n-oleoylethanolamine and Body-Weight

Oleoylethanolamide (OEA), the naturally occurring amide of ethanolamine and oleic acid, is an endogenous lipid that modulates feeding, body weight and lipid metabolism by binding with high affinity to the ligand-activated transcription factor, peroxisome proliferator-activated receptor-alpha (PPAR-alpha). In the present article, we describe the biochemical pathways responsible for the initiation and termination of OEA signaling, and outline the pharmacological properties of this compound in relation to its ability to activate PPAR-alpha. Finally, we discuss the possible role of OEA as a peripheral satiety hormone.

Topics: Adipose Tissue; Animals; Body Weight; Eating; Endocannabinoids; Feeding Behavior; Molecular Structure; Neurons, Afferent; Oleic Acids; PPAR alpha; Receptors, Drug; Signal Transduction; Vagus Nerve

Topics: Appetite Regulation; Body Weight; Humans; Ligands; Oleic Acids; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Vagus Nerve

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

Obesity is currently a major epidemic in the developed world. However, we lack a wide range of effective pharmacological treatments and therapies against obesity, and those approved are not devoid of adverse effects. Dietary components such as palmitoleic acid have been proposed to improve metabolic disbalance in obesity, although the mechanisms involved are not well understood. Both palmitoleic acid (POA) and oleic acid (OA) can be transformed in N-acylethanolamines (NAEs), mediating the effects of dietary POA and OA. To test this hypothesis, here, we study the effects on food intake and body weight gain of palmitoleylethanolamide (POEA) and the OA-derived NAE analogue, oleoylethanolamide (OEA), in Sprague-Dawley rats with a hypercaloric cafeteria diet (HFD). Plasma biochemical metabolites, inflammatory mediators, and lipogenesis-associated liver protein expression were also measured. The results indicate that POEA is able to improve health status in diet-induced obesity, decreasing weight, liver steatosis, inflammation, and dyslipemia. The action of POEA was found to be almost identical to that of OEA, which is an activator of the nuclear peroxisome proliferator receptor alpha (PPARα), and it is structurally related to POEA. These results suggest that the dietary administration of either POA or POEA might be considered as nutritional intervention as complementary treatment for complicated obesity in humans.

Topics: Animals; Body Weight; Cytokines; Diet; Endocannabinoids; Ethanolamines; Fatty Acids; Fatty Acids, Monounsaturated; Fatty Liver; Humans; Insulin Resistance; Lipogenesis; Liver; Male; Obesity; Oleic Acid; Oleic Acids; Rats; Rats, Sprague-Dawley

No data are available on whether a diet deficient of the essential fatty acids is able to modulate tissue levels of endocannabinoids and congeners. Male rats fed for 12 weeks a diet deficient of essential fatty acids, palmitic and oleic acids (EFAD), replaced with saturated fatty acids (SAFA), showed lowered n-3 and n-6 PUFAs levels in plasma, liver and adipose tissue, with concomitant steep increase of oleic and mead acids, while in hypothalamus no changes in PUFA concentration were detected and only palmitoleic acid was found increased. We found a reduction of anandamide and palmitoylethanolamide in liver and brain, while oleoylethanolamide increased significantly in liver and adipose tissue, associated to a 50 % body weight decrease. Changes in N-acylethanolamide profile may contribute to body weight reduction distinctive of EFA deficiency.

Topics: Adipose Tissue; Amides; Animals; Arachidonic Acids; Body Weight; Brain Chemistry; Endocannabinoids; Ethanolamines; Fatty Acids; Fatty Acids, Essential; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Liver; Male; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; Rats

Topics: Animals; Anti-Obesity Agents; Antioxidants; Body Weight; Calorimetry, Differential Scanning; Capsaicin; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Drug Liberation; Endocannabinoids; Feeding Behavior; Kinetics; Lipids; Mice; Nanostructures; Obesity; Oleic Acids; Particle Size; Static Electricity; Temperature

Regulation of appetite and food intake is partly regulated by

Topics: Adult; Aging; Amides; Body Weight; Breast Feeding; Cohort Studies; Denmark; Endocannabinoids; Ethanolamines; Female; Humans; Infant; Milk, Human; Oleic Acids; Palmitic Acids; Stearic Acids

