Interleukin-6; Liver Cirrhosis; Male; NF-kappa B; Non-alcoholic Fatty Liver Disease; Obesity; Oleic Acids; Weight Loss

The effects of oleoylethanolamide (OEA) on NAFLD are yet to be examined in human. The objective of the present study was to examine the effects of OEA supplementation along with weight loss intervention on the expression of PPAR-α, uncoupling proteins 1and 2 (UCP1 and UCP2) genes in the peripheral blood mononuclear cells (PBMCs), metabolic parameters, and anthropometric indices among obese patients with NAFLD. In this triple-blind placebo-controlled randomized clinical trial, 76 obese patients newly diagnosed with NAFLD were randomly allocated into either OEA or placebo group along with calorie-restricted diets for 12 weeks. At pre-and post-intervention phase, mRNA expression levels of PPAR-α, UCP1, and UCP2 genes in the PBMCs, serum levels of metabolic parameters as well as diet and appetite sensations were assessed. There was a significant increase in the expression levels of PPAR-α, UCP1, and UCP2 genes in the PBMCs, compared to the placebo at the endpoint. A significant decrease in the anthropometric indices, energy and carbohydrate intakes, glycemic parameters, except for hemoglobin A1c concentration was also observed in the OEA group, compared to the placebo group. OEA treatment significantly resulted in decreased serum levels of triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST, increased serum levels of high-density lipoprotein cholesterol (HDL-C), and improved appetite sensations. Importantly, a significant improvement in TG, ALT, AST, ALT/AST, HDL-C levels as well as appetite sensations by OEA were under the influence of body mass index (BMI). Although liver steatosis severity was significantly reduced in both groups, the between-group differences did not reach statistical significance (P = 0.061). In conclusion, the present study, for the first time, revealed that OEA supplementation significantly improved anthropometric and metabolic risk factors related to NAFLD.

Topics: Adult; Anthropometry; Appetite Regulation; Body Mass Index; Caloric Restriction; Combined Modality Therapy; Dietary Supplements; Endocannabinoids; Feeding Behavior; Female; Gene Expression Regulation; Humans; Iran; Leukocytes, Mononuclear; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Oleic Acids; PPAR alpha; Time Factors; Treatment Outcome; Uncoupling Protein 1; Uncoupling Protein 2; Weight Loss; Young Adult

Obesity is a crucial public health problem worldwide and is considered as the main cause of many chronic diseases. The present study evaluated the effects of Oleoylethanolamide (OEA) supplementation on proximal proliferator-activated receptor-α (PPAR-α) gene expression, appetite sensations, and anthropometric measurements in obese people. This randomized, double-blind, placebo-controlled clinical trial was carried out on 60 healthy obese people in Tabriz, Iran, in 2016. The eligible subjects were divided into an intervention group (who received two 125 mg OEA capsules daily) and a placebo group (who received the same amount of starches) and treated for 60 days. Anthropometric measurements and body composition were assessed in a fasting state at baseline and at the end of the study. The visual analogue scales (VAS) were used to assess appetite sensations. Quantitative real-time PCR analysis targeting the 16S rRNA gene of PPAR-α was done. Analysis was done on 56 participants who continued intervention until the end of the study. A significant increase in PPAR-α gene expression was observed in the intervention group (p < 0.001). Weight, body mass index, waist circumference, and fat percent decreased significantly at the end of the study in the intervention group (all p < 0.01). Hunger, the desire to eat, and cravings for sweet foods decreased significantly and fullness increased significantly by the end of study in the intervention group at the end of study (all p < 0.01). The fullness item increased significantly by the end of study in the intervention group (p < 0.001). Use of OEA as a complementary approach could be effective in suppressing appetite and modulating energy balance in obese people.

Topics: Adolescent; Adult; Appetite; Body Weight; Diet, Reducing; Dietary Supplements; Double-Blind Method; Endocannabinoids; Female; Humans; Iran; Male; Middle Aged; Obesity; Oleic Acids; PPAR alpha; Satiation; Treatment Outcome; Weight Loss; Young Adult

Topics: Adult; Aged; Amides; Arachidonic Acids; Blood Pressure; Body Mass Index; Cardiovascular Diseases; Cholesterol; Diet, High-Protein; Endocannabinoids; Ethanolamines; Glycerides; Humans; Lipoproteins, LDL; Middle Aged; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; Weight Loss

