Oleoylethanolamide

Oleoylethanolamide (OEA) is an endogenous regulator of appetite which suppresses food intake.^[1] It is in the class of molecules known as acylethanolamides, which are ethanolamide molecules based off of fatty acids and usually related to the arachidonic acid derivative and cannabinoid known as anandamide.^[2] Also in this category of molecules is the endogenous sleep regulator oleamide, which is structurally similar to anandamide and OEA.

OEA is thought to be an endogenous regulator of satiety. Basal concentrations of OEA in the intestines (where it initially acts) without supplementation are in the range of 300nM during daylight hours in rats when they are satiated, and this concentration is enough to fully saturate the receptor it acts upon (PPARα).^[3] At night time, when rats tend to increase food intake, its concentrations drop to levels that no longer saturate the receptor.^[3]

It is synthesized in vivo from fatty acids from cell membranes, and is released when feeding occurs.^[4]

OEA appears to be present in the intestinal tract and its concentration in tissue seems to be associated with the level of satiety in rats. Its secretion is increased when food is ingested, suggesting a link between OEA and feeding-induced satiety.

OEA can be synthesized in neurons in rats.^[5]

OEA is eliminated by enzymatic hydrolysis similar to most acylethanolamides, where enzymes known as amidases cleave OEA into a fatty acid component (in the case of OEA, oleic acid) which can then be used in phospholipid production, and ethanolamine which can be shunted into phosphatidylethanolamine production.^[6][7]

An N-acyl-phosphatidylethanolamine (NAPE) is a phosphatidylethanolamine molecule with the three standard glycerol binding spots containing fatty acids with the amine group further acylated by another fatty acid; if this fatty acid is oleic acid the resulting molecule is N-oleoyl-phosphatidylethanolamine (NOPE). NOPE is a natural constituent of soy lecithin, and when any NAPE molecule is cleaved by the enzyme N-acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD) the lipid bound to the amine is released. In the case of NOPE, the lipid that is released is oleoylethanolamide (OEA).

NOPE can be produced endogenously when phosphatidylcholine (PC) donates an oleic acid molecule from the sn-1 position towards the amine group of phosphatidylethanolamine (PE), creating NOPE. When this occurs, the standard metabolism via NAPE-PLD can again produce OEA.

Oleoylethanolamide (OEA) is known to be a PPARα agonist, which accounts for its appetite-suppressing effects, since these effects are not seen in mice lacking this receptor and a reduction in food intake can be induced with synthetic PPARα agonists.^[3] This reduction in food intake appears to reflect an increase in time between feedings rather than an decrease in food intake upon feeding in free-feeding rats based on their eating patterns. However in food-deprived rats OEA reduces food intake per meal as well as increases time between meals.^[8]

OEA activates PPARα with an EC₅₀ value of 120nM whereas its actions on PPARβ/δ were significantly weaker (1,100nM, or 1.1µM) and activity on PPARγ was undetectable up to concentrations of 50µM, suggesting relative selectivity for PPARα.^[3] This activity on PPARα is also significantly more than the similarly-structured fatty acids oleic acid (EC₅₀ of 10.3µM) and other acylethanlamides tested such as anandamide which had no significant effect.^[3]

The G-Protein Coupled Receptor (GPR) known as GPR119 was, up until recently, considered an orphan receptor (a receptor with no known endogenous ligand); however, it was found that OEA appears to be the endogenous agonist of GPR119^[9][10] with an EC₅₀ of around 2.3µM.^[10] The orphan receptor GPR55 also binds OEA with an EC₅₀ of around 4nM,^[11] and is related in function to peripheral cannabinoid receptors (which do not contribute to the classical psychogenic activity attributed to cannabinoids).^[12][13]

These receptors are also present in the intestines where they have roles in the secretion of the intestinal hormone Glucagon-Like Peptide-1 (GLP-1) and play a role in appetite suppression via the GPR119 receptor^[9][10] and in regulating intestinal motility (unrelated to PPARα activity^[14]).

Two GPR receptors, GPR55 and GPR 119, interact with OEA and may account for some of its effects in the body.

Oleoylethanolamide (OEA) has been hypothesized^[15] to have poor availability, since an enzyme that degrades it, fatty acid amide hydrolase (FAAH), is present in high levels in the intestinal tract and liver.^[16][17]

Only 0.48% of the orally-administered dose was found to be intact in the intestines 90 minutes after ingestion of 10mg/kg in rats, but this still increased the basal concentration in intestinal tissue (0.354nM/g) 11-fold to 3.91+/-0.98nM/g and was as effective as 5mg/kg peripheral injections in suppressing food intake.^[15] Combining oral oleate and ethanolamine separately did not replicate the effect of OEA even when controlled for the same oral dose, suggesting the metabolites of OEA did not affect feeding at this concentration^[15] (oleate itself could suppress appetite, but it requires a significantly higher concentration in the intestines^[18]).

