The ongoing oleoylethanolamide story: therapeutic implications in the control of obesity and its comorbidities

This is a preprint and has not been peer reviewed. Data may be preliminary. The ongoing oleoylethanolamide story: therapeutic implications in the control of obesity and its comorbidities Abstract The global burden of obesity continues to rise, demanding effective pharmacological strategies for individuals in whom prevention alone is insufficient. Recent incretin-based and multi-agonist therapies have delivered unprecedented weight loss, demonstrating that the simultaneous modulation of multiple metabolic pathways can optimize body weight control and improve obesity-related comorbidities. Yet the biological heterogeneity of obesity, interindividual variability in treatment response, and uncertainties regarding long-term outcomes highlight the need to explore complementary mechanisms and diversify therapeutic options. Oleoylethanolamide (OEA) is an endogenous lipid mediator synthesized on demand by enterocytes from membrane phospholipids in response to dietary lipid intake. Acting primarily through peroxisome proliferator-activated receptor-α (PPAR-α), endogenous OEA functions as a physiological postprandial satiety signal that promotes fatty acid oxidation and coordinates gut–brain communication. Disruption of this pathway-through genetic or dietary manipulations-impairs metabolic homeostasis, underscoring its regulatory role. Pharmacological administration of OEA in preclinical models reduces food intake without inducing malaise, enhances lipid utilization, and ameliorates diet-induced metabolic dysfunction, while recruiting central circuits governing both homeostatic and reward-driven feeding. Early clinical studies report modest but consistent improvements in body weight and selected cardiometabolic markers, although limited trial size and duration preclude definitive conclusions. Clarifying pharmacokinetics, brain exposure, responder phenotypes, and rational combinations with incretin-based therapies will be essential to define OEA’s place within a more personalized and physiologically grounded anti-obesity therapeutic framework. 1. Introduction The regulation of body weight relies on adaptive mechanisms that continuously integrate nutritional cues, metabolic demands, and neuroendocrine signals to preserve energy homeostasis (Morton et al., 2014). Under physiological conditions, energy homeostasis depends on flexible adjustments of energy intake and expenditure in response to nutrient availability and metabolic demands (Morton et al., 2014). Chronic energy surplus can progressively impair this flexibility, leading to maladaptive remodeling of regulatory systems (Levin et al., 2025). Consequently, compensatory mechanisms that initially support energy balance can paradoxically promote the persistent accumulation of adipose tissue, contributing to the development of obesity, a chronic disease driven by multifactorial processes (Levin et al., 2025; Młynarska et al., 2025). Among the endogenous systems that participate in this adaptive control, a lipid-derived mediator generated in response to dietary fat has emerged as key regulator of postprandial metabolic responses. Oleoylethanolamide (OEA) functions as an “on demand” intestinal signal linking nutrient sensing to coordinated behavioral and metabolic adaptations (Piomelli, 2013). Beyond excess fat accumulation, obesity is increasingly recognized as a systemic condition characterized by persistent low-grade inflammation, endocrine and metabolic dysfunction, and impaired inter-organ communication (Blüher, 2019, 2025). In this context, insulin resistance and impaired glucose homeostasis represent early and central features of this condition, closely linked to alterations in lipid metabolism and inflammatory signaling (Hotamisligil, 2017). Among obesity-related comorbidities, hepatic involvement is particularly prominent. In most cases obesity is associated to non-alcoholic fatty liver disease (NAFLD) reflecting the central role of the liver in lipid handling and metabolic integration (Fabbrini et al., 2010). Obesity is also strongly associated with cardiovascular complications, including endothelial dysfunction, hypertension, and atherosclerotic disease, which are sustained by systemic inflammation, adverse lipid profiles and persistent metabolic stress (Powell-Wiley et al., 2021). In parallel, growing evidence highlights the contribution of gut-related alterations, such as changes in gut microbiota composition and intestinal barrier integrity, which may further exacerbate metabolic dysregulation through gut-brain signaling pathways (Asadi et al., 2022; Shen et al., 2025). In this review we will focus on those comorbidities for which OEA signaling shows the most coherent mechanistic and experimental support, particularly hepatic steatosis, cardiometabolic dysfunction, and alterations of the gut-brain-microbiota axis. In recent years, obesity pharmacotherapy has entered a transformative phase, driven by the development of incretin-based and multi-agonist therapies that have achieved unprecedented and clinically meaningful weight loss, together with well-documented glucoregulatory and cardioprotective benefits (Ben-Porat et al., 2025). These agents represent a breakthrough in obesity management and have rapidly expanded the therapeutic landscape. However, growing evidence indicates that, even highly effective, incretin-based therapies remain subject to fundamental biological and physiological mechanisms (Ben-Porat et al., 2025). Their sustained efficacy is challenged by the activation of compensatory responses at both peripheral and central levels, including metabolic adaptations, reductions in lean body mass and basal energy expenditure, gastrointestinal side effects, and alterations in dietary intake and eating behaviors (Ben-Porat et al., 2025). Collectively, these factors may limit long-term weight maintenance, contribute to weight regain upon treatment suspension, and introduce new clinical and nutritional vulnerabilities (Ben-Porat et al., 2025). These observations underscore that durable obesity management is unlikely to rely exclusively on pharmacological suppression of appetite or energy intake, even in the era of next-generation incretin mimetics. Moreover, they highlight the need to explore complementary regulatory pathways capable of modulating energy homeostasis in a more integrated and physiologically aligned manner. In this context, OEA, by acting as a modulator of nutrient sensing and metabolic flexibility, might be useful, potentially complementing multi-target pharmacological approaches by restoring endogenous lipid-responsive signaling networks. OEA belongs to a group of naturally occurring bioactive lipids derived from saturated and unsaturated fatty acid precursors and acting as signaling molecules, the N-acylethanolamines (NAEs), which, include also anandamide (AEA), palmitoylethanolamide (PEA), docosahexaenoylethanolamide (DHEA), stearoylethanolamide (SEA), and linoleoylethanolamide (LEA) (Friuli et al., 2025; Romano et al., 2023). While AEA has been mostly characterized for its role as an endogenous ligand of cannabinoid receptors, other NAEs exert biological actions independently of canonical endocannabinoid signaling, leading to the definition of the so-called paracannabinoid system, which comprises structurally related lipid mediators with distinct molecular targets and pharmacological profiles (Friuli et al., 2025). More recently, this broader lipid signaling network has been conceptualized as the “endocannabinoidome” (eCBome), encompassing classical endocannabinoids, structurally related NAEs such as OEA, and their diverse enzymatic pathways and molecular targets beyond CB 1 and CB 2 receptors (Arturo & Fabiana, 2018). Accumulating evidence highlights the involvement of NAEs in distinct biological activities with potential therapeutic relevance across different pathological contexts, spanning metabolic homeostasis, obesity-related dysfunctions, and inflammatory and neurodegenerative conditions (Beggiato et al., 2019; Colizzi et al., 2022; Friuli et al., 2025; Keppel Hesselink et al., 2014; Maccarrone et al., 2002; Tovar et al., 2023). Within this framework, OEA, a monounsaturated NAE derived from the omega-9 fatty acid, oleic acid, has emerged as one of the most extensively investigated unsaturated lipid mediators within the NAE family (Friuli et al., 2025; Romano et al., 2023). A large body of experimental evidence indicates that, when administered exogenously, OEA produces marked effects on food intake and lipid metabolism with a favorable safety profile (Bowen et al., 2017; Lo Verme et al., 2005; Thabuis et al., 2007, 2008). Based on these observations, OEA has attracted considerable interest as a pharmacological tool to explore lipid-responsive pathways involved in energy homeostasis. Nevertheless, several key issues remain under active investigation. These, include the relative contribution of direct central versus peripheral gut–brain mechanisms, following systemic administration, the modest yet reproducible magnitude of clinical effects observed in human studies, and pharmacokinetic challenges related to formulation and bioavailability. Addressing these questions is essential for defining the translational potential of OEA-responsive pathways in obesity management. In this review, we critically evaluate the current evidence on OEA, focusing on its biosynthesis, regulation, and molecular targets, as well as its central and peripheral actions in the control of energy homeostasis. Specifically, we aim to: (i) summarize the biochemical and molecular framework governing OEA synthesis and signaling within the eCBome; (ii) analyze the central and peripheral mechanisms, through which OEA modulates feeding behavior and metabolic homeostasis; and (iii) discuss the evidence supporting its role in obesity-related comorbidities as well as its potential positioning within the current era of multi-target anti-obesity pharmacotherapy. 2. Biosynthesis, degradation, and molecular targets of OEA 2.1 Enzymatic mechanisms underlying OEA as a lipid sensor OEA, a member of NAEs family, is a lipid mediator whose biological effects are critically dependent on the enzymatic processes governing its synthesis and degradation in peripheral tissues. As the other NAEs, OEA is not stored but generated on demand from membrane phospholipid precursors and rapidly inactivated by hydrolytic enzymes, resulting in tightly controlled and spatially restricted regulation of its tissue levels (Friuli et al., 2025). At the biochemical level, OEA biosynthesis follows pathways common to NAEs and is primarily based on the generation of N-acylphosphatidylethanolamines (NAPEs) as immediate precursors (Friuli et al., 2025). In the classical route, NAPE formation is mediated by calcium-dependent N-acyltransferase activity, which transfers an oleoyl group from donor glycerophospholipids, such as phosphatidylcholine, to phosphatidylethanolamine (Romano et al., 2015). However, experimental evidence indicates that NAPEs can also be produced through calcium-independent phospholipase A/acyltransferase (PLA/AT) activities, suggesting that precursor generation can occur through multiple enzymatic mechanisms depending on the cellular context (Bowen et al., 2017). Following their formation, oleoyl-containing NAPEs are hydrolyzed by NAPE-specific phospholipase D (NAPE-PLD), resulting in the release of OEA and phosphatidic acid (Romano et al., 2015). NAPE-PLD is broadly expressed in peripheral tissues and shows preferential expression within the enterocyte layer of the proximal small intestine, consistent with a role in locally coupling lipid absorption to the production of bioactive NAEs (Piomelli, 2013). In parallel with the NAPE-PLD-dependent pathway, OEA can also be generated through alternative biosynthetic routes that do not require NAPE-PLD activity (Bowen et al., 2017). In these pathways, NAPEs undergo stepwise deacylation to yield intermediate metabolites that are subsequently converted into NAEs. A key enzyme involved in this process is α/β-hydrolase domain-containing protein 4 (ABHD4), which catalyzes the removal of acyl chains from NAPEs and related intermediates, generating lyso-NAPE and glycerophospho-NAE species (Bowen et al., 2017). These intermediates are further processed by glycerophosphodiesterphosphodiesterases, including GDE1, GDE4 and GDE7, to yield NAEs such as OEA (Bowen et al., 2017). The coexistence of NAPE-PLD-dependent and -independent pathways provides biochemical redundancy and may allow tissue- and context-specific modulation of OEA production under different nutritional or metabolic conditions. Preclinical observations suggest that among peripheral organs, the proximal small intestine represents the most nutritionally responsive site of OEA mobilization (Fu et al., 2007; Igarashi et al., 2021; Piomelli, 2013). OEA levels increase markedly in the duodenum and jejunum after feeding and decline during fasting, with these fluctuations largely confined to the intestinal mucosa (Fu et al., 2007; Igarashi et al., 2021; Piomelli, 2013). By contrast, comparable postprandial changes are not observed in distal intestinal regions or in extra-intestinal tissues (Fu et al., 2007; Igarashi et al., 2021; Piomelli, 2013). The increase in intestinal OEA observed after