Topics: Animals; Antigens, Neoplasm; Body Weight; Disease Models, Animal; Eating; Endocannabinoids; Jejunum; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oleic Acids; Prader-Willi Syndrome; Proteins; Signal Transduction

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

Topics: Animals; Body Weight; Endocannabinoids; Energy Metabolism; Enzymes; Fatty Acids; Gene Expression Regulation; Glucose; Glycogen; Goldfish; Injections, Intraperitoneal; Lipid Metabolism; Liver; Locomotion; Oleic Acids; PPAR alpha

Obesity prevalence in developed countries has promoted the need to identify the mechanisms involved in control of feeding and energy balance. We have tested the hypothesis that different fats present in diet composition may contribute in body weight gain and body indexes by regulation of oxytocin gene (oxt) expression in hypothalamus and Oleylethanolamide (OEA) levels in plasma. Sprague-Dawley rats were fed two high fat diets, based on corn (HCO) and extra virgin olive oil (HOO) and results were compared to a low fat diet (LF). LC-MS/MS analysis showed an increasing trend of OEA plasma levels in HOO group, although no significant differences were found. However, body weight gain of LF and HOO were similar and significantly lower than HCO. HCO rats also had higher Lee index than HOO. Rats fed HOO diet showed higher levels of hypothalamic oxt mRNA expression, which could indicate that oxytocin may be modulated by dietary lipids.

Topics: Animals; Body Mass Index; Body Weight; Chromatography, High Pressure Liquid; Chromatography, Liquid; Corn Oil; Diet, Fat-Restricted; Diet, High-Fat; Dietary Fats; Male; Obesity; Oleic Acids; Olive Oil; Oxytocin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tandem Mass Spectrometry; Weight Gain

β-adrenergic receptor activation promotes brown adipose tissue (BAT) β-oxidation and thermogenesis by burning fatty acids during uncoupling respiration. Oleoylethanolamide (OEA) can inhibit feeding and stimulate lipolysis by activating peroxisome proliferator-activating receptor-α (PPARα) in white adipose tissue (WAT). Here we explore whether PPARα activation potentiates the effect of β3-adrenergic stimulation on energy balance mediated by the respective agonists OEA and CL316243. The effect of this pharmacological association on feeding, thermogenesis, β-oxidation, and lipid and cholesterol metabolism in epididymal (e)WAT was monitored. CL316243 (1 mg/kg) and OEA (5 mg/kg) co-administration over 6 days enhanced the reduction of both food intake and body weight gain, increased the energy expenditure and reduced the respiratory quotient (VCO2/VO2). This negative energy balance agreed with decreased fat mass and increased BAT weight and temperature, as well as with lowered plasma levels of triglycerides, cholesterol, nonessential fatty acids (NEFAs), and the adipokines leptin and TNF-α. Regarding eWAT, CL316243 and OEA treatment elevated levels of the thermogenic factors PPARα and UCP1, reduced p38-MAPK phosphorylation, and promoted brown-like features in the white adipocytes: the mitochondrial (Cox4i1, Cox4i2) and BAT (Fgf21, Prdm16) genes were overexpressed in eWAT. The enhancement of the fatty-acid β-oxidation factors Cpt1b and Acox1 in eWAT was accompanied by an upregulation of de novo lipogenesis and reduced expression of the unsaturated-fatty-acid-synthesis enzyme gene, Scd1. We propose that the combination of β-adrenergic and PPARα receptor agonists promotes therapeutic adipocyte remodelling in eWAT, and therefore has a potential clinical utility in the treatment of obesity.

Topics: Adipocytes, Brown; Adipocytes, White; Adipokines; Adrenergic beta-3 Receptor Agonists; Animals; Body Composition; Body Weight; Cholesterol; Dioxoles; Eating; Endocannabinoids; Epididymis; Homeostasis; Lipids; Liver; Male; Mitochondria; Obesity; Oleic Acids; Oxygen; Phenotype; Phosphorylation; PPAR alpha; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Temperature; Thermogenesis

