Introduction
What are NAEs?
NAEs in metabolic health
NAEs and cognition
Therapeutic and lifestyle implications
Challenges and future directions
Conclusions
References
Further reading
From appetite control to neuroprotection, N-acylethanolamines are emerging as powerful lipid messengers that connect metabolism, inflammation, and brain health through intricate biochemical signaling pathways.
Image Credit: SergeiShimanovich / Shutterstock.com
Introduction
This article explores N-acylethanolamines (NAEs) as endogenous lipid signaling molecules that regulate metabolism, inflammation, appetite, and energy balance, and discusses their biosynthesis and degradation, as well as their roles in metabolic health and cognition. NAEs belong to a broader class of bioactive fatty acid ethanolamides that participate in lipid signaling networks controlling physiological processes such as inflammation, neurotransmission, and energy metabolism.
What are NAEs?
NAEs are lipid-based endogenous signaling molecules that are produced by combining long-chain fatty acids with ethanolamine. Collectively, NAEs include both endocannabinoids and structurally related lipid mediators that do not directly activate cannabinoid receptors. The biosynthesis of NAEs begins with N-acyltransferases that transfer an acyl chain from the sn-1 position of phospholipids to phosphatidylethanolamine (PE), subsequently generating N-acyl-phosphatidylethanolamine (NAPE), the direct precursor of NAEs.
This initial reaction is mediated by Ca2+-dependent cytosolic phospholipase A2ε (cPLA2ε) and Ca2+-independent phospholipase A and acyltransferase (PLAAT) enzymes. The resultant NAPE is converted to NAEs primarily by NAPE-hydrolyzing phospholipase D (NAPE-PLD). However, several alternative multi-step pathways have also been described, including routes involving α/β-hydrolase domain-containing protein 4 (ABHD4), lysophospholipase reactions, and glycerophosphodiesterases such as GDE1 and GDE4.
NAEs function as signals for the regulation of multiple body functions, with the activity of each NAE determined by the type of fatty acid within its structure. Anandamide (AEA), for example, is a widely studied NAE that activates cannabinoid receptors, whereas other NAEs like N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA) primarily act through non-cannabinoid pathways, including peroxisome proliferator-activated receptor-α (PPARα) signaling.1,3 Among NAEs, anandamide is a partial agonist of cannabinoid CB1 and CB2 receptors and is therefore classified as an endocannabinoid.
PEA, OEA, and stearolyethanolamide (SEA) are highly abundant NAEs that arise from the N-acylation of saturated and monounsaturated fatty acids like palmitic, oleic, and stearic acids, respectively. These saturated and monounsaturated NAEs are typically far more abundant in tissues than anandamide and generally exert biological effects through PPARα or other non-cannabinoid signaling mechanisms rather than direct CB1 or CB2 activation.
In many tissues, NAEs such as PEA and OEA occur at concentrations significantly higher than those of anandamide, highlighting their potential importance as physiological lipid mediators.
Several NAEs function as important regulators of inflammation, a shared feature of metabolic disorders. PEA, which was originally isolated from soybeans, eggs, and peanuts, exhibits anti-inflammatory, analgesic, anti-epileptic, and neuroprotective properties, largely attributed to its interaction with PPARα signaling pathways.
PEA has been widely studied in both preclinical and clinical settings for its therapeutic potential in treating chronic inflammatory conditions, such as eczema, as well as pain and neurodegeneration. Currently, PEA is available as a natural food supplement in both the United States and Europe, where consumers utilize this nutraceutical for managing chronic pain.4 PEA and related NAEs can also influence inflammatory signaling by reducing pro-inflammatory cytokine production and modulating transcriptional pathways involved in immune regulation.
OEA is endogenously produced by the small intestine following dietary fat intake. Like PEA, OEA binds to PPARα, leading to anorexic activity, suggesting that OEA dysfunction may be implicated in weight gain and obesity.4 In addition to PPARα activation, OEA can engage receptors such as GPR119 and influence satiety signaling pathways involved in energy balance. These observations have led researchers to investigate OEA analogs and inhibitors of OEA-degrading enzymes, such as fatty acid amide hydrolase (FAAH), for their potential utility in supporting weight loss.
NAEs and cognition
Docosahexaenoylethanolamide, which is more commonly known as synaptamide, is the ethanolamide of docosahexaenoic acid, a major omega-3 polyunsaturated fatty acid. Synaptamide promotes the biogenesis of new neurons and synapses, both of which are activities mediated by G-protein coupled receptor 110 (GPR110).4 This signaling pathway has been linked to increased neurogenesis, neurite outgrowth, and synapse formation in experimental systems.
The anti-inflammatory effects of NAEs extend beyond peripheral effects to also regulate neuroinflammation, which requires a delicate balance between maintaining its protective activity while preventing negative consequences. Experimental results indicate that higher intracranial levels of NAEs such as AEA, OEA, PEA, and DHEA can influence immune responses by reducing glial activation, thereby preventing negative consequences, such as the release of pro-inflammatory cytokines. These effects may involve multiple signaling targets, including cannabinoid receptors, transient receptor potential channels such as TRPV1, and nuclear receptors, including PPARα.
Several studies have also reported dysregulated brain NAE levels in neurological disorders, with high levels of AEA observed among cerebrospinal fluid (CSF) samples of multiple sclerosis and Parkinson’s disease patients.2
Image Credit: JitendraJadhav / Shutterstock.com
Therapeutic and lifestyle implications
NAEs can originate from both plant and animal sources. For example, high OEA concentrations are primarily found in wheat, flour, cocoa, and coffee, whereas corn, tomatoes, peanuts, soybeans, and cotton seeds are abundant in PEA2. Animal products like eggs, chicken, and beef are the only known sources of AEA, in addition to their notable DHEA and eicosapentaenoylethanolamine (EPEA) content.
Within cells, NAE concentrations are tightly controlled through both biosynthetic pathways and enzymatic degradation processes. Caloric intake and dietary fat