feeding reflects a coordinated modulation of its synthesis and degradation, resulting in a transient accumulation of OEA during nutrient absorption (Fu et al., 2007; Igarashi et al., 2021; Piomelli, 2013). These observations support the concept that intestinal OEA functions as a locally generated lipid messenger that links nutrient availability to adaptive metabolic responses. A distinctive feature of intestinal OEA biosynthesis is its close dependence on dietary oleic acid availability (Igarashi et al., 2021). Experimental evidence indicates that OEA is synthesized upon the absorption of luminal oleic acid across the apical enterocyte membrane, rather than upon the uptake of circulating fatty acids (Schwartz et al., 2008). In this context, the fatty acid translocase CD36 plays a key upstream role by facilitating the uptake of long-chain unsaturated fatty acids in the proximal small intestine (Guijarro et al., 2010; Schwartz et al., 2008). Consistently, genetic disruption of CD36 abolishes feeding-induced OEA mobilization and prevents rise of NAPE and OEA pools, thereby identifying CD36 as a critical molecular link between dietary lipid uptake and intracellular OEA biosynthetic pathways (Guijarro et al., 2010). This tight dependence on dietary lipid sensing further reinforces the view of OEA as a nutrient-responsive signal rather than a constitutive metabolic regulator. Termination of OEA signaling is primarily mediated by enzymatic hydrolysis. Fatty acid amide hydrolase (FAAH) represents the principal catabolic enzyme responsible for OEA degradation in metabolic tissues, including the small intestine and liver, and is predominantly localized to intracellular membranes such as the endoplasmic reticulum and mitochondria (Lo Verme et al., 2005). In the proximal small intestine, FAAH activity is dynamically regulated by nutritional status, with feeding reducing its activity and thereby contributing to postprandial OEA accumulation (Fu et al., 2007). In addition to FAAH, N-acylethanolamine acid amidase (NAAA) contributes to NAE degradation in selected cellular contexts, particularly within immune cells, although this enzyme displays lower affinity for OEA and preferentially hydrolyses other NAEs, such as PEA (Piomelli, 2013; Ueda et al., 2010). While FAAH inhibition can increase OEA levels, its broad substrate specificity within the eCBome complicates selective pharmacological manipulation of OEA tone. Chronic nutritional overload disrupts this regulatory framework. Both short- and long-term exposure to high-fat diets attenuate or abolish feeding-induced OEA mobilization in the proximal small intestine and reduce jejunal OEA levels (Igarashi et al., 2021). These alterations have been linked primarily to impaired upstream biosynthetic steps, including reduced NAPE formation (Igarashi et al., 2021), rather than to changes in degradative activity. Thus, sustained excess of dietary fat appears to blunt the adaptive intestinal OEA response, potentially contributing to the loss of postprandial satiety signaling observed in obesity. 2.2 PPAR-α and beyond: receptor targets and downstream signaling OEA exerts its biological effects through interaction with multiple molecular targets, among which the nuclear peroxisome proliferator-activated receptor alpha (PPAR-α) represents the best-characterized and functionally dominant mediator (Fu et al., 2005). Quantitative binding studies indicate that OEA activates PPAR-α with nanomolar potency (EC₅₀ ≈ 120 nM), displaying greater efficacy than other natural ligands such as oleic acid and superior or comparable activity to synthetic PPAR-α agonists, including fibrates (Fu et al., 2005). Engagement of PPAR-α by exogenously administered OEA initiates a canonical ligand-dependent transcriptional program. Upon ligand binding, PPAR-α forms heterodimers with the retinoid X receptor (RXR) and binds to peroxisome proliferator response elements within the promoter regions of target genes, leading to the coordinated regulation of pathways involved in fatty acid uptake, intracellular trafficking, and mitochondrial β-oxidation (Rakhshandehroo et al., 2010). This transcriptional shift promotes lipid utilization rather than storage, reinforcing the concept of OEA as a metabolic reprogramming signal rather than a direct lipolytic stimulus. Among the genes induced by OEA-driven PPAR-α activation are key regulators of lipid handling, such as CD36 and fatty acid transport proteins, as well as PPAR-α itself, suggesting the presence of autoregulatory amplification loops (Brown et al., 2017). In rodent models of obesity, chronic OEA administration reproduces the expected downstream consequences of sustained PPAR-α activation, including enhanced fatty-acid catabolism, reductions in circulating lipid levels, attenuation of hepatic steatosis and decreased body-weight gain (Fu et al., 2003; Lo Verme et al., 2005). Importantly, these effects are largely abolished in PPAR-α-deficient mice, confirming that this receptor is required for the metabolic actions of exogenous OEA (Fu et al., 2003). Beyond metabolic regulation, PPAR-α activation is also essential for the hypophagic effects of OEA. Genetic ablation of PPAR-α completely abolishes OEA-induced suppression of food intake, demonstrating that this receptor is an obligatory mediator of OEA-driven satiety (Fu et al., 2003). Notably, PPAR-α-deficient mice retain normal sensitivity to other anorexigenic agents, including d-fenfluramine and cholecystokinin (CCK), indicating that the loss of responsiveness is selective for OEA rather than reflecting a generalized impairment of feeding control mechanisms (Fu et al., 2003). These findings position PPAR-α as the central molecular hub linking peripheral lipid sensing to behavioral output regulated by OEA. Alongside its well-established transcriptional activity, PPAR-α activation by OEA has also been associated with rapid non-genomic signaling mechanisms. In dopaminergic neurons of the ventral tegmental area (VTA), OEA can activate PPAR-α to rapidly suppress neuronal activity through negative modulation of β 2 -containing nicotinic acetylcholine receptors (Melis et al., 2010, 2013). This effect occurs within minutes and does not involve gene transcription, but rather intracellular signaling processes likely involving tyrosine kinase-dependent phosphorylation mechanisms that alter receptor function (Melis et al., 2010). Through this pathway, OEA reduces the spontaneous firing of VTA dopamine neurons and the number of active dopaminergic cells, suggesting that PPAR-α signaling may rapidly modulate dopaminergic tone; however, the precise physiological relevance of these rapid effects remain less well defined than the canonical transcriptional program. OEA can also engage additional molecular targets that contribute to its pleiotropic signaling profile, without being essential for its anorexigenic effects (Bowen et al., 2017). At micromolar concentrations, OEA activates the transient receptor potential vanilloid-1 (TRPV1) channel, as demonstrated in heterologous expression systems and primary sensory neuron (Bowen et al., 2017; Lo Verme et al., 2005). Moreover, experiments on mice treated with a high dose of OEA (25 mg kg −1 ) showed that TRPV1 activation by OEA induces inward currents in capsaicin-sensitive nodose ganglion neurons and elicits nociceptive and visceral pain-related behaviours. Both effects are absent in TRPV1-null animals or following pharmacological blockade of the channel (Wang et al., 2005). Notably, the concentrations required for robust TRPV1 activation exceed those typically associated with endogenous OEA fluctuations. Similarly, the dose able to produce pain-related behaviours was double the dose producing hypophagia, an effect that is still detectable in TRPV1-null animals, thus, indicating that TRPV1 signaling is not essential for the satiety mediation and that OEA anorexiant effects is not caused by visceral pain (Wang et al., 2005). OEA has been identified, also, as a medium-potency endogenous agonist of the G protein-coupled receptor GPR119, which is expressed predominantly in the gastrointestinal tract and pancreas (Lauffer et al., 2009). Through GPR119 activation, OEA can stimulate glucagon-like peptide-1 (GLP-1) secretion from intestinal L-cells, linking lipid sensing to enteroendocrine signaling (Lauffer et al., 2009). However, genetic ablation of GPR119 does not prevent OEA-induced suppression of food intake, demonstrating that this receptor is unnecessary for the hypophagic response (Lan et al., 2009). Thus, while GPR119 may contribute to metabolic modulation, it does not represent the primary mediator of OEA-driven satiety. Importantly, OEA does not bind or activate cannabinoid CB 1 or CB 2 receptors, distinguishing its signaling profile from that of classical endocannabinoids (Friuli et al., 2025). Instead, OEA operates within the paracannabinoid system, engaging non-cannabinoid receptors to counterbalance endocannabinoid-driven orexigenic signaling. Collectively, these findings identify PPAR-α as the central integrative hub mediating both transcriptional and behavioural effects of exogenously administered OEA, whereas additional targets such as TRPV1 and GPR119 provide context-dependent ancillary contributions rather than obligatory mediators of satiety. 2.3 Crosstalk with endocannabinoid tone and lipid metabolic pathways OEA is part of a broader lipid-signaling framework, in which endocannabinoid and paracannabinoid mediators cooperate to regulate energy homeostasis through dynamic interactions with lipid metabolic pathways. Within this network - now conceptualized as the eCBome (Iannotti & Di Marzo, 2025) - bioactive lipids derived from membrane phospholipids integrate nutritional status, lipid flux and metabolic demands, thereby shaping the balance between energy intake, storage, and utilization. A fundamental basis for crosstalk between OEA, AEA and 2-arachidonoylglycerol (2-AG) lies in their shared biochemical origin. These mediators are synthesized on demand from membrane phospholipids in response to metabolic cues and are not stored in preformed pools (Mock et al., 2023). OEA and AEA belong to the NAE family and originate from NAPE precursors embedded within the phospholipid bilayer, whereas 2-AG derives primarily from phospholipase C-dependent hydrolysis of membrane phospholipids via diacylglycerol intermediates (Mock et al., 2023). Despite these structural differences, the synthesis of all three mediators is tightly coupled to membrane lipid remodeling and fatty acid availability, placing their signaling activity under direct metabolic control (J. Liu et al., 2008; Mock et al., 2023; Silvestri & Di Marzo, 2013). The interdependence of OEA and endocannabinoid signaling is further reinforced by shared enzymatic pathways. AEA and OEA can be generated through both canonical NAPE-PLD-dependent routes and alternative NAPE-PLD-independent pathways (Mock et al., 2023). At the level of degradation, FAAH represents a major point of convergence, as it hydrolyses multiple NAEs and plays a central role in determining local NAE tone. Although 2-AG is primarily degraded by monoacylglycerol lipase (MAGL), FAAH may contribute to its turnover in specific cellular contexts, further linking endocannabinoid and paracannabinoid metabolism (J. Liu et al., 2008; Mock et al., 2023; Silvestri & Di Marzo, 2013). Importantly, alterations in the expression or activity of these enzymes have been reported under conditions of high-fat feeding and obesity, suggesting that nutritional overload can reshape the enzymatic landscape governing lipid mediator balance (Mock et al., 2023). Through these shared metabolic routes, OEA and endocannabinoids may influence each other’s signaling efficacy. While direct in vivo competition for FAAH remains context-dependent and difficult to quantify, changes in the availability of one mediator can theoretically modify the persistence and functional impact of others by altering substrate access and enzymatic capacity (Mock et al., 2023). In this framework, elevations in OEA could modulate endocannabinoid tone indirectly, whereas sustained increases in endocannabinoid levels may shift membrane lipid composition or enzyme activity in ways that attenuate OEA production. Such bidirectional modulation likely reflects metabolic interdependence, rather than direct receptor-level antagonism. Functionally, OEA and endocannabinoids exert largely opposing effects on lipid metabolism and energy balance. OEA acts primarily as a peripheral satiety signal that promotes fatty acid utilization and catabolic pathways (Silvestri & Di Marzo, 2013), whereas AEA and 2-AG, acting through cannabinoid receptor-dependent mechanisms, favor energy storage, lipogenesis, and reduced energy expenditure (Silvestri & Di Marzo, 2013). In conditions of nutritional excess and obesity, hyperactivation of the endocannabinoid system is frequently observed, shifting this balance toward anabolic states (Silvestri & Di Marzo, 2013). Both experimental models and human studies indicate that obesity is associated with an increased AEA tone and altered circulating or tissue NAE ratios, including reduced OEA/AEA balance, consistent with enhanced appetite drive and impaired satiety signaling (Mock et al., 2023; Silvestri & Di Marzo, 2013). Within this context, OEA signaling can be viewed as a counter-regulatory mechanism that opposes excessive endocannabinoid activity and contributes to metabolic restraint (Friuli et al., 2025; Silvestri & Di Marzo, 2013). These interactions are particularly relevant in metabolically active tissues such as intestine, liver, and adipose tissue, where dietary lipids continuously feed into membrane phospholipid pools (Silvestri & Di Marzo, 2013). In these compartments, fluctuations in fatty acid flux influence the synthesis and degradation of OEA, AEA and 2-AG, linking lipid metabolism to signaling pathways that regulate feeding behavior, lipid storage and peripheral energy homeostasis (Mock et al., 2023). At the intestinal level, where lipid absorption, nutrient sensing and local lipid mediator mobilization converge, OEA may play a particularly prominent role in buffering endocannabinoid-driven responses associated with chronic high-fat feeding (Silvestri & Di Marzo, 2013; Vari et al., 2025). Collectively, this evidence supports the view that OEA does not operate in isolation but functions within an integrated lipid signaling network that dynamically coordinates endocannabinoid tone and metabolic pathways. Through shared precursors, partially overlapping enzymatic systems and opposing functional outputs, the eCBome provides the flexibility required to shift between energy storage and energy utilization. Disruption of this balance in obesity may therefore reflect not only increased endocannabinoid signaling but also impaired OEA-mediated counter-regulation, reinforcing the translational relevance of restoring lipid mediator equilibrium. 