Newly synthesized acylethanolamide derivatives oleoyl-L-valinolamide (1), oleoyl-D-valinolamide (2), elaidoyl-L-valinolamide (3), elaidoyl-D-valinolamide (4) stearoyl-L-valinolamide (5), and palmitoyl-L-valinolamide (6) were investigated in mice as antiobesity compounds. Compounds 1, 2, 5, 6 significantly decreased body weight by 6.57% following eight injections of 1 mg/kg i.p. during 39 days, while 3 and 4 showed no such activity. Receptor binding indicated that no compound activated CB1, CB2, PPARα, or TRPV1 receptors. Hypothalamic RT-PCR showed that mRNA expression of the anorexigenic genes POMC and CART was up-regulated by 1, 2, 5 and 1, 2, respectively, while that of the orexigenic genes NPY and CaMKK2 was down-regulated by the respective compounds 1, 5, 6 and 1, 2, 5. Oleoyl-L-valinolamide enhances anorectic pathways and lead to decreased glucose levels, enhanced locomotor activity, and improved cognition. Effects of oleoyl-L-valinolamide on weight were dose-dependent, and it could be given orally. 1, 2, 4, 5 down-regulated FAAH mRNA expression.

Topics: Amides; Animals; Anti-Obesity Agents; Body Weight; Eating; Ethanolamines; Female; Hypothalamus; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Nuclear Magnetic Resonance, Biomolecular; Oleic Acids; Pro-Opiomelanocortin; Valine

The tissue-specific sources and regulated production of physiological signals that modulate food intake are incompletely understood. Previous work showed that L-Fabp(-/-) mice are protected against obesity and hepatic steatosis induced by a high-fat diet, findings at odds with an apparent obesity phenotype in a distinct line of aged L-Fabp(-/-) mice. Here we show that the lean phenotype in L-Fabp(-/-) mice is recapitulated in aged, chow-fed mice and correlates with alterations in hepatic, but not intestinal, fatty acid amide metabolism. L-Fabp(-/-) mice exhibited short-term changes in feeding behavior with decreased food intake, which was associated with reduced abundance of key signaling fatty acid ethanolamides, including oleoylethanolamide (OEA, an agonist of PPARα) and anandamide (AEA, an agonist of cannabinoid receptors), in the liver. These reductions were associated with increased expression and activity of hepatic fatty acid amide hydrolase-1, the enzyme that degrades both OEA and AEA. Moreover, L-Fabp(-/-) mice demonstrated attenuated responses to OEA administration, which was completely reversed with an enhanced response after administration of a nonhydrolyzable OEA analog. These findings demonstrate a role for L-Fabp in attenuating obesity and hepatic steatosis, and they suggest that hepatic fatty acid amide metabolism is altered in L-Fabp(-/-) mice.

Topics: Adiposity; Age Factors; Amidohydrolases; Animals; Arachidonic Acids; Body Weight; Chromosomes; Diet, Fat-Restricted; Endocannabinoids; Enzyme Activation; Fatty Acid-Binding Proteins; Fatty Liver; Feeding Behavior; Female; Lipid Metabolism; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Oleic Acids; Polyunsaturated Alkamides; PPAR gamma; Quantitative Trait Loci; Signal Transduction

We evaluated the biological basis of reduced fat gain by oleoylethanolamide (OEA) in high-fat-fed mice and sought to determine how degradation of OEA affected its efficiency by comparing its effects to those of KDS-5104, a nonhydrolyzable lipid OEA analog. Mice were given OEA or KDS-5104 by the oral route (100 mg/kg body weight). Sixty-eight variables per mouse, describing six biological processes (lipid transport, lipogenesis, energy intake, energy expenditure, endocannabinoid signaling, and glucose metabolism), spanning gene expression of biochemical and physiological parameters were examined to determine the primary target whereby OEA reduces fat gain. Although KDS-5104 but not OEA was resistant to fatty acid amide hydrolase hydrolysis, OEA was degraded by an unidentified hydrolysis system in the liver. Nevertheless, both compounds equally decreased body fat pads after 5 weeks (20%; P < 0.05). The six biological functions constructed from the 68 initial variables predicted up to 58% of adipose fat variations. Lipid transport appeared central to the explanation for body fat deposition (16%; P < 0.0001), in which decreased expression of the FAT/CD36 gene was the component most related to adipose depots. Lipid transport appears to be a determinant player in the OEA fat-lowering response, with adipose tissue FAT/CD36 expression being the most relevant bioindicator of OEA action.