Orally-ingested OEA appears to be extensively metabolized in the intestine, but despite this near-complete metabolism, orally-ingested OEA is still effective in modifying food intake in rats.

Peripheral injections of 5-20mg/kg oleoylethanolamide (OEA) into rats increased noradrenaline concentrations in the hypothalamus between 13-26% after one hour in a dose-dependent manner.^[1]

Despite increasing noradrenaline and dopamine, peripheral injections of 5-20mg/kg OEA into rats failed to alter concentrations of serotonin or its metabolite (5-HIAA) in the hypothalamus.^[1]

Injections of 5-20mg/kg OEA into rats were able to increase hypothalamic dopamine concentrations in a dose-dependent manner between 116-140% whereas concentrations of the major metabolite of dopamine (DOPAC) were unaltered after one hour.^[1] Injections of OEA directly into the brain of rats also increased dopamine levels in the nucleus accumbens.^[19]

Oxytocin is a hormone involved in a variety of processes including suppressing appetite^[20][21] and exerting antiobese effects,^[21][22] and although atypical of hormones oxytocin appears to be able to induce its own synthesis and release.^[23]

OEA has been shown to increase oxytocin levels in the brain in a manner dependent on PPARα activation^[24] and oxytocin itself stimulates the production of OEA in adipocytes (following intracerebroventricular infusion and without stimulating serum OEA or cannabinoid metabolites^[21]) and appears to also require the presence of PPARα.^[21]

Due to a positive feedback mechanism between OEA and oxytocin, both agents are implicated in increasing levels of the other. Increases in central oxytocin appear to be able to be transported towards adipocytes and increases local OEA production

The mechanism underlying the ability of OEA to suppress food intake is via PPARα activation in the intestines, as mice lacking PPARα do not experience the reduction of food intake from OEA (implicating that receptor) and damaging the vagus nerve below the diaphragm also ablated the effects (indicating that OEA is not acting centrally in suppressing food intake).^[3] The small intestine is known to contain large amounts of the PPARα receptor^[25][26] and since even intraperitoneal injections of OEA activate PPARα in this tissue^[3] while injections directly into the brain do not work to suppress food intake (despite ultimately influencing the brain)^[27] OEA's interaction with intestinal PPARα is thought to be the inital step in the signalling cascade.

The properties of OEA differ from the appetite-suppressing hormone cholecystokinin (CCK), which does not delay time to next meal in free-feeding rats like OEA does.^[8] CCK is secreted from the intestines in response to a meal to cause satiety acutely.^[28]

Oleoylethanolamide appears to work in the intestines, activating a receptor known as PPARα to ultimately influence the brain to reduce food intake. Injecting directly into the brain does not appear effective in reducing food intake despite ultimately influencing the brain.

Following an injection of 5mg/kg OEA into rats, the levels of appetite-stimulating peptides NPY and AgRP failed to be altered in either the fed or 24-hour fasted state relative to control injections, despite both peptides increasing greatly during the fasting period.^[1]

The concentration of the anorectic (appetite-suppressing) peptide known as the Cocaine and Amphetamine Regulated Transcript (CART) has been affected by peripheral injections of OEA when measured in the paraventricular nucleus but not the arcuate nucleus, where two hours after the injection of OEA the reduction in CART induced by fasting (15-20%) was ablated.^[1]

When looking at central (in the brain) peptides regulating food intake, it appears that OEA administration may preserve a decrease in appetite-suppressing peptides yet it does not necessarily blunt an increase in the appetite-promoting peptides seen during fasting.

The same injections of 5mg/kg OEA to rats caused time-dependent reductions in peptide YY (PYY, a hormone secreted from the gut^[29]) in both the fasted and fed state.^[1]

With respect to peripheral peptides regulating hunger, PYY (an appetite-stimulating hormone) appears to be reduced with injections of OEA in rats.

Injections of OEA at 5mg/kg to rats appeared to reduce spontaneous food intake over the course of the next four hours,^[1] and acute suppression of food intake in rats is known to occur with peripheral injections of OEA in rats.^[3][8] When comparing fed rats to fasted rats reintroduced to food, OEA administration seems more effective in the latter and there does not appear to be recompensation for this anorectic effect.^[1][8]

Oral ingestion of OEA (10mg/kg) given to fasted rats 90 minutes prior to food reintroduction reduces food intake by 15.5% relative to control.^[15]

Injections appear to be effective in reducing food intake in rats, and OEA has also been shown to be effective within 90 minutes of being given to rats orally.