3. Central and peripheral mechanisms mediating OEA’s anti-obesity effects 3.1 Central mechanisms mediating OEA’s effects on feeding behavior Feeding behavior results from the integration of homeostatic mechanisms that monitor energy needs and metabolic status with non-homeostatic processes encoding motivational, emotional, and contextual aspects of food intake (C. M. Liu & Kanoski, 2018; Romano, Friuli et al., 2020). Homeostatic control primarily relies on hypothalamic and brainstem circuits integrating peripheral metabolic signals, whereas non-homeostatic regulation involves corticolimbic networks governing reward processing and stress responsiveness (C. M. Liu & Kanoski, 2018; Romano, Friuli et al., 2020). Dysregulation within or between these domains contributes to overeating and obesity (Brown et al., 2017; Friuli et al., 2025). In this framework, OEA has emerged as a lipid mediator capable of influencing both homeostatic and reward-related circuits, rather than acting as a nonspecific anorexigenic signal (Brown et al., 2017). Experimental evidence indicates that systemic administration of OEA recruits central pathways spanning these domains, providing a mechanistic basis for its anti-obesity effects observed in different preclinical models (Brown et al., 2017; Friuli et al., 2025). Early studies in rats under physiological feeding conditions showed that peripheral administration of OEA induces rapid and selective activation of discrete brainstem and hypothalamic nuclei, as assessed by Fos immunoreactivity (Brown et al., 2017; Friuli et al., 2025; Romano et al., 2015). These include the area postrema (AP; Romano et al., 2014) and the nucleus of the solitary tract (NST; (Gaetani et al., 2010; Rodríguez de Fonseca et al., 2001; Romano et al., 2013, 2014) in the brainstem (Romano et al., 2014), as well as hypothalamic nuclei such as the paraventricular (PVN; Gaetani et al., 2010; Rodríguez de Fonseca et al., 2001; Romano et al., 2013, 2014), supraoptic (SON; Gaetani et al., 2010; Rodríguez de Fonseca et al., 2001; Romano et al., 2013, 2014), and tuberomammillary nuclei (TMN; Provensi at al., 2014). Collectively, these regions represent major integrative hubs for visceral and metabolic information and coordinate neuroendocrine and behavioral responses to peripheral signals (Friuli et al., 2025; Gaetani et al., 2010; Provensi et al., 2014; Rodriguez de Fonseca; Romano et al. 2013, 2014, 2015). Notably, OEA-induced hypophagia is characterized primarily by delayed meal initiation (Azari et al., 2014; Gaetani et al., 2003; Oveisi et al., 2004), without markers of visceral malaise or stress activation (Proulx et al., 2005; Rodríguez de Fonseca et al., 2001), consistent with engagement of physiological satiety pathways rather than aversive suppression of feeding (Proulx et al., 2005). Within the hypothalamus, OEA robustly engages oxytocinergic signaling pathways. In fact, studies in rats demonstrated that systemic administration of OEA increases oxytocin gene expression and release, elevating, also, circulating oxytocin levels (Gaetani et al., 2010). These effects are abolished in PPAR-α knockout mice and prevented by central oxytocin receptor antagonism, which blocks also OEA’s effects on food intake, thus demonstrating that activation of PVN and SON oxytocinergic neurons is required for OEA-induced hypophagia (Gaetani et al., 2010). These findings identify oxytocin as a critical downstream mediator of OEA actions on feeding and suggest that this system might represent a key effector linking peripheral lipid sensing to central satiety control. Brainstem-hypothalamic connectivity is essential in mediating OEA’s central effects. Using neurotoxic approaches in rats, it was shown that selective disruption of noradrenergic projections from the NST to the PVN prevents both oxytocinergic activation and food intake suppression following OEA administration (Romano et al., 2013). Consistently, peripheral OEA administration increases hypothalamic noradrenaline levels, further supporting a functional role for noradrenergic transmission in the central actions of OEA (Romano et al., 2013). The histaminergic system provides an additional modulatory central component. In histamine-deficient mice or in rats subjected to pharmacological depletion of brain histamine, OEA fails to activate hypothalamic oxytocinergic neurons and does not suppress food intake (Provensi et al., 2014). These findings suggest that coordinated engagement of catecholaminergic and histaminergic pathways upstream of oxytocin is required for full expression of OEA’s central effects. Beyond these classical homeostatic pathways, OEA also modulates neural circuits involved in motivational and reward-related aspects of feeding (Melis et al., 2013; Murillo-Rodríguez et al., 2011; Romano et al., 2015; Romano, Micioni Di Bonaventura, et al., 2020; Serrano et al., 2011; Tellez et al., 2013). Direct modulation of mesolimbic dopamine signaling has been demonstrated in vivo. Microdialysis studies in freely feeding rats show that OEA administration into the lateral hypothalamus or the dorsal raphe nucleus increased extracellular dopamine levels in the nucleus accumbens (Murillo-Rodríguez et al., 2011). In addition, in adult rats, OEA modulates the excitability of midbrain dopaminergic neurons via activation of PPAR-α, which negatively regulates β 2 -containing nicotinic acetylcholine receptors expressed on dopaminergic neurons of the VTA. This PPAR-α–dependent mechanism provides a cellular substrate through which OEA may constrain excessive dopaminergic activation, while preserving physiological dopamine signaling under basal conditions (Melis et al., 2010, 2013). The functional relevance of OEA-dopamine interactions in the context of feeding behavior has been demonstrated in dietary models of reward dysfunction. Sub-chronic OEA treatment restores normal reward responsiveness in rats exposed to chronic high-fat diet, a condition associated with dopaminergic hypofunction and reduced sensitivity to food reward (Tellez et al., 2013). Moreover, in a model of frustration stress-induced binge-like eating with female rats, acute OEA administration suppresses excessive intake of palatable food without affecting baseline feeding (Romano, Micioni Di Bonaventura, et al., 2020). This behavioral modulation is accompanied by reduced activation of stress- and reward-related brain regions, including the nucleus accumbens and the amygdala, and enhanced activation of hypothalamic and midbrain nuclei implicated in feeding control, such as the PVN and the VTA (Romano, Micioni Di Bonaventura, et al., 2020). In the same model, OEA dampens stress-induced dopamine release in the nucleus accumbens shell while enhancing serotonergic and noradrenergic tone and modulating central corticotropin-releasing factor and oxytocinergic systems (Romano, Micioni Di Bonaventura, et al., 2020). Collectively, the available evidence indicates that OEA regulates feeding behavior through coordinated engagement of homeostatic and non-homeostatic circuits. The central neural pathways through which OEA modulates feeding behavior are schematically illustrated in Figure 1. Rather than acting solely as a satiety signal, OEA appears to rebalance interactions between metabolic needs and reward-driven motivation. This multimodal central profile distinguishes OEA from purely appetite-suppressing agents and supports its potential relevance in conditions characterized by reward dysregulation or stress-driven overeating However, the extent to which these central effects translate into clinically meaningful outcomes in humans remains to be determined, underscoring the need for studies that directly assess neurobehavioral endpoints alongside metabolic efficacy. 3.2 Peripheral mechanisms mediating OEA’s effects and gut-brain communication The ability of peripherally administered OEA to engage central circuits involved in the regulation of feeding behavior has raised the question of how this lipid mediator communicates with the brain (Romano et al., 2023). Clarifying the relative contribution of neural versus humoral pathways is critical not only for understanding OEA physiology but also for defining its pharmacokinetic and translational potential as a therapeutic candidate (Romano et al., 2023; Tutunchi, Saghafi-Asl, et al., 2020). Initial studies implicated visceral vagal afferents, as OEA-induced hypophagia was attenuated in rats subjected to total subdiaphragmatic vagotomy or treated with neurotoxic doses of capsaicin (Rodríguez De Fonseca et al., 2001; Fu et al., 2003; Romano et al., 2023). However, subsequent analyses highlighted important methodological limitations of both experimental approaches. Total subdiaphragmatic vagotomy removes both afferent and efferent fibers, thereby disrupting the physiological bidirectional communication between the gastrointestinal tract and the brain and producing profound alterations in digestive and metabolic function that may confound behavioral outcomes (Romano et al., 2023). Similarly, capsaicin treatment lacks selectivity for vagal afferents, as it induces neurotoxic damage to unmyelinated visceral sensory neurons of both vagal and spinal origin. Moreover, it has been shown to affect neurons within the AP and the NST, regions critically involved in the central processing of visceral signals (Romano et al., 2017, 2023). These limitations complicate interpretation of early findings. More selective subdiaphragmatic vagal deafferentation (SDA) in rats - a surgical procedure that can spare a substantial proportion of vagal efferent fibers (Azari et al., 2014) - demonstrated that OEA retains its hypophagic efficacy despite removal of abdominal vagal afferents (Azari et al., 2014; Romano et al., 2023). These data indicate that intact vagal sensory transmission is not required for the anorexigenic action of exogenous OEA and suggest the involvement of alternative signaling routes from the periphery to the brain. The AP has emerged as a critical interface in this context (Romano et al., 2017, 2023). As a circumventricular organ devoid of a functional blood-brain barrier, the AP is uniquely positioned to detect circulating metabolic signals (Romano et al., 2017). Surgical ablation of the AP abolishes both OEA-induced hypophagia and associated neurochemical effects, suggesting that circulating OEA can access and activate central feeding circuits via AP-dependent mechanisms (Romano et al., 2023). Recent pharmacokinetic analyses further support this interpretation. Following systemic administration, intact OEA appears in the circulation and accumulates in discrete brain regions implicated in feeding regulation, including the AP, NST, arcuate nucleus/median eminence, and hippocampus (Romano et al., 2023). Notably, the earliest and most pronounced increase occurs in the AP, reinforcing its role as a primary sensing site for circulating OEA (Romano et al., 2023). These findings substantially revise earlier models that exclusively emphasized vagal mediation. Moreover, the rapid detection of OEA in the adjacent NST further support the functional coupling between these brainstem structures, consistent with sequential engagement of AP-NST circuits involved in the central integration of peripheral metabolic signals (Romano et al., 2023). The AP-centered model also reconciles previous inconsistences across experimental models. The loss of OEA efficacy following capsaicin treatment may reflect collateral disruption of AP/NST circuitry rather than selective vagal blockade (Romano et al., 2023). Conversely, the lack of consistent hypophagic effects following intracerebroventricular administration of OEA may relate on rapid enzymatic degradation by FAAH at ventricular interfaces, whereas FAAH expression appears limited in the AP, potentially conferring increased sensitivity to circulating OEA (Piomelli, 2013; Romano et al., 2023). In parallel with these direct access mechanisms, peripheral metabolic actions of OEA may contribute indirectly to gut-brain communication. OEA is a high-affinity agonist of PPAR-α, which is abundantly expressed in the proximal small intestine and liver, where it regulates fatty acid oxidation and ketogenesis (Igarashi et al., 2021; Piomelli, 2013). Experimental studies have shown that peripheral OEA administration increases intestinal fatty acid oxidation and elevates circulating β-hydroxybutyrate levels (Azari et al., 2014), raising the possibility that OEA-induced humoral signals may participate in conveying metabolic information to the brain independently of direct neural pathways (Igarashi et al., 2021; Piomelli, 2013). Although the causal contribution of such metabolic intermediates to OEA’s central effects remains to be fully elucidated, this humoral component is consistent with the persistence of OEA-induced hypophagia in the absence of intact vagal afferents. Collectively, the available evidence indicates that exogenously administered OEA engages central feeding circuits through a combination of mechanisms: include direct access of circulating OEA to circumventricular brain regions -particularly the AP- and secondary metabolic signaling downstream of peripheral PPAR-α activation. The peripheral mechanisms through which OEA engages gut-brain communication are schematically illustrated in Figure 1. From a pharmacological standpoint, these findings underscore the importance of systemic exposure profiles, route of administration, and dose selection in determining central efficacy. They also suggest that OEA’s mode of action differs fundamentally from gut hormone-based therapies that rely predominantly on receptor-mediated neural signaling, positioning OEA as a lipid-derived modulator of gut–brain communication rather than a classical peptide hormone analogue. 