Topics: Adipose Tissue; Adiposity; Administration, Oral; Animals; Biological Transport; Body Weight; Dietary Fats; Dietary Supplements; Endocannabinoids; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Oleic Acids

Apart from its role during labor and lactation, oxytocin is involved in several other functions. Interestingly, oxytocin- and oxytocin receptor-deficient mice develop late-onset obesity with normal food intake, suggesting that the hormone might exert a series of beneficial metabolic effects. This was recently confirmed by data showing that central oxytocin infusion causes weight loss in diet-induced obese mice. The aim of the present study was to unravel the mechanisms underlying such beneficial effects of oxytocin. Chronic central oxytocin infusion was carried out in high fat diet-induced obese rats. Its impact on body weight, lipid metabolism and insulin sensitivity was determined. We observed a dose-dependent decrease in body weight gain, increased adipose tissue lipolysis and fatty acid β-oxidation, as well as reduced glucose intolerance and insulin resistance. The additional observation that plasma oxytocin levels increased upon central infusion suggested that the hormone might affect adipose tissue metabolism by direct action. This was demonstrated using in vitro, ex vivo, as well as in vivo experiments. With regard to its mechanism of action in adipose tissue, oxytocin increased the expression of stearoyl-coenzyme A desaturase 1, as well as the tissue content of the phospholipid precursor, N-oleoyl-phosphatidylethanolamine, the biosynthetic precursor of the oleic acid-derived PPAR-alpha activator, oleoylethanolamide. Because PPAR-alpha regulates fatty acid β-oxidation, we hypothesized that this transcription factor might mediate the oxytocin effects. This was substantiated by the observation that, in contrast to its effects in wild-type mice, oxytocin infusion failed to induce weight loss and fat oxidation in PPAR-alpha-deficient animals. Altogether, these results suggest that oxytocin administration could represent a promising therapeutic approach for the treatment of human obesity and type 2 diabetes.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Diet; Dose-Response Relationship, Drug; Endocannabinoids; Gene Knockout Techniques; Insulin Resistance; Male; Mice; Obesity; Oleic Acids; Oxytocin; PPAR alpha; Rats

Fatty acid amide hydrolase (FAAH) is the main degrading enzyme of the fatty acid ethanolamides anandamide (AEA) and oleoylethanolamide (OEA), which have opposite effects on food intake and energy balance. AEA, an endogenous ligand of CB(1) cannabinoid receptors, enhances food intake and energy storage, whereas OEA binds to peroxisome proliferator-activated receptors-alpha to reduce food intake and promoting lipolysis. To elucidate the role of FAAH in food intake and energy balance, we have evaluated different metabolic and behavioral responses related to feeding in FAAH-deficient (FAAH(-/-)) mice and their wild-type littermates.. Total daily food intake was similar in both genotypes, but high-fat food consumption was enhanced during the dark hours and decreased during the light hours in FAAH(-/-) mice. The reinforcing and motivational effects of food were also enhanced in FAAH(-/-) mice as revealed by operant behavioral paradigms. These behavioral responses were reversed by the administration of the selective CB(1) cannabinoid antagonist rimonabant. Furthermore, body weight, total amount of adipose tissue, plasma-free fatty acids and triglyceride content in plasma, liver, skeletal muscle and adipose tissue, were increased in FAAH(-/-) mice. Accordingly, leptin levels were increased and adiponectin levels decreased in these mutants, FAAH(-/-) mice also showed enhanced plasma insulin and blood glucose levels revealing an insulin resistance. As expected, both AEA and OEA levels were increased in hypothalamus, small intestine and liver of FAAH(-/-) mice.. These results indicate that the lack of FAAH predominantly promotes energy storage by food intake-independent mechanisms, through the enhancement of AEA levels rather than promoting the anorexic effects of OEA.