Peripheral injections of OEA sufficient to cause food intake reduction do not appear to modify stress hormones or anxiety in rats.^[27]

Mice who were given 1.5-6 mg/kg OEA started 7 days into a 28-day period of chronic unpredictable mild stress had improvements in signs of depression (behavior in an open field test and sucrose preference) to a degree similar to 6 mg/kg fluoxetine.^[30] This was accompanied by a mitigated hormonal stress response and normalized brain-derived neurotrophic factor levels in the hippocampus and prefrontal cortex.^[30]

Injections of oleoylethanolamide (OEA) at 5mg/kg into rats in the fed state does not appear to have a significant influence on circulating adiponectin concentrations,^[1] while injecting the same dose of OEA into rats that have been fasted appears to increase adiponectin after two hours but not six hours.^[1] Adiponectin has been noted to be increased elsewhere with the same injected dose, albeit over six continual days. This 11.8% increase did not occur, however, when the β3-adrenergic agonist CL316243 was coadministered.^[31]

Although coadministration of CL316243 and OEA is able to reduce leptin concentrations in rats (possibly associated with increases in energy expenditure and reductions in fat mass), neither agent in isolation affects leptin.^[31]

Repeated doses over six days, but not single dosing, of injected OEA may increase adiponectin levels by 12% in rats.

The β-adrenergic receptors are known to positively mediate body fat loss (mice lacking the receptors experience obesity^[32]) and activation of the β3-adrenergic receptor encourages a reduction in food intake and fat loss in rodents,^[33] in part via activating uncoupling proteins such as UCP1.^[34][35]

OEA targets PPARα, and PPARα is known to have increased effects when the β3 receptor is activated^[36] which partly mediates the effects of β3 on other lipolytic proteins such as PGC-1α and Uncoupling Protein 1 (UCP1) in brown adipose tissue.^[37][38] In accordance with the hypotheses, coadministration of OEA (5mg/kg peripheral injection) and a β3 agonist appear to be additive in reducing food intake and synergistic in reducing fat mass in rats associated with an increase in energy expenditure (with no influence on locomotor activity).^[31] At least in rats, the increase in PPARα and UCP1 (thought to reflect the increase in energy expenditure) occurred in both white and brown adipose tissue alongside improvements in mitochondrial biomarkers (Cox4i1, Cox4i2, Fgf21 and Prdm16).^[31]

OEA appears to be able to enhance the thermogenic actions and mitochondrial effects of β3-adrenergic receptor activation in rats in both white and brown adipose tissues, at the same dose as that used to suppress appetite.

One study assessing the actions of a complex between NOPE (85mg) and EGCG from green tea catechins (50mg via 121mg green tea extract) taken twice daily alongside a mild caloric deficit for eight weeks in overweight adults noted that supplementation was associated with greater dietary adherence (94% of the group completing the trial relative to 74% in placebo).^[39] Persons given the NOPE-EGCG complex reported less symptoms of binge eating and depressive symptoms and more meal-induced satiety, although overall weight loss during the trial did not differ between groups.^[39]

A later study using the same formulation with modified dosages (120mg NOPE and 105mg EGCG) noted similar effects after four weeks although the benefit to compliance and mood was no longer apparent after eight weeks.^[40]

Peripheral injections of oleoylethanolamide (OEA) administered to rats deprived of food for 24-hours did not influence ghrelin within two hours, but after six hours there was a significant reduction in this appetite-stimulating hormone by 40-50%;^[1] OEA had no influence on the ghrelin concentrations of fed rats.^[1]

Injections of 5mg/kg OEA to rats appears to cause time-dependent reductions in peptide YY (PYY, a hormone secreted from the gut^[29]) in both the fasted and fed state.^[1]

With respect to peripheral peptides regulating hunger, PYY (an appetite-stimulating hormone) appears to be reduced with injections of OEA in rats.

Oleoylethanolamide (OEA) is a known endogenous agonist of the fatty acid receptor GPR119,^[9] and activation of this receptor in the pancreas or enteroendocrine cells of mouse intestines stimulates release of the hormone GLP-1.^[41][42]

There are some pancreatic protective effects of OEA in the concentration range of 5-100µM (maximal at 60µM) in vitro, although these are not related to either GPR119 or PPARα activation.^[43] Since inhibiting Fatty Acid Amide Hydrolase (FAAH, which is the enzyme that degrades OEA) removes the protective effects, these effects are thought to be due to oleate, which is a metabolite of OEA.^[43]

In dopaminergic neurons from the substantia nigra in vitro, 0.5-15μM (0.16-4.8 μg/mL) oleoylethanolamide (OEA) added prior to the dopaminergic toxin 6-OHDA results in a bell curve of protective effects peaking in efficacy at 1μM.^[44] It is thought to act via the PPARα receptor expressed in these neurons^[44][45] as other PPARα agonists (fibrates) have been noted to be protective.^[46] This mechanism of action, however, has not been directly confirmed, and antagonism of TRPV1 as OEA's mechanism of action is also plausible since these receptors are expressed in the same neurons.^[47]