3.3 Evidence for the anti-obesity effects of OEA OEA was initially characterized as a lipid mediator involved in the regulation of energy intake and body weight, and suppression of food intake remains the most consistently reported functional outcome following exogenous administration in experimental models (Azari et al., 2014; Fu et al., 2003, 2005; Laleh et al., 2019; Rodríguez De Fonseca et al., 2001; Tovar et al., 2021; Tutunchi, Saghafi-Asl, et al., 2020). In rodents, peripheral OEA administration reduces feeding primarily by delaying meal initiation, without inducing behavioural signs of stress, visceral illness, or alterations in locomotor activity or water intake (Azari et al., 2014; Fu et al., 2003; Rodríguez De Fonseca et al., 2001). Importantly, the magnitude and pattern of feeding suppression are influenced by metabolic context. In free-feeding animals, intraperitoneal OEA administration (1-20 mg/kg) produces a dose-dependent delay in feeding onset, with limited disruption of meal structure, whereas in food-deprived conditions both feeding latency and meal size may be reduced (Azari et al., 2014; Gaetani et al., 2003; Romano et al., 2015). These observations indicate state-dependent modulation of energy intake rather than indiscriminate appetite suppression (Azari et al., 2014; Fu et al., 2003). In models of diet-induced obesity, repeated OEA administration reduces cumulative caloric intake and attenuates body weight gain and adiposity (Fu et al., 2005; Tovar et al., 2021; Tutunchi, Saghafi-Asl, et al., 2020). These effects are evident within days and persist throughout the treatment (Fu et al., 2005; Tovar et al., 2021; Tutunchi, Saghafi-Asl, et al., 2020). Notably, these effects are markedly more pronounced in obese animals than in lean controls fed with a standard diet, indicating that the anti-obesity efficacy of OEA may depend on metabolic state (Fu et al., 2005; Tovar et al., 2021; Tutunchi, Saghafi-Asl, et al., 2020). Comparative investigations among structurally related NAEs further indicate that OEA produces more robust and reproducible reductions in food intake and body weight than other lipid congeners, supporting a degree of functional specificity within the NAE family (Tovar et al., 2021). Across experimental paradigms, reductions in body weight induced by OEA are closely associated with decreased energy intake rather than aversive or nonspecific behavioral effects. Systematic evaluation of the preclinical literature confirms that suppression of food intake represents the primary driver of OEA-induced attenuation of body weight gain, with consistent effects observed across species, dietary paradigms, and treatment regimens (Tutunchi, Saghafi-Asl, et al., 2020). Clinical evidence, although more limited, is congruent with preclinical observations (Laleh et al., 2018). Randomized controlled trials in overweight and obese individuals report that oral OEA supplementation is associated with reductions in body weight, body mass index, and waist circumference, often accompanied by decreased appetite ratings and improved adherence to dietary interventions (Laleh et al., 2019). While the magnitude of weight loss remains modest, these findings support a translational relevance of OEA-mediated control of energy intake. Collectively, these data identify OEA as an endogenous lipid-derived regulator with reproducible anti-obesity effects primarily driven by modulation of food intake. The consistency of this phenotype across species and metabolic contexts supports the positioning of OEA among physiologically grounded lipid-derived modulators of energy balance with potential relevance for obesity management particularly in strategies aimed at complementing, rather than replacing, existing pharmacological approaches. 4. OEA and metabolic comorbidities associated with obesity 4.1 Metabolic homeostasis and insulin sensitivity Beyond its well-established role in the control of feeding behavior, OEA has emerged as a relevant modulator of metabolic homeostasis in experimental models of obesity (Bowen et al., 2017). Acute OEA administration does not consistently or directly alter circulating glucose, insulin, or glucagon levels across rodent studies, and available evidence does not support a robust insulinotropic profile (Piomelli, 2013). Nevertheless, depending on dose, nutritional state, and metabolic context, OEA can influence glucose handling through indirect mechanisms, and more reproducible metabolic benefits are generally reported following repeated administration, in parallel with changes in substrate utilization and lipid metabolism. In preclinical settings, OEA has been shown to modulate energy metabolism in rodent models of diet-induced obesity, thereby influencing pathways that are tightly linked to insulin responsiveness (Ivashkevich, Ponomarenko, Manzhulo, & Dyuizen, 2025). In the obese state, dysregulation of hepatic lipid handling and gluconeogenic activity represents a major driver of systemic metabolic imbalance (Ivashkevich, Ponomarenko, Manzhulo, & Dyuizen, 2025). In this context, OEA administration has been associated with reduced metabolic stress and improved substrate utilization (Ivashkevich, Ponomarenko, Manzhulo, & Dyuizen, 2025). Mechanistic evidence from high-fat diet-fed rats indicates that these effects involve, among others, PPAR-α-dependent hepatic pathways, including reduced lipid accumulation, enhanced fatty-acid oxidation, and downregulation of key gluconeogenic enzymes, collectively reflecting improved hepatic metabolic flexibility (Ivashkevich, Ponomarenko, Manzhulo, & Dyuizen, 2025). Notably, additional signaling routes have also been implicated in selected models, supporting the view that OEA may affect hepatic glucose metabolism through multiple, context-dependent mechanisms (Ren et al., 2020; Tutunchi et al., 2019). The relevance of PPAR-α–dependent mechanisms for the regulation of insulin responsiveness in obesity is further supported by experimental studies in which PPAR-α activity is selectively enhanced in peripheral tissues (Araki et al., 2018; Takahashi et al., 2017). In mice with diet-induced obesity, adipose tissue-specific overexpression of PPAR-α was associated with improved insulin responsiveness, as evidenced by insulin tolerance tests, and reduced insulin levels during oral glucose challenge (Araki et al., 2018; Takahashi et al., 2017). These changes occurred alongside decreased adipocyte hypertrophy, attenuation of obesity-associated inflammatory markers in white adipose tissue, and marked alterations in lipid handling, including reduced levels of saturated fatty acids and arachidonic acids (Araki et al., 2018; Takahashi et al., 2017). Modulation of branched-chain amino acid metabolism was also observed, consistent with an overall improvement in metabolic efficiency in the obese state (Araki et al., 2018; Takahashi et al., 2017). In line with these observations, pharmacological activation of PPAR-α using selective agonists has been shown to protect against diet-induced obesity and to improve systemic metabolic homeostasis in mice (Araki et al., 2018; Takahashi et al., 2017). Treatment with the PPAR-α agonist pemafibrate attenuated weight gain and improved lipid and energy metabolism in high-fat diet-fed animals, further supporting the contribution of sustained PPAR-α activation to the modulation of obesity-associated metabolic dysfunction (Araki et al., 2018; Takahashi et al., 2017). Within this framework, chronic OEA treatment has also been reported to be associated with improved glucose handling in an experimental model of diet-induced obesity, as reflected by reduced fasting glycemia and improved glucose tolerance, in parallel with attenuation of body weight gain and adiposity (Araki et al., 2018; Takahashi et al., 2017). Importantly, when present, these changes are generally interpreted as secondary to improved metabolic efficiency, reduced lipotoxic stress, and tissue-level reprogramming of substrate partitioning, rather than to direct modulation of insulin secretion. Physiological evidence further supports a role for endogenous OEA signaling in the regulation of metabolic homeostasis under physiological conditions (Igarashi et al., 2021). OEA is synthesized in the small intestine upon the intake of dietary oleic acid and has been proposed to act as a lipid-derived signal linking fat ingestion to postprandial metabolic responses (Igarashi et al., 2021). In experimental studies, endogenous OEA production has been associated with the coordination of satiety signaling and peripheral metabolic adaptations, contributing to the maintenance of glucose and energy balance without directly altering circulating glucose or insulin levels (Igarashi et al., 2021). In line with this view, broader analyses of endocannabinoid-like lipid mediators identify OEA as part of a nutrient-sensitive signaling network involved in metabolic flexibility and the fine regulation of insulin responsiveness (Rahman et al., 2021). Translational evidence in humans, although still limited, is broadly consistent with these preclinical observations. In a randomized, double-blind, placebo-controlled trial conducted in obese but otherwise healthy individuals, oral supplementation with OEA (125 mg twice daily for 8 weeks) resulted in a significant reduction in circulating triglyceride levels, while fasting blood glucose remained unchanged and no major modifications in reported dietary habits or physical activity were observed (Ostadrahimi et al., 2024). Similarly, reductions in body weight, body mass index, and waist circumference have been reported following OEA supplementation, together with increased expression of PPAR-α–related metabolic markers, supporting an improvement in metabolic efficiency rather than a direct modulation of glycemic control (Laleh et al., 2018). Consistent with these findings, systematic evaluations of the available preclinical and clinical literature conclude that OEA treatment is associated with modest but reproducible improvements in metabolic parameters in overweight and obese conditions, particularly with respect to lipid handling and energy balance, while effects on glucose homeostasis appear limited and context-dependent (Tutunchi, Saghafi-Asl, et al., 2020). A recent systematic review and meta-analysis of randomized controlled trials similarly indicates that OEA supplementation is associated with context-dependent changes in parameters linked to insulin sensitivity rather than with uniform effects on insulin secretion (Eslahi et al., 2025). Across clinical studies, OEA treatment was consistently associated with improvements in fasting glycemia, triglyceride levels, waist circumference, and inflammatory and oxidative stress markers, whereas effects on circulating insulin levels appeared variable and dependent on baseline metabolic status and study design (Eslahi et al., 2025). This pattern supports the view that OEA influences glucose handling and insulin responsiveness primarily through improvements in metabolic efficiency and tissue lipid utilization, rather than through direct insulinotropic actions (Eslahi et al., 2025). Taken together, these data indicate that OEA contributes to the regulation of metabolic homeostasis in obesity primarily by modulating lipid metabolism, energy utilization, and inflammatory tone in peripheral tissues, processes that are functionally linked to insulin sensitivity. Where improvements in glucose handling are observed, they most probably reflect indirect consequences of enhanced metabolic flexibility and reduced lipotoxic stress, rather than consistent, primary insulinotropic actions. This mode of action is consistent with the role of OEA as a nutrient-responsive lipid signal operating within a broader metabolic network coordinating energy balance and insulin responsiveness under obese conditions. 