Long-acting glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists (GLP-1RA), such as exendin-4 (Ex4), promote weight loss. On the basis of a newly discovered interaction between GLP-1 and oleoylethanolamide (OEA), we tested whether OEA enhances GLP-1RA-mediated anorectic signaling and weight loss. We analyzed the effect of GLP-1+OEA and Ex4+OEA on canonical GLP-1R signaling and other proteins/pathways that contribute to the hypophagic action of GLP-1RA (AMPK, Akt, mTOR, and glycolysis). We demonstrate that OEA enhances canonical GLP-1R signaling when combined with GLP-1 but not with Ex4. GLP-1 and Ex4 promote phosphorylation of mTOR pathway components, but OEA does not enhance this effect. OEA synergistically enhanced GLP-1- and Ex4-stimulated glycolysis but did not augment the hypophagic action of GLP-1 or Ex4 in lean or diet-induced obese (DIO) mice. However, the combination of Ex4+OEA promoted greater weight loss in DIO mice than Ex4 or OEA alone during a 7-day treatment. This was due in part to transient hypophagia and increased energy expenditure, phenotypes also observed in Ex4-treated DIO mice. Thus, OEA augments specific GLP-1RA-stimulated signaling but appears to work in parallel with Ex4 to promote weight loss in DIO mice. Elucidating cooperative mechanisms underlying Ex4+OEA-mediated weight loss could, therefore, be leveraged toward more effective obesity therapies.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Obesity Agents; CHO Cells; Cricetulus; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Endocannabinoids; Exenatide; Feeding Behavior; Glucagon-Like Peptide-1 Receptor; Glycolysis; Incretins; Male; Mice, Inbred C57BL; Obesity; Oleic Acids; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Weight Loss

Bariatric surgery remains the single most effective long-term treatment modality for morbid obesity, achieved mainly by lowering caloric intake through as yet ill-defined mechanisms. Here we show in rats that Roux-en-Y gastric bypass (RYGB)-like rerouting of ingested fat mobilizes lower small intestine production of the fat-satiety molecule oleoylethanolamide (OEA). This was associated with vagus nerve-driven increases in dorsal striatal dopamine release. We also demonstrate that RYGB upregulates striatal dopamine 1 receptor (D1R) expression specifically under high-fat diet feeding conditions. Mechanistically, interfering with local OEA, vagal, and dorsal striatal D1R signaling negated the beneficial effects of RYGB on fat intake and preferences. These findings delineate a molecular/systems pathway through which bariatric surgery improves feeding behavior and may aid in the development of novel weight loss strategies that similarly modify brain reward circuits compromised in obesity.

Topics: Administration, Oral; Animals; Appetite; Body Weight; Diet, High-Fat; Dietary Fats; Dopamine; Endocannabinoids; Feeding Behavior; Food Preferences; Gastric Bypass; Gastrointestinal Tract; Intestine, Small; Male; Mice, Obese; Models, Biological; Neostriatum; Obesity; Oleic Acids; PPAR alpha; Rats, Wistar; Receptors, Dopamine D1; Signal Transduction; Vagus Nerve; Weight Loss

Paradoxically, morbid obesity was suggested to protect from cardiovascular co-morbidities as compared to overweight/obese patients. We hypothesise that this paradox could be inferred to modulation of the "endocannabinoid" system on systemic and subcutaneous adipose tissue (SAT) inflammation. We designed a translational project including clinical and in vitro studies at Geneva University Hospital. Morbid obese subjects (n=11) were submitted to gastric bypass surgery (GBS) and followed up for one year (post-GBS). Insulin resistance and circulating and SAT levels of endocannabinoids, adipocytokines and CC chemokines were assessed pre- and post-GBS and compared to a control group of normal and overweight subjects (CTL) (n=20). In vitro cultures with 3T3-L1 adipocytes were used to validate findings from clinical results. Morbid obese subjects had baseline lower insulin sensitivity and higher hs-CRP, leptin, CCL5 and anandamide (AEA) levels as compared to CTL. GBS induced a massive weight and fat mass loss, improved insulin sensitivity and lipid profile, decreased C-reactive protein, leptin, and CCL2 levels. In SAT, increased expression of resistin, CCL2, CCL5 and tumour necrosis factor and reduced MGLL were shown in morbid obese patients pre-GBS when compared to CTL. GBS increased all endocannabinoids and reduced adipocytokines and CC chemokines. In morbid obese SAT, inverse correlations independent of body mass index were shown between palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA) levels and inflammatory molecules. In vitro, OEA inhibited CCL2 secretion from adipocytes via ERK1/2 activation. In conclusion, GBS was associated with relevant clinical, metabolic and inflammatory improvements, increasing endocannabinoid levels in SAT. OEA directly reduced CCL2 secretion via ERK1/2 activation in adipocytes.

Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Adult; Animals; Case-Control Studies; Chemokine CCL2; Endocannabinoids; Enzyme Activation; Ethanolamines; Extracellular Signal-Regulated MAP Kinases; Female; Gastric Bypass; Hospitals, University; Humans; Inflammation Mediators; Insulin Resistance; Lipids; Longitudinal Studies; Male; Mice; Middle Aged; Obesity, Morbid; Oleic Acids; Panniculitis; Pilot Projects; Prospective Studies; Signal Transduction; Subcutaneous Fat; Switzerland; Time Factors; Treatment Outcome; Weight Loss

To measure the circulating levels of endocannabinoids and related molecules at fasting, after acute hyperinsulinemia and after weight loss in insulin sensitive vs. insulin resistant obese postmenopausal women.. The sample consisted of 30 obese postmenopausal women (age: 58.9 ± 5.2 yrs; BMI: 32.9 ± 3.6 kg/m(2) ). Subjects underwent a 3-hour hyperinsulinaemic-euglycaemic clamp (HEC) (glucose disposal rate (M-value): 10.7 ± 3.3 mg min(-1) kg(-1) FFM) and 6-month weight loss intervention. Participants were classified as insulin sensitive obese (ISO) or insulin resistant obese (IRO) based on a predefined cutoff. Plasma levels of the endocannabinoids, anandamide (AEA), 2-arachidonoylglycerol (2-AG), and of the AEA-related compounds, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), were measured by liquid chromatography-mass spectrometry.. IRO presented higher levels of 2-AG (P < 0.05) independently of the HEC and weight loss, whereas the HEC had an independent inhibitory effect on AEA, PEA, and OEA levels (P < 0.05) in both groups. Furthermore, there was an independent stimulatory effect of weight loss only on PEA levels in both groups (P < 0.05).. This study is the first to show that higher circulating levels of the endocannabinoid 2-AG are found in IRO compared to ISO postmenopausal women, and that weight loss is associated with an increase in PEA, a PPAR-α ligand.

Topics: Amides; Arachidonic Acids; Body Composition; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Cohort Studies; Endocannabinoids; Ethanolamines; Female; Glucose Clamp Technique; Glycerides; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Middle Aged; Obesity; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; Postmenopause; Triglycerides; Weight Loss

The increase in the prevalence of human obesity highlights the need to identify molecular and cellular mechanisms involved in control of feeding and energy balance. Oleoylethanolamide (OEA), an endogenous lipid produced primarily in the small intestine, has been identified to play an important role in the regulation of animal food intake and body weight. Previous studies indicated that OEA activates peroxisome proliferator-activated receptor-alpha, which is required to mediate the effects of appetite suppression, reduces blood lipid levels, and enhances peripheral fatty acid catabolism. However, the effect of OEA on enterocyte function is unclear. In this study, we have examined the effect of OEA on intestinal fatty acid uptake and FAT/CD36 expression in vivo and in vitro. We intraperitoneally administered OEA to rats and examined FAT/CD36 mRNA level and fatty acid uptake in enterocytes isolated from the proximal small intestine, as well as in adipocytes. Our results indicate that OEA treatment significantly increased FAT/CD36 mRNA expression in intestinal mucosa and isolated jejunal enterocytes. In addition, we also found that OEA treatment significantly increases fatty acid uptake in isolated enterocytes in vitro. These results suggest that in addition to appetite regulation, OEA may regulate body weight by altered peripheral lipid metabolism, including increased lipolysis in adipocytes and enhanced fatty acid uptake in enterocytes, both in conjunction with increased expression of FAT/CD36. This study may have important implications in understanding the mechanism of OEA in the regulation of fatty acid absorption in human physiological and pathophysiological conditions.

Topics: Adipocytes; Animals; Boron Compounds; CD36 Antigens; Eating; Endocannabinoids; Enterocytes; Fatty Acids; Fluorescent Dyes; Intestine, Small; Lipids; Lipolysis; Male; Oleic Acids; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation; Weight Loss