Topics: Adiposity; Amidohydrolases; Animals; Arachidonic Acids; Body Weight; Cannabinoid Receptor Modulators; Conditioning, Operant; Darkness; Dietary Fats; Eating; Endocannabinoids; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motivation; Obesity; Oleic Acids; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rimonabant; Triglycerides

Fatty acids ethanolamides (FAEs) are a family of lipid mediators. A member of this family, anandamide, is an endogenous ligand for cannabinoid receptors targeted by the marijuana constituent Delta-9-tetrahydrocannabinol. Anandamide is now established as a brain endocannabinoid messenger and multiple roles for other FAEs have also been proposed. One emerging function of these lipid mediators is the regulation of feeding behavior and body weight. Anandamide causes overeating in rats because of its ability to activate cannabinoid receptors. This action is of therapeutic relevance: cannabinoid agonists are currently used to alleviate anorexia and nausea in AIDS patients, whereas the cannabinoid receptor CB1 antagonist rimonabant was recently found to be effective in the treatment of obesity. In contrast to anandamide, its monounsatured analogue, oleoylethanolamide (OEA), decreases food intake and body weight gain through a cannabinoid receptor-independent mechanism. In the rat proximal small intestine, endogenous OEA levels decrease during fasting and increase upon refeeding. These periprandial fluctuations may represent a previously undescribed signal that modulates between-meal satiety. Pharmacological studies have shown, indeed, that, as a drug, OEA produces profound anorexiant effects in rats and mice, due to selective prolongation of feeding latency and post-meal interval. The effects observed after chronic administration of OEA to different animal models of obesity, clearly indicate that inhibition of eating is not the only mechanism by which OEA can control energy metabolism. In fact, stimulation of lipolysis is responsible for the reduced fat mass and decrease of body weight gain observed in these models. Although OEA may bind to multiple receptors, several lines of evidence indicate that peripheral PPAR-alpha mediates the effects of this compound. The pathophysiological significance of OEA in the regulation of eating and body weight is further evidenced by preliminary clinical results, showing altered levels of this molecule in the cerebrospinal fluid and plasma of subjects recovered from eating disorders. These results complete previous observation on anandamide content, which resulted altered in plasma of women affected by anorexia nervosa or binge-eating disorder.

Topics: Adult; Analysis of Variance; Appetite Depressants; Body Weight; Cannabinoid Receptor Modulators; Case-Control Studies; Eating; Endocannabinoids; Feeding and Eating Disorders; Female; Humans; Obesity; Oleic Acids; PPAR alpha

The fatty-acid ethanolamide, oleoylethanolamide (OEA), is a naturally occurring lipid that regulates feeding and body weight [Rodriguez de Fonseca, F., Navarro, M., Gomez, R., Escuredo, L., Nava, F., Fu, J., Murillo-Rodriguez, E., Giuffrida, A., LoVerme, J., Gaetani, S., Kathuria, S., Gall, C., Piomelli, D., 2001. An anorexic lipid mediator regulated by feeding. Nature 414, 209-212], and serves as an endogenous agonist of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) [Fu, J., Gaetani, S., Oveisi, F., Lo Verme, J., Serrano, A., Rodriguez De Fonseca, F., Rosengarth., A., Luecke, H., Di Giacomo, B., Tarzia, G., Piomelli, D., 2003. Oleoylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 425, 90-93], a ligand-activated transcription factor that regulates several aspects of lipid metabolism [. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr. Rev. 20, 649-688]). OEA reduces food intake in wild-type mice, but not in mice deficient in PPAR-alpha (PPAR-alpha(-/-)), an effect that is also observed with the PPAR-alpha agonists Wy-14643 and GW7647 [Brown, P.J., Chapman, J.M., Oplinger, J.A., Stuart, L.W., Willson, T.M. and Wu, Z., 2000. Chemical compounds as selective activators of PPAR-alpha. PCT Int. Appl., 32; . The PPARs: from orphan receptors to drug discovery. J. Med. Chem. 43, 527-550]. By contrast, specific agonists of PPAR-delta/beta (GW501516) or PPAR-gamma (ciglitazone) have no such effect. In obese Zucker rats, which lack functional leptin receptors, OEA reduces food intake and lowers body-weight gain along with plasma lipid levels. Similar effects are seen in diet-induced obese rats and mice. In the present study, we report that subchronic OEA treatment (5mgkg(-1), intraperitoneally, i.p., once daily for two weeks) in Zucker rats initiates transcription of PPAR-alpha and other PPAR-alpha target genes, including fatty-acid translocase (FAT/CD36), liver fatty-acid binding protein (L-FABP), and uncoupling protein-2 (UCP-2). Moreover, OEA decreases neutral lipid content in hepatocytes, as assessed by Oil red O staining, as well as serum cholesterol and triglyceride levels. The results suggest that OEA regulates lipid metabolism and that this effect may contribute to its anti-obesity properties.

Topics: Animals; Body Weight; Butyrates; CD36 Antigens; Cholesterol; Coenzyme A Ligases; Eating; Endocannabinoids; Fatty Acid-Binding Proteins; Hepatocytes; Hyperlipidemias; Ion Channels; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Obesity; Oleic Acids; Phenylurea Compounds; PPAR alpha; Pyrimidines; Rats; Rats, Inbred WF; Rats, Zucker; RNA, Messenger; Thiazoles; Thiazolidinediones; Triglycerides; Uncoupling Protein 2

Amides of fatty acids with ethanolamine (FAE) are biologically active lipids that participate in a variety of biological functions, including the regulation of feeding. The polyunsaturated FAE anandamide (arachidonoylethanolamide) increases food intake by activating G protein-coupled cannabinoid receptors. On the other hand, the monounsaturated FAE oleoylethanolamide (OEA) reduces feeding and body weight gain by activating the nuclear receptor PPAR-alpha (peroxisome proliferator-activated receptor alpha). In the present report, we examined whether OEA can also influence energy utilization. OEA (1-20 microm) stimulated glycerol and fatty acid release from freshly dissociated rat adipocytes in a concentration-dependent and structurally selective manner. Under the same conditions, OEA had no effect on glucose uptake or oxidation. OEA enhanced fatty acid oxidation in skeletal muscle strips, dissociated hepatocytes, and primary cardiomyocyte cultures. Administration of OEA in vivo (5 mg kg(-1), intraperitoneally) produced lipolysis in both rats and wild-type mice, but not in mice in which PPAR-alpha had been deleted by homologous recombination (PPAR-alpha(-/-)). Likewise, OEA was unable to enhance lipolysis in adipocytes or stimulate fatty acid oxidation in skeletal muscle strips isolated from PPAR-alpha mice. The synthetic PPAR-alpha agonist Wy-14643 produced similar effects, which also were dependent on the presence of PPAR-alpha. Subchronic treatment with OEA reduced body weight gain and triacylglycerol content in liver and adipose tissue of diet-induced obese rats and wild-type mice, but not in obese PPAR-alpha(-/-) mice. The results suggest that OEA stimulates fat utilization through activation of PPAR-alpha and that this effect may contribute to its anti-obesity actions.

Topics: Adipose Tissue; Animals; Body Weight; Cell Nucleus; Cells, Cultured; Dose-Response Relationship, Drug; Endocannabinoids; Fatty Acids; Glucose; Glycerol; Hepatocytes; Ligands; Lipid Metabolism; Lipolysis; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oleic Acids; Oxygen; Polymerase Chain Reaction; Pyrimidines; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Time Factors; Transcription Factors

Oleylethanolamide (OEA) is a naturally occurring lipid that regulates satiety and body weight. Although structurally related to the endogenous cannabinoid anandamide, OEA does not bind to cannabinoid receptors and its molecular targets have not been defined. Here we show that OEA binds with high affinity to the peroxisome-proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor that regulates several aspects of lipid metabolism. Administration of OEA produces satiety and reduces body weight gain in wild-type mice, but not in mice deficient in PPAR-alpha. Two distinct PPAR-alpha agonists have similar effects that are also contingent on PPAR-alpha expression, whereas potent and selective agonists for PPAR-gamma and PPAR-beta/delta are ineffective. In the small intestine of wild-type but not PPAR-alpha-null mice, OEA regulates the expression of several PPAR-alpha target genes: it initiates the transcription of proteins involved in lipid metabolism and represses inducible nitric oxide synthase, an enzyme that may contribute to feeding stimulation. Our results, which show that OEA induces satiety by activating PPAR-alpha, identify an unexpected role for this nuclear receptor in regulating behaviour, and raise possibilities for the treatment of eating disorders.

Topics: Animals; Appetite Depressants; Body Weight; Circadian Rhythm; Feeding Behavior; Gene Deletion; Gene Expression Regulation; HeLa Cells; Humans; Intestinal Mucosa; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oleic Acid; Oleic Acids; Protein Binding; Receptors, Cytoplasmic and Nuclear; Transcription Factors