4.2 Hepatic steatosis and metabolic-associated fatty liver disease Obesity is closely linked to hepatic steatosis and the broader spectrum of metabolic-associated fatty liver diseases (MAFLD) (Eslam et al., 2020). Excess adiposity and insulin resistance enhance the flux of free fatty acids to the liver, stimulate de novo lipogenesis, impair mitochondrial fatty acid oxidation, and promote intrahepatic triglyceride accumulation (Samuel & Shulman, 2018). These alterations lead to hepatic steatosis, which represents the earliest and most prevalent manifestation of obesity-related liver disease (Fabbrini et al., 2010). In a substantial proportion of individuals, steatosis may progress toward inflammatory liver injury, oxidative and endoplasmic reticulum stress, and fibrotic remodeling, thereby contributing to the development of more advanced liver dysfunction (Karin & Kim, 2025). Given the central role of the liver in systemic lipid and glucose metabolism, modulation of hepatic metabolic pathways represents a key therapeutic target in obesity-associated metabolic complications (Dukewich et al., 2025). Within this framework, a growing body of evidence indicates that OEA exerts direct hepatoprotective actions in the context of obesity-associated hepatic steatosis and metabolic-associated fatty liver disease, through coordinated effects on lipid metabolism, oxidative stress, endoplasmic reticulum stress and transcriptional regulation of metabolic pathways (Giudetti et al., 2021; Ivashkevich, Ponomarenko, Manzhulo, & Dyuizen, 2025; Lin et al., 2022; Romano et al., 2021; Tutunchi, Ebrahimi-Mameghani, et al., 2023; Tutunchi et al., 2019; Tutunchi, Naeini, et al., 2020; Tutunchi, Ostadrahimi, et al., 2020). Mechanistically, these effects are associated with suppression of the de novo lipogenesis and triglyceride synthesis through transcriptional mechanisms involving sterol regulatory element-binding proteins and PPAR-dependent pathways (Romano et al., 2021), as demonstrated in rat models. In high-fat-diet-fed rats two-week-OEA treatment has additionally been shown to attenuate oxidative stress and endoplasmic reticulum stress, decreasing hepatic malondialdehyde and protein carbonylation, restoring antioxidant enzyme activities (superoxide dismutase, catalase, and glutathione peroxidase), and improving markers of endoplasmic reticulum homeostasis (Giudetti et al., 2021). Evidence from murine models further suggest that obesity may disrupt endogenous hepatic OEA signaling. Long-term exposure to a high-fat diet suppresses fasting-induced histamine release into portal circulation and the consequent histamine-dependent synthesis of OEA in the liver (Lin et al., 2022). Restoration of OEA signaling through exogenous administration reduced hepatic lipid accumulation, inflammatory responses, and fibrosis in obese mice, highlighting the relevance of impaired OEA production in the pathophysiology of obesity-associated liver disease (Lin et al., 2022). More recent studies using dietary-induced obesity models further support a broad hepatoprotective profile of OEA. In mice fed a high-fat, high-cholesterol diet, supplementation with an OEA-based formulation normalized serum cholesterol levels, reduced hepatic inflammation and apoptosis, increased expression of PPAR-α and genes involved in fatty acid oxidation (including Acox1 and Cpt1a), and improved markers of lipid and cholesterol handling, collectively indicating a coordinated improvement of MAFLD-related hepatic alterations (Ivashkevich, Ponomarenko, Manzhulo, Egoraeva, et al., 2025). Translational relevance is supported by several randomized controlled trials in obese patients with non-alcoholic fatty liver disease (NAFLD). In these subjects, undergoing calorie-restricted diets, OEA supplementation for 12 weeks significantly improved metabolic and hepatic parameters, including reductions in serum triglycerides, alanine and aspartate aminotransferases, and improvements in anthropometric indices (Tutunchi, Ostadrahimi, et al., 2020). At the molecular level, OEA increased the expression of PPAR-α and uncoupling proteins (UCP1 and UCP2) in peripheral blood mononuclear cells, suggesting enhanced systemic fatty acid oxidation and energy dissipation (Tutunchi, Ostadrahimi, et al., 2020). Additional clinical trials in obese patients with NAFLD reported that OEA supplementation improves atherogenic indices, lipid profiles and inflammatory biomarkers, when administered alongside dietary interventions, further supporting its beneficial impact on hepatic and metabolic risk factors (Tutunchi et al., 2023; Tutunchi, Naeini, et al., 2020). Moreover, OEA treatment has been associated with modulation of lipid metabolism-related gene expression and increased circulating levels of neuregulin-4, a hepatokine implicated in lipid homeostasis (Tutunchi, Ebrahimi-Mameghani, et al., 2023). Taken together, current evidence supports a multifaceted hepato-metabolic action of OEA in obesity, characterized by modulation of lipid metabolism, activation of fatty acid oxidation pathways, and attenuation of oxidative and endoplasmic reticulum stress, all direct effects, rather than secondary to reduced food intake. The hepato-metabolic mechanisms through which OEA modulates lipid metabolism and protects against obesity-associated hepatic steatosis are schematically illustrated in Figure 1. Overall, the convergence of robust preclinical mechanistic observations and early translational evidence positions OEA as a biologically plausible modulator of obesity-associated hepatic steatosis within the broader landscape of metabolic-targeted therapies. 4.3 Cardiovascular dysfunction associated with obesity Obesity is strongly associated with cardiac and vascular dysfunctions that substantially contribute to increased morbidity and mortality (Powell-Wiley et al., 2021). Beyond the hemodynamic burden imposed by excess body weight, obesity induces profound metabolic alterations that impair myocardial energy metabolism, promote ectopic lipid accumulation, and alter vascular homeostasis, thereby predisposing to cardiometabolic remodeling and increased atherogenic risk (Powell-Wiley et al., 2021).Within this context, metabolic regulators that influence lipid handling, oxidative balance and tissue-specific energy utilization may critically influence cardiovascular outcomes in obese conditions (Khan et al., 2022). Preclinical evidence supports a cardioprotective action of OEA in obesity-related cardiometabolic dysfunction (Comella et al., 2024; Ivashkevich, Ponomarenko, Manzhulo, Egoraeva, et al., 2025). In murine models of diet-induced obesity, chronic supplementation with an OEA-based dietary formulation was shown to normalize circulating cholesterol levels and modulate key molecular determinants of atherogenesis, including down-regulation of the pro-atherogenic factor PCSK9 and restoration of LDL receptor-related pathways (Ivashkevich, Ponomarenko, Manzhulo, Egoraeva, et al., 2025). These effects were paralleled by a marked reduction in systemic and hepatic inflammation, oxidative stress, and hepatocellular lipid accumulation, indicating that dietary supplementation of OEA exerts cardiometabolic protection primarily by targeting metabolic and inflammatory mechanisms that link obesity, dyslipidemia, and cardiovascular dysfunction (Ivashkevich, Ponomarenko, Manzhulo, Egoraeva, et al., 2025). Evidence of direct myocardial effects remains more limited. In high-fat diet–fed mice, OEA administration has been associated with reduced cardiac lipid accumulation, attenuation of oxidative stress, and preservation of selected cardiac functional parameters. These findings suggest that modulation of myocardial lipid utilization may contribute to improved cardiac resilience under metabolic stress. However, detailed assessments of cardiac structure, long-term functional outcomes, and dose–response relationships remain scarce (Comella et al., 2024). Clinical data are preliminary and primarily focus on surrogate cardiometabolic risk markers (Tutunchi, Naeini, et al., 2020). In a randomized, placebo-controlled trials in obese patients with NAFLD, OEA supplementation (250 mg/day for 12 weeks), in combination with caloric restriction, significantly improved several atherogenic lipid ratios, including those reflecting the balance between low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol (Tutunchi, Naeini, et al., 2020). These effects occurred without major changes in blood pressure, pointing to a selective impact on lipid-driven cardiovascular risk rather than on hemodynamic parameters (Tutunchi, Naeini, et al., 2020). Meta-analyses of randomized controlled trials report significant reductions in fasting glucose, insulin levels, triglycerides, and waist circumference following OEA administration, parameters that are known to contribute to myocardial metabolic stress and cardiometabolic burden (Bahari et al., 2025; Eslahi et al., 2025). In contrast, effects on total cholesterol and low-density lipoprotein-cholesterol appear less consistent across studies, underscoring a limited impact on classical lipid fractions (Bahari et al., 2025; Eslahi et al., 2025). Taken together, current evidence suggests that OEA influences cardiovascular risk in obesity predominantly through modulation of lipid metabolism, inflammatory status, and systemic metabolic control, processes that critically influence myocardial and vascular vulnerability under obese conditions. The cardiometabolic mechanisms through which OEA may influence cardiovascular risk in obesity are schematically illustrated in Figure 1. While preclinical data indicate potential benefits at the myocardial level, clinical evidence is limited to improvements in surrogate risk markers. At present, OEA should be regarded as a modulator of cardiometabolic determinants rather than as a direct cardioprotective agent. Further studies incorporating functional and imaging-based cardiovascular endpoints will be required to define its true impact on obesity-associated cardiovascular remodeling. 4.4 Intestinal dysfunction and gut-brain-microbiota axis alterations Obesity is increasingly recognized as a condition characterized by altered gut-brain communication and disruption of intestinal homeostasis, with relevant consequences for systemic metabolic regulation (Asadi et al., 2022). Impairments of epithelial barrier integrity, dysregulated nutrient sensing, and gut microbiota dysbiosis contribute to a defective signaling between the gastrointestinal tract, the central nervous system, and peripheral metabolic organs, thereby promoting metabolic inflexibility and low-grade inflammation characteristic of obese states (Shen et al., 2025). Within this framework, intestinal lipid-derived mediators like OEA represent critical components of nutrient-responsive signaling networks linking luminal fat sensing to central and peripheral metabolic adaptation (DiPatrizio & Piomelli, 2015). Under physiological conditions, OEA is synthesized in the proximal small intestine in response to dietary fat intake and acts as a lipid sensor within the gut-brain axis (Schwartz et al., 2008). Beyond its established role in the control of feeding behavior, OEA has been implicated in the modulation of epithelial integrity, immune-metabolic signaling, and local lipid handling processes that contribute to intestinal homeostasis. Under physiological conditions, this system supports coordinated communication between the gastrointestinal tract, central feeding circuits, and peripheral metabolic organs (De Filippo et al., 2023). Accumulating experimental evidence indicates that obesity is associated with a disruption of endogenous intestinal OEA signaling (De Filippo et al., 2023). Diet-induced obesity impairs postprandial OEA mobilization in the proximal intestine, blunting the normal coupling between dietary lipid sensing and downstream appropriate metabolic and neuroendocrine responses (De Filippo et al., 2023). Alterations in gut microbiota composition and intestinal inflammatory tone further contribute to this dysfunction, positioning defective OEA signaling as a component of the broader dysregulation of the microbiota-gut-brain axis observed in obese states (De Filippo et al., 2023). Within this pathological context, the administration of exogenous OEA has been widely employed in preclinical studies, and more recently explored in clinical settings, as a strategy to compensate for defective endogenous lipid-mediated signaling (De Filippo et al., 2023). Preclinical studies suggest that restoration of OEA tone may partially counteract obesity-associated intestinal dysfunction (Cimmino et al., 2025; Igarashi et al., 2023; Payahoo et al., 2019; Seguella et al., 2025; Vari et al., 2025). In high-fat diet-fed mice, administration of an OEA-producing strain of Lactobacillus paracasei improved epithelial barrier integrity, reduced intestinal permeability, normalized microbiota composition, alongside improvements in metabolic and behavioral alterations associated with obesity (Seguella et al., 2025).These findings support a functional interaction between microbiota-derived OEA and host metabolic regulation, although the relative contribution of bacterial versus host-derived OEA requires further clarification. Complementary experimental studies further indicate that OEA contributes to the preservation of intestinal structure and metabolic homeostasis under high-fat dietary conditions (Vari et al., 2025). Pharmacological modulation of endocannabinoid-like lipid signaling, including OEA, limits diet-induced alterations in epithelial integrity, intestinal permeability, and metabolic signaling pathways, highlighting a protective role against obesity-associated intestinal dysfunction (Vari et al., 2025). Additional mechanistic insight is provided by studies showing that OEA interacts with the eCBome and influences mitochondrial bioenergetics, lipid signaling networks, and gut microbiota composition in models of diet-induced obesity, collectively contributing to improve metabolic flexibility and energy homeostasis (Cimmino et al., 2025). Emerging clinical evidence supports translational relevance, albeit indirectly. In randomized controlled trials conducted in obese individuals, OEA supplementation has been associated with increased relative abundance of Akkermansia muciniphila, a bacterial species linked to improved metabolic health and intestinal barrier function (Payahoo et al., 2019). These microbiota changes were accompanied by modifications in dietary intake, suggesting that OEA supplementation may influence host-microbiota interactions and feeding-related behaviors in obese subjects. However, causal relationships between microbiota shifts and metabolic improvements remain to be established, and most studies rely on compositional rather than functional microbiome analyses. At the molecular level, convergence between microbial metabolites and host lipid mediators may further influence gut-brain communication (Igarashi et al., 2023). Microbiota-derived metabolites can activate intestinal receptors involved in metabolic regulation, including GPR119, a recognized molecular target of OEA (Igarashi et al., 2023). Although direct causal links between microbiota-derived metabolites, OEA signaling, and GPR119 activation remain to be fully established, available evidence supports the existence of overlapping signaling pathways through which intestinal lipid mediators and microbial products jointly modulate metabolic and neurobehavioral outcomes in obesity (Igarashi et al., 2023). Taken together, available evidence indicates that OEA contributes to the modulation of gut-brain-microbiota interactions in obesity through effects on intestinal lipid sensing, barrier integrity, and metabolic signaling. The mechanisms through which OEA modulates intestinal homeostasis and microbiota-gut-brain communication are schematically illustrated in Figure 1. Although mechanistic links remain incompletely defined, restoration of OEA signaling in obesogenic conditions may represent a biologically plausible strategy to improve intestinal metabolic communication. Further studies integrating microbiome function, host lipid mediator dynamics, and neurobehavioral endpoints will be required to clarify the extent of OEA’s role within the complex microbiota–gut–brain network. 5. OEA in the time of incretin-based therapies OEA and incretin-based therapies regulate energy homeostasis through fundamentally distinct molecular targets, yet converge on partially overlapping physiological outcomes, including reduced energy intake and remodeling of systemic metabolic balance (Moiz et al., 2025). While both systems ultimately influence satiety, metabolic efficiency, and body weight regulation, they operate through divergent receptor architectures, signaling dynamics, and regulatory hierarchies, reflecting distinct levels of metabolic control (Zheng et al., 2024). OEA exerts its biological actions primarily through activation of PPAR-α, which heterodimerize with the retinoid X receptor and regulate transcriptional programs involved in fatty acid transport, mitochondrial β-oxidation, lipogenesis, and metabolic flexibility (Tutunchi et al., 2019). Through transcriptional reprogramming, OEA coordinates nutrient handling and energy in a manner that secondarily influence feeding behaviour. Its effects on appetite suppression therefore seems to arise within a broader metabolic framework, rather than from direct, rapid receptor-mediated inhibition of hunger signals (Schwartz et al., 2008). In contrast, GLP-1 receptor agonists act through high-affinity receptor activation that directly modulates glucose-dependent insulin secretion, suppress glucagon release, delay gastric emptying and exert potent anorectic effects through direct and indirect actions on central nervous system circuits controlling appetite, reward processing, and satiety. These receptor-driven mechanisms translate into robust reductions in caloric intake and reproducible weight loss, with a magnitude and consistency that currently exceed those observed with OEA supplementation (Moiz et al., 2025). The temporal profile of incretin-based therapies is also distinct, characterized by rapid pharmacodynamic effects tightly linked to receptor occupancy (Sfairopoulos et al., 2018). Despite these differences, a relevant point of interaction between OEA and incretin signaling emerges at the level of the gut. Although OEA’s hypophagic actions are largely independent of classical incretin pathways, OEA can activate GPR119 in enteroendocrine L-cells, leading to stimulation of GLP-1 secretion in vitro and in vivo (Lauffer et al., 2009). This mechanism represents the main well-established contribution of GPR119 to OEA signaling and suggests that OEA may indirectly engage incretin pathways under specific physiological contexts, without relying on GLP-1 receptor activation as its primary mode of action (Lauffer et al., 2009). Beyond indirect GLP-1 release, preclinical evidence also indicates that OEA can modulate GLP-1 receptor agonist signaling in a context-dependent manner (Brown et al., 2018). In diet-induced obese mice, combined administration of OEA and exendin-4 (a long-acting GLP-1 receptor agonist) resulted in greater short-term weight loss, as compared to either compound alone, an effect attributed to parallel and partially additive actions on feeding behavior and energy expenditure, rather than true pharmacological synergy (Brown et al., 2018). These findings suggest that OEA and GLP-1 receptor agonists operate on complementary metabolic axes: one primarily transcriptional and lipid-centered, the other receptor-driven and neuroendocrine (Brown et al., 2018). Emerging translational observations indicate that the eCBome, including OEA-related signaling pathways, may influence individual responsiveness to GLP-1 receptor agonist (Matias et al., 2023). Associations between circulating endocannabinoid-like molecules and variability in treatment outcomes raise the possibility that baseline lipid signaling states could shape incretin efficacy, although causal relationships remain to be established (Matias et al., 2023). Taken together, current evidence supports a conceptual framework in which OEA, and incretin-mimetics should not be viewed as competing interventions, but as complementary therapies acting at distinct regulatory tiers of energy homeostasis. GLP-1 agonists provide potent receptor-mediated control of appetite and glycemia, whereas OEA modulates nutrient-responsive lipid-signaling and metabolic flexibility through transcriptional mechanisms. Understanding how these distinct signaling systems intersect may help refine future combination or sequential strategies aimed at improving metabolic health and long-term regulation of energy balance beyond weight loss alone. 6. Conclusions and future directions The evidence reviewed herein positions OEA as a biologically coherent and functionally relevant lipid mediator linking intestinal nutrient sensing to systemic metabolic regulation. Unlike receptor-specific anti-obesity pharmacotherapies that primarily target single receptors or pathways, OEA engages distributed signaling networks integrating nutrient sensing, lipid metabolism, and central feeding circuits. This systems-level mode of action supports the view that OEA functions as a metabolic modulator operating within physiological regulatory networks, rather than as a conventional anorectic or weight-loss drug. From a translational perspective, several features make OEA conceptually attractive for obesity management. Its endogenous origin, well-characterized biosynthetic and degradative pathways and favorable tolerability profile in preclinical and early clinical studies suggest biological compatibility with long-term use. Importantly, OEA appears to induce coordinated changes in food intake, adiposity, lipid handling, and inflammatory tone, rather than rapid, pharmacologically enforced weight loss. Such a profile may be particularly relevant in strategies aimed at enhancing metabolic flexibility and sustaining adaptive regulatory response over time. However, important limitations remain. Human studies are small, relatively short in duration, and largely restricted to surrogate metabolic endpoints. The magnitude of weight reduction observed thus far is modest, and evidence supporting durable effects on long-term weight maintenance or hard cardiometabolic outcomes is lacking. Furthermore, pharmacokinetic parameters, brain exposure, optimal dosing strategies, and formulation issues require clearer definition. At present, the clinical evidence base does not support positioning OEA as a stand-alone anti-obesity therapy. In the context of the current therapeutic landscape - dominated by multi-agonist incretin-based agents that achieve substantial weight loss through potent receptor activation - OEA should not be viewed as a competing intervention. Rather, its mechanism, suggests potential complementarity. By modulating nutrient-responsive lipid signaling and metabolic reprogramming, OEA may address dimensions of metabolic flexibility, lipid partitioning, and reward-related feeding that are not fully targeted by incretin pathways. Future translational efforts should therefore prioritize: (i) rigorous pharmacokinetic characterization; (ii) identification of responsive metabolic phenotypes; (iii) long-term, adequately powered clinical trials incorporating both metabolic and behavioral endpoints; and (iv) evaluation of rational combination strategies with established anti-obesity pharmacotherapies. Whether modulation of paracannabinoid signaling can yield sustained clinical benefit will depend on defining these parameters with the same level of precision currently applied to receptor-targeted metabolic drugs. 0pt 2.5ex plus 1ex minus .2ex 1.5ex plus .2ex 0pt 2ex plus .5ex minus .2ex 1ex plus .2ex 0pt 1.5ex plus .5ex minus .2ex 0.8ex plus .2ex Bibliography Araki, M., Nakagawa, Y., Oishi, A., Han, S. I., Wang, Y., Kumagai, K., Ohno, H., Mizunoe, Y., Iwasaki, H., Sekiya, M., Matsuzaka, T., & Shimano, H. (2018). The Peroxisome Proliferator-Activated Receptor α (PPARα) Agonist Pemafibrate Protects against Diet-Induced Obesity in Mice. International Journal of Molecular Sciences, 19 (7), 2148. https://doi.org/10.3390/ijms19072148 Arturo, I. F., & Fabiana, P. (2018). Endocannabinoidome. Encyclopedia of Life Sciences, 1–10. https://doi.org/10.1002/9780470015902.a0028301 Asadi, A., Shadab Mehr, N., Mohamadi, M. H., Shokri, F., Heidary, M., Sadeghifard, N., & Khoshnood, S. (2022). Obesity and gut-microbiota-brain axis: A narrative review. Journal of Clinical Laboratory Analysis, 36 (5). https://doi.org/10.1002/jcla.24420 Azari, E. K., Ramachandran, D., Weibel, S., Arnold, M., Romano, A., Gaetani, S., Langhans, W., & Mansouri, A. (2014). Vagal afferents are not necessary for the satiety effect of the gut lipid messenger oleoylethanolamide. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 307 (2). https://doi.org/10.1152/ajpregu.00067.2014 Bahari, H., Jazinaki, M. S., Aghakhani, L., Hatami, A., Rahnama, I., & Malekahmadi, M. (2025). Oleoylethanolamide supplementation on cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials. Frontiers in Nutrition, 12, 1553288. https://doi.org/10.3389/fnut.2025.1553288 Beggiato, S., Tomasini, M. C., & Ferraro, L. (2019). Palmitoylethanolamide (PEA) as a potential therapeutic agent in Alzheimer’s disease. Frontiers in Pharmacology, 10, 468723. https://doi.org/10.3389/fphar.2019.00821 Ben-Porat, T., Sherf-Dagan, S., Côté, M., Miner, C. J., & Buch, A. (2025). Nutritional Challenges of Incretin-Based Obesity Management Medications: Implications for Clinical Practice. Advances in Nutrition, 16 (11), 100522. https://doi.org/10.1016/j.advnut.2025.100522 Blüher, M. (2019). Obesity: global epidemiology and pathogenesis. Nature Reviews Endocrinology, 15 (5), 288–298. https://doi.org/10.1038/s41574-019-0176-8 Blüher, M. (2025). An overview of obesity‐related complications: The epidemiological evidence linking body weight and other markers of obesity to adverse health outcomes. Diabetes, Obesity & Metabolism, 27 (Suppl 2), 3-19. https://doi.org/10.1111/dom.16263 Bowen, K. J., Kris-Etherton, P. M., Shearer, G. C., West, S. G., Reddivari, L., & Jones, P. J. H. (2017). Oleic acid-derived oleoylethanolamide: A nutritional science perspective. Progress in Lipid Research, 67, 1–15. https://doi.org/10.1016/j.plipres.2017.04.001 Brown, J. D., Karimian Azari, E., & Ayala, J. E. (2017). Oleoylethanolamide: A fat ally in the fight against obesity. Physiology & Behavior, 176, 50–58. https://doi.org/10.1016/j.physbeh.2017.02.034 Brown, J. D., McAnally, D., Ayala, J. E., Burmeister, M. A., Morfa, C., Smith, L., & Ayala, J. E. (2018). Oleoylethanolamide modulates glucagon-like peptide-1 receptor agonist signaling and enhances exendin-4-mediated weight loss in obese mice. American Journal of Physiology- Regulatory, Integrative and Comparative Physiology, 315 (4), R595–R608. https://doi.org/10.1152/ajpregu.00459.2017 Cimmino, F., Silvestri, C., Trinchese, G., Petrella, L., Cavaliere, G., Fogliano, C., Piscitelli, F., Cristino, L., Avallone, B., Banni, S., Sihag, J., Di Marzo, V., & Mollica, M. P. (2025). Anti-obesity effects of Oleoylethanolamide: Modulation of mitochondrial bioenergetics, endocannabinoidome and gut microbiome. Biomedicine and Pharmacotherapy, 188, 118201. https://doi.org/10.1016/j.biopha.2025.118201 Colizzi, M., Bortoletto, R., Colli, C., Bonomo, E., Pagliaro, D., Maso, E., Di Gennaro, G., & Balestrieri, M. (2022). Therapeutic effect of palmitoylethanolamide in cognitive decline: A systematic review and preliminary meta-analysis of preclinical and clinical evidence. Frontiers in Psychiatry, 13, 1038122. https://doi.org/10.3389/fpsyt.2022.1038122 Comella, F., Aragón-Herrera, A., Pirozzi, C., Feijóo-Bandin, S., Lama, A., Opallo, N., Melini, S., Del Piano, F., Gualillo, O., Meli, R., Mattace Raso, G., & Lago, F. (2024). Oleoylethanolamide mitigates cardiometabolic disruption secondary to obesity induced by high-fat diet in mice. Life Sciences, 359, 123226. https://doi.org/10.1016/j.lfs.2024.123226 De Filippo, C., Costa, A., Becagli, M. V., Monroy, M. M., Provensi, G., & Passani, M. B. (2023). Gut microbiota and oleoylethanolamide in the regulation of intestinal homeostasis. Frontiers in Endocrinology, 14 . https://doi.org/10.3389/fendo.2023.1135157 DiPatrizio, N. V., & Piomelli, D. (2015). Intestinal lipid-derived signals that sense dietary fat. The Journal of Clinical Investigation, 125 (3), 891–898. https://doi.org/10.1172/JCI76302 Dukewich, M., Yuan, L., & Terrault, N. A. (2025). At the Crossroads of Health and Disease: Consequences of Fat in the Liver. Annual Review of Physiology, 87 (1), 325-352. https://doi.org/10.1146/annurev-physiol-022724-105515 Eslahi, M., Rohani, P., Fatahi, S., & Sohouli, M. H. (2025). The effect of oleoylethanolamide supplementation on cardiometabolic factors: a systematic review and meta-analysis. Cardiovascular Endocrinology & Metabolism, 14 (3). https://doi.org/10.1097/XCE.0000000000000339 Eslam, M., Newsome, P. N., Sarin, S. K., Anstee, Q. M., Targher, G., Romero-Gomez, M., Zelber-Sagi, S., Wai-Sun Wong, V., Dufour, J. F., Schattenberg, J. M., Kawaguchi, T., Arrese, M., Valenti, L., Shiha, G., Tiribelli, C., Yki-Järvinen, H., Fan, J. G., Grønbæk, H., Yilmaz, Y., George, J. (2020). A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. Journal of Hepatology, 73 (1), 202–209. https://doi.org/10.1016/j.jhep.2020.03.039 Fabbrini, E., Sullivan, S., & Klein, S. (2010). Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology, 51 (2), 679–689. https://doi.org/10.1002/hep.23280 Friuli, M., Eramo, B., Sepe, C., Kiani, M., Casolini, P., & Zuena, A. R. (2025). The endocannabinoid and paracannabinoid systems in natural reward processes: possible pharmacological targets? Physiology & Behavior, 296, 114929. https://doi.org/10.1016/j.physbeh.2025.114929 Fu, J., Astarita, G., Gaetani, S., Kim, J., Cravatt, B. F., Mackie, K., & Piomelli, D. (2007). Food intake regulates oleoylethanolamide formation and degradation in the proximal small intestine. Journal of Biological Chemistry, 282 (2), 1518–1528. https://doi.org/10.1074/jbc.M607809200 Fu, J., Gaetani, S., Oveisi, F., Lo Verme, J., Serrano, A., De Fonseca, F. R., Rosengarth, A., Luecke, H., Di Giacomo, B., Tarzia, G., & Piomelli, D. (2003). Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature, 425, 90–93. https://doi.org/10.1038/nature01921 Fu, J., Oveisi, F., Gaetani, S., Lin, E., & Piomelli, D. (2005). Oleoylethanolamide, an endogenous PPAR-α agonist, lowers body weight and hyperlipidemia in obese rats. Neuropharmacology, 48 (8), 1147–1153. https://doi.org/10.1016/j.neuropharm.2005.02.013 Gaetani, S., Fu, J., Cassano, T., Dipasquale, P., Romano, A., Righetti, L., Cianci, S., Laconca, L., Giannini, E., Scaccianoce, S., Mairesse, J., Cuomo, V., & Piomelli, D. (2010). The fat-induced satiety factor oleoylethanolamide suppresses feeding through central release of oxytocin. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 30 (24), 8096–8101. https://doi.org/10.1523/JNEUROSCI.0036-10.2010 Gaetani, S., Oveisi, F., & Piomelli, D. (2003). Modulation of Meal Pattern in the Rat by the Anorexic Lipid Mediator Oleoylethanolamide. Neuropsychopharmacology, 28, 1311–1316. https://doi.org/10.1038/sj.npp.1300166 Giudetti, A. M., Vergara, D., Longo, S., Friuli, M., Eramo, B., Tacconi, S., Fidaleo, M., Dini, L., Romano, A., & Gaetani, S. (2021). Oleoylethanolamide Reduces Hepatic Oxidative Stress and Endoplasmic Reticulum Stress in High-Fat Diet-Fed Rats. Antioxidants, 10 (8). https://doi.org/10.3390/antiox10081289 Guijarro, A., Fu, J., Astarita, G., & Piomelli, D. (2010). CD36 gene deletion decreases oleoylethanolamide levels in small intestine of free-feeding mice. Pharmacological Research, 61 (1), 27–33. https://doi.org/10.1016/j.phrs.2009.09.003 Hotamisligil, G. S. (2017). Inflammation, metaflammation and immunometabolic disorders. Nature, 542, 177–185. https://doi.org/10.1038/nature21363 Iannotti, F. A., & Di Marzo, V. (2025). The endocannabinoidomes: Pharmacological redundancy and promiscuity, and multi-kingdom variety of sources and molecular targets. Pharmacological Reviews, 77 (4). https://doi.org/10.1016/j.pharmr.2025.100070 Igarashi, M., Hayakawa, T., Tanabe, H., Watanabe, K., Nishida, A., & Kimura, I. (2023). Intestinal GPR119 activation by microbiota-derived metabolites impacts feeding behavior and energy metabolism. Molecular Metabolism, 67 . https://doi.org/10.1016/j.molmet.2022.101649 Igarashi, M., Iwasa, K., & Yoshikawa, K. (2021). Feeding regulation by oleoylethanolamide synthesized from dietary oleic acid. Prostaglandins Leukotrienes and Essential Fatty Acids, 165, 102228. https://doi.org/10.1016/j.plefa.2020.102228 Ivashkevich, D., Ponomarenko, A., Manzhulo, I., & Dyuizen, I. (2025). Mechanistic Insights into N-Oleoylethanolamide-Mediated Hepatoprotection via PPAR-α. BIOCELL, 49 (4), 607–627. https://doi.org/10.32604/biocell.2025.061606 Ivashkevich, D., Ponomarenko, A., Manzhulo, I., Egoraeva, A., & Dyuizen, I. (2025). Hepatoprotective and Antiatherosclerotic Effects of Oleoylethanolamide-Based Dietary Supplement in Dietary-Induced Obesity in Mice. Pathophysiology, 32(2), 16. https://doi.org/10.3390/pathophysiology32020016 Karin, M., & Kim, J. Y. (2025). Endoplasmic reticulum stress at the forefront of fatty liver diseases and cancer. Pharmacological Reviews, 77 (6). https://doi.org/10.1016/j.pharmr.2025.100096 Keppel Hesselink, J. M., Kopsky, D. J., & Sajben, N. L. (2014). Vulvodynia and proctodynia treated with topical baclofen 5 % and palmitoylethanolamide. Archives of Gynecology and Obstetrics, 290 (2), 389–393. https://doi.org/10.1007/s00404-014-3218-4 Khan, M., Völkers, M., & Wende, A. R. (2022). Editorial: Metabolic Regulation of Cardiac and Vascular Cell Function: Physiological and Pathophysiological Implications. Frontiers in Physiology, 13, 849869. https://doi.org/10.3389/fphys.2022.849869 Laleh, P., Yaser, K., Abolfazl, B., Shahriar, A., Mohammad, A. J., Nazila, F., & Alireza, O. (2018). Oleoylethanolamide increases the expression of PPAR-Α and reduces appetite and body weight in obese people: A clinical trial. Appetite, 128, 44–49. https://doi.org/10.1016/j.appet.2018.05.129 Laleh, P., Yaser, K., & Alireza, O. (2019). Oleoylethanolamide: A novel pharmaceutical agent in the management of obesity-an updated review. Journal of Cellular Physiology, 234 (6), 7893–7902. https://doi.org/10.1002/jcp.27913 Lan, H., Vassileva, G., Corona, A., Liu, L., Baker, H., Golovko, A., Abbondanzo, S. J., Hu, W., Yang, S., Ning, Y., Del Vecchio, R. A., Poulet, F., Laverty, M., Gustafson, E. L., Hedrick, J. A., & Kowalski, T. J. (2009). GPR119 is required for physiological regulation of glucagon-like peptide-1 secretion but not for metabolic homeostasis. The Journal of Endocrinology, 201 (2), 219–230. https://doi.org/10.1677/JOE-08-0453 Lauffer, L. M., Iakoubov, R., & Brubaker, P. L. (2009). GPR119 Is Essential for Oleoylethanolamide-Induced Glucagon-Like Peptide-1 Secretion From the Intestinal Enteroendocrine L-Cell. Diabetes, 58 (5), 1058–1066. https://doi.org/10.2337/DB08-1237 Levin, B. E., Geary, N., & Lutz, T. A. (2025). The (dys)regulation of energy storage in obesity. 105 (3), 803–895. https://doi.org/10.1152/physrev.00002.2024 Lin, L., Mabou Tagne, A., Squire, E. N., Lee, H. L., Fotio, Y., Ramirez, J., Zheng, M., Torrens, A., Ahmed, F., Ramos, R., Plikus, M. V., & Piomelli, D. (2022). Diet-Induced Obesity Disrupts Histamine-Dependent Oleoylethanolamide Signaling in the Mouse Liver. Pharmacology, 107 (7–8), 423–432. https://doi.org/10.1159/000524753 Liu, C. M., & Kanoski, S. E. (2018). Homeostatic and non-homeostatic controls of feeding behavior: Distinct vs. common neural systems. Physiology & Behavior, 193, 223–231. https://doi.org/10.1016/j.physbeh.2018.02.011 Liu, J., Wang, L., Harvey-White, J., Huang, B. X., Kim, H. Y., Luquet, S., Palmiter, R. D., Krystal, G., Rai, R., Mahadevan, A., Razdan, R. K., & Kunos, G. (2008). Multiple pathways involved in the biosynthesis of anandamide. Neuropharmacology, 54 (1), 1–7. https://doi.org/10.1016/j.neuropharm.2007.05.020 Lo Verme, J., Gaetani, S., Fu, J., Oveisi, F., Burton, K., & Piomelli, D. (2005). Regulation of food intake by oleoylethanolamide. Cellular and Molecular Life Sciences, 62, 708–716. https://doi.org/10.1007/s00018-004-4494-0 Maccarrone, M., Pauselli, R., Di Rienzo, M., & Finazzi-Agrò, A. (2002). Binding, degradation and apoptotic activity of stearoylethanolamide in rat C6 glioma cells. Biochemical Journal, 366 (1), 137–144. https://doi.org/10.1042/BJ20020438 Matias, I., Lehmann, E. W., Zizzari, P., Byberg, S., Cota, D., Torekov, S. S., & Quarta, C. (2023). Endocannabinoid-related molecules predict the metabolic efficacy of GLP-1 receptor agonism in humans with obesity. Journal of Endocrinological Investigation, 47 (5), 1289–1294. https://doi.org/10.1007/s40618-023-02228-8 Melis, M., Carta, S., Fattore, L., Tolu, S., Yasar, S., Goldberg, S. R., Fratta, W., Maskos, U., & Pistis, M. (2010). Peroxisome proliferator-activated receptors-alpha modulate dopamine cell activity through nicotinic receptors. Biological Psychiatry, 68 (3), 256-264. https://doi.org/10.1016/j.biopsych.2010.04.016 Melis, M., Carta, G., Pistis, M., & Banni, S. (2013). Physiological role of peroxisome proliferator-activated receptors type α on dopamine systems. CNS & Neurological Disorders Drug Targets, 12 (1), 70–77. https://doi.org/10.2174/1871527311312010012 Młynarska, E., Bojdo, K., Bulicz, A., Frankenstein, H., Gąsior, M., Kustosik, N., Rysz, J., & Franczyk, B. (2025). Obesity as a Multifactorial Chronic Disease: Molecular Mechanisms, Systemic Impact, and Emerging Digital Interventions. Current Issues in Molecular Biology 2025, 47 (10). https://doi.org/10.3390/cimb47100787 Mock, E. D., Gagestein, B., & van der Stelt, M. (2023). Anandamide and other N-acylethanolamines: A class of signaling lipids with therapeutic opportunities. Progress in Lipid Research, 89 . https://doi.org/10.1016/j.plipres.2022.101194 Moiz, A., Filion, K. B., Tsoukas, M. A., Yu, O. H., Peters, T. M., & Eisenberg, M. J. (2025). Mechanisms of GLP-1 Receptor Agonist-Induced Weight Loss: A Review of Central and Peripheral Pathways in Appetite and Energy Regulation. American Journal of Medicine, 138 (6), 934–940. https://doi.org/10.1016/j.amjmed.2025.01.021 Morton, G. J., Meek, T. H., & Schwartz, M. W. (2014). Neurobiology of food intake in health and disease. Nature Reviews Neuroscience, 15 (6), 367–378. https://doi.org/10.1038/nrn3745 Murillo-Rodríguez, E., Palomero-Rivero, M., Millán-Aldaco, D., Arias-Carrión, O., & Drucker-Colín, R. (2011). Administration of URB597, oleoylethanolamide or palmitoylethanolamide increases waking and dopamine in rats. PloS One, 6 (7). https://doi.org/10.1371/journal.pone.0020766 Ostadrahimi, A., Khajebishak, Y., Moradi, F., & Payahoo, L. (2024). The effect of Oleoylethanolamide supplementation on lipid profile, fasting blood sugar and dietary habits in obese people: a randomized double-blind placebo-control trial. BMC Endocrine Disorders, 24 (1). https://doi.org/10.1186/s12902-024-01738-7 Oveisi, F., Gaetani, S., Eng, K. T. P., & Piomelli, D. (2004). Oleoylethanolamide inhibits food intake in free-feeding rats after oral administration. Pharmacological Research, 49(5), 461–466. https://doi.org/10.1016/j.phrs.2003.12.006 Payahoo, L., Khajebishak, Y., Alivand, M. R., Soleimanzade, H., Alipour, S., Barzegari, A., & Ostadrahimi, A. (2019). Investigation the effect of oleoylethanolamide supplementation on the abundance of Akkermansia muciniphila bacterium and the dietary intakes in people with obesity: A randomized clinical trial. Appetite, 141 . https://doi.org/10.1016/j.appet.2019.05.032 Piomelli, D. (2013). A fatty gut feeling. Trends in Endocrinology and Metabolism, 24 (7), 332–341. https://doi.org/10.1016/j.tem.2013.03.001 Powell-Wiley, T. M., Poirier, P., Burke, L. E., Després, J. P., Gordon-Larsen, P., Lavie, C. J., Lear, S. A., Ndumele, C. E., Neeland, I. J., Sanders, P., & St-Onge, M. P. (2021). Obesity and Cardiovascular Disease A Scientific Statement From the American Heart Association. Circulation, 143 (21), E984–E1010. https://doi.org/10.1161/CIR.0000000000000973 Proulx, K., Cota, D., Castañeda, T. R., Tschöp, M. H., D’Alessio, D. A., Tso, P., Woods, S. C., & Seeley, R. J. (2005). Mechanisms of oleoylethanolamide-induced changes in feeding behavior and motor activity, 289 (3), 729–737. https://doi.org/10.1152/ajpregu.00029.2005 Provensi, G., Coccurello, R., Umehara, H., Munari, L., Giacovazzo, G., Galeotti, N., Nosi, D., Gaetani, S., Romano, A., Moles, A., Blandina, P., & Passani, M. B. (2014). Satiety factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake. Proceedings of the National Academy of Sciences of the United States of America, 111 (31), 11527–11532. https://doi.org/10.1073/pnas.1322016111 Rahman, S. M. K., Uyama, T., Hussain, Z., & Ueda, N. (2021). Roles of Endocannabinoids and Endocannabinoid-Like Molecules in Energy Homeostasis and Metabolic Regulation: A Nutritional Perspective. Annual Review of Nutrition, 41, 177–202. https://doi.org/10.1146/annurev-nutr-043020-090216 Rakhshandehroo M, Knoch B, Müller M, Kersten S. (2010). Peroxisome proliferator-activated receptor alpha target genes. PPAR Research, 612089. https://doi.org/10.1155/2010/612089 Ren, T., Ma, A., Zhuo, R., Zhang, H., Peng, L., Jin, X., Yao, E., & Yang, L. (2020). Oleoylethanolamide increases glycogen synthesis and inhibits hepatic gluconeogenesis via the LKB1/AMPK pathway in type 2 diabetic model. The Journal of Pharmacology and Experimental Therapeutics, 373 (1), 81–91. https://doi.org/10.1124/jpet.119.262675 Rodríguez De Fonseca, F., Navarro, M., Gómez, R., Escuredo, L., Nava, F., Fu, J., Murillo-Rodríguez, E., Giuffrida, A., Loverme, J., Gaetani, S., Kathuria, S., Gall, C., & Piomelli, D. (2001). An anorexic lipid mediator regulated by feeding. Nature, 414 (6860), 209–212. https://doi.org/10.1038/35102582 Romano, A., Friuli, M., Cifani, C., & Gaetani, S. (2020). Oxytocin in the neural control of eating: At the crossroad between homeostatic and non-homeostatic signals. Neuropharmacology, 171, 108082. https://doi.org/10.1016/j.neuropharm.2020.108082 Romano, A., Friuli, M., Del Coco, L., Longo, S., Vergara, D., Del Boccio, P., Valentinuzzi, S., Cicalini, I., Fanizzi, F. P., Gaetani, S., & Giudetti, A. M. (2021). Chronic Oleoylethanolamide Treatment Decreases Hepatic Triacylglycerol Level in Rat Liver by a PPARγ/SREBP-Mediated Suppression of Fatty Acid and Triacylglycerol Synthesis. Nutrients, 13 (2), 1–19. https://doi.org/10.3390/nu13020394 Romano, A., Friuli, M., Eramo, B., Gallelli, C. A., Koczwara, J. B., Azari, E. K., Paquot, A., Arnold, M., Langhans, W., Muccioli, G. G., Lutz, T. A., & Gaetani, S. (2023). “To brain or not to brain”: evaluating the possible direct effects of the satiety factor oleoylethanolamide in the central nervous system. Frontiers in Endocrinology, 14, 1158287. https://doi.org/10.3389/fendo.2023.1158287 Romano, A., Gallelli, C. A., Koczwara, J. B., Braegger, F. E., Vitalone, A., Falchi, M., Micioni Di Bonaventura, M. V., Cifani, C., Cassano, T., Lutz, T. A., & Gaetani, S. (2017). Role of the area postrema in the hypophagic effects of oleoylethanolamide. Pharmacological Research, 122, 20–34. https://doi.org/10.1016/j.phrs.2017.05.017 Romano, A., Karimian Azari, E., Tempesta, B., Mansouri, A., Micioni Di Bonaventura, M. V., Ramachandran, D., Lutz, T. A., Bedse, G., Langhans, W., & Gaetani, S. (2014). High dietary fat intake influences the activation of specific hindbrain and hypothalamic nuclei by the satiety factor oleoylethanolamide . Physiology & Behavior, 136 (5), 55–62. https://doi.org/10.1016/j.physbeh.2014.04.039 Romano, A., Micioni Di Bonaventura, M. V., Gallelli, C. A., Koczwara, J. B., Smeets, D., Giusepponi, M. E., De Ceglia, M., Friuli, M., Micioni Di Bonaventura, E., Scuderi, C., Vitalone, A., Tramutola, A., Altieri, F., Lutz, T. A., Giudetti, A. M., Cassano, T., Cifani, C., & Gaetani, S. (2020). Oleoylethanolamide decreases frustration stress-induced binge-like eating in female rats: a novel potential treatment for binge eating disorder. Neuropsychopharmacology, 45 (11), 1931–1941. https://doi.org/10.1038/s41386-020-0686-z Romano, A., Potes, C. S., Tempesta, B., Cassano, T., Cuomo, V., Lutz, T., & Gaetani, S. (2013). Hindbrain noradrenergic input to the hypothalamic PVN mediates the activation of oxytocinergic neurons induced by the satiety factor oleoylethanolamide. American journal of physiology. Endocrinology and metabolism, 305 (10), E1266–E1273. https://doi.org/10.1152/ajpendo.00411.2013 Romano, A., Tempesta, B., Provensi, G., Passani, M. B., & Gaetani, S. (2015). Central mechanisms mediating the hypophagic effects of oleoylethanolamide and N-acylphosphatidylethanolamines: different lipid signals?. Frontiers in pharmacology, 6, 137. https://doi.org/10.3389/fphar.2015.00137 Samuel, V. T., & Shulman, G. I. (2018). Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases. Cell Metabolism, 27 (1), 22–41. https://doi.org/10.1016/j.cmet.2017.08.002 Schwartz, G. J., Fu, J., Astarita, G., Li, X., Gaetani, S., Campolongo, P., Cuomo, V., & Piomelli, D. (2008). The lipid messenger OEA links dietary fat intake to satiety. Cell Metabolism, 8 (4), 281. https://doi.org/10.1016/j.cmet.2008.08.005 Seguella, L., Corpetti, C., Lu, J., Pesce, M., Franzin, S. B., Palenca, I., Zilli, A., Vincenzi, M., Caprioli, D., Paytuví-Gallart, A., Sanseverino, W., Rurgo, S., Sarnelli, G., & Esposito, G. (2025). Oleoylethanolamide-producing Lactobacillus paracasei F19 improves metabolic and behavioral disorders by restoring intestinal permeability and microbiota-gut-brain axis in high-fat diet-induced obese male mice. Brain, Behavior, and Immunity, 127, 25–44. https://doi.org/10.1016/j.bbi.2025.02.014 Serrano, A., Pavón, F. J., Tovar, S., Casanueva, F., Señarís, R., Diéguez, C., & Rodríguez De Fonseca, F. (2011). Oleoylethanolamide: Effects on hypothalamic transmitters and gut peptides regulating food intake. Neuropharmacology, 60 (4), 593–601. https://doi.org/10.1016/j.neuropharm.2010.12.007 Sfairopoulos, D., Liatis, S., Tigas, S., & Liberopoulos, E. (2018). Clinical pharmacology of glucagon-like peptide-1 receptor agonists. Hormones (Athens, Greece), 17 (3), 333–350. https://doi.org/10.1007/s42000-018-0038-0 Shen, Y., Fan, N., Ma, S. xia, Cheng, X., Yang, X., & Wang, G. (2025). Gut Microbiota Dysbiosis: Pathogenesis, Diseases, Prevention, and Therapy. MedComm, 6 (5). https://doi.org/10.1002/mco2.70168 Silvestri, C., & Di Marzo, V. (2013). The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metabolism, 17 (4), 475–490. https://doi.org/10.1016/j.cmet.2013.03.001 Takahashi, H., Sanada, K., Nagai, H., Li, Y., Aoki, Y., Ara, T., Seno, S., Matsuda, H., Yu, R., Kawada, T., & Goto, T. (2017). Over-expression of PPARα in obese mice adipose tissue improves insulin sensitivity. Biochemical and Biophysical Research Communications, 493 (1), 108–114. https://doi.org/10.1016/j.bbrc.2017.09.067 Tellez, L. A., Medina, S., Han, W., Ferreira, J. G., Licona-Limón, P., Ren, X., Lam, T. K. T., Schwartz, G. J., & De Araujo, I. E. (2013). A gut lipid messenger links excess dietary fat to dopamine deficiency. Science (New York, N.Y.), 341 (6147), 800–802. https://doi.org/10.1126/science.1239275 Thabuis, C., Destaillats, F., Tissot‐Favre, D., & Martin, J. (2007). Oleoyl‐ethanolamide (OEA): A bioactive lipid derived from oleic acid and phosphatidylethanol‐amine. Lipid Technology, 19 (10), 225–227. https://doi.org/10.1002/lite.200700074 Thabuis, C., Tissot-Favre, D., Bezelgues, J. B., Martin, J. C., Cruz-Hernandez, C., Dionisi, F., & Destaillats, F. (2008). Biological Functions and Metabolism of Oleoylethanolamide. Lipids, 43 (10), 887–894. https://doi.org/10.1007/s11745-008-3217-y Tovar, R., de Ceglia, M., Ubaldi, M., Rodríguez-Pozo, M., Soverchia, L., Cifani, C., Rojo, G., Gavito, A., Hernandez-Folgado, L., Jagerovic, N., Ciccocioppo, R., Baixeras, E., Rodríguez de Fonseca, F., & Decara, J. (2023). Administration of Linoleoylethanolamide Reduced Weight Gain, Dyslipidemia, and Inflammation Associated with High-Fat-Diet-Induced Obesity. Nutrients, 15 (20). https://doi.org/10.3390/nu15204448 Tovar, R., Gavito, A. L., Vargas, A., Soverchia, L., Hernandez-Folgado, L., Jagerovic, N., Baixeras, E., Ciccocioppo, R., de Fonseca, F. R., & Decara, J. (2021). Palmitoleoylethanolamide Is an Efficient Anti-Obesity Endogenous Compound: Comparison with Oleylethanolamide in Diet-Induced Obesity. Nutrients, 13 (8). https://doi.org/10.3390/nu13082589 Tutunchi, H., Ebrahimi-Mameghani, M., Hosseinzadeh-Attar, M. J., Roshanravan, N., Mobasseri, M., Najafipour, F., Naeini, F., Naghshi, S., Asghari, S., Akbarzadeh, M., Soleimanzadeh, H., & Ostadrahimi, A. (2023). Effects of oleoylethanolamide supplementation on the expression of lipid metabolism-related genes and serum NRG4 levels in patients with non-alcoholic fatty liver disease: A randomized controlled trial. Clinical Nutrition ESPEN, 58, 311–319. https://doi.org/10.1016/j.clnesp.2023.10.013 Tutunchi, H., Naeini, F., Saghafi-Asl, M., Farrin, N., Monshikarimi, A., & Ostadrahimi, A. (2020). Effects of oleoylethanolamide supplementation on atherogenic indices and hematological parameters in patients with nonalcoholic fatty liver disease: A clinical trial. Health Promotion Perspectives, 10 (4), 373–382. https://doi.org/10.34172/hpp.2020.56 Tutunchi, H., Ostadrahimi, A., Saghafi-Asl, M., Hosseinzadeh-Attar, M. J., Shakeri, A., Asghari-Jafarabadi, M., Roshanravan, N., Farrin, N., Naemi, M., & Hasankhani, M. (2020). Oleoylethanolamide supplementation in obese patients newly diagnosed with non-alcoholic fatty liver disease: Effects on metabolic parameters, anthropometric indices, and expression of PPAR-α, UCP1, and UCP2 genes. Pharmacological Research, 156 . https://doi.org/10.1016/j.phrs.2020.104770 Tutunchi, H., Ostadrahimi, A., Saghafi-Asl, M., & Maleki, V. (2019). The effects of oleoylethanolamide, an endogenous PPAR-α agonist, on risk factors for NAFLD: A systematic review. Obesity Reviews, 20 (7), 1057–1069. https://doi.org/10.1111/obr.12853 Tutunchi, H., Saghafi-Asl, M., & Ostadrahimi, A. (2020). A systematic review of the effects of oleoylethanolamide, a high-affinity endogenous ligand of PPAR-α, on the management and prevention of obesity. Clinical and Experimental Pharmacology and Physiology, 47 (4), 543–552. https://doi.org/10.1111/1440-1681.13238 Tutunchi, H., Zolrahim, F., Nikbaf-Shandiz, M., Naeini, F., Ostadrahimi, A., Naghshi, S., Salek, R., & Najafipour, F. (2023). Effects of oleoylethanolamide supplementation on inflammatory biomarkers, oxidative stress and antioxidant parameters of obese patients with NAFLD on a calorie-restricted diet: A randomized controlled trial. Frontiers in Pharmacology, 14 . https://doi.org/10.3389/fphar.2023.1144550 Ueda, N., Tsuboi, K., & Uyama, T. (2010). N-acylethanolamine metabolism with special reference to N-acylethanolamine-hydrolyzing acid amidase (NAAA). Progress in Lipid Research, 49 (4), 299–315. https://doi.org/10.1016/j.plipres.2010.02.003 Vari, F., Serra, I., Friuli, M., Cavallo, V., Gammaldi, N., Vergara, D., Salzet, M., & Giudetti, A. M. (2025). Pharmacological potential of endocannabinoid and endocannabinoid-like compounds in protecting intestinal structure and metabolism under high-fat conditions. Frontiers in Pharmacology, 16, 1567543. https://doi.org/10.3389/fphar.2025.1567543 Wang, X., Miyares, R. L., & Ahern, G. P. (2005). Oleoylethanolamide excites vagal sensory neurones, induces visceral pain and reduces short-term food intake in mice via capsaicin receptor TRPV1. The Journal of Physiology, 564 (Pt 2), 541. https://doi.org/10.1113/jphysiol.2004.081844 Zheng, Z., Zong, Y., Ma, Y., Tian, Y., Pang, Y., Zhang, C., & Gao, J. (2024). Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduction and Targeted Therapy, 9, 234. https://doi.org/10.1038/s41392-024-01931-z Figure legend Figure 1. Central and peripheral mechanisms underlying OEA-mediated regulation of feeding behavior and metabolic homeostasis Schematic representation of the central and peripheral pathways through which oleoylethanolamide (OEA) regulates feeding behavior and metabolic homeostasis. AP, area postrema; NST, nucleus of the solitary tract; DMV, dorsal motor nucleus of the vagus; PVN, paraventricular nucleus of the hypothalamus; Arc/ME, arcuate nucleus/median eminence; vTMN, ventral tuberomammillary nucleus; HIPPO, hippocampus. OEA, oleoylethanolamide; OXY, oxytocin; ↑ up-regulation; ↓ down-regulation; pink color indicates biological effects mediated by PPAR-α activation. Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Metrics & Citations Metrics Article Usage 252views 94downloads Citations Download citation Marzia Friuli, Alessia Campagna, Barbara Eramo, et al. The ongoing oleoylethanolamide story: therapeutic implications in the control of obesity and its comorbidities. Authorea. 10 March 2026. DOI: https://doi.org/10.22541/au.177313174.48225874/v1 DOI: https://doi.org/10.22541/au.177313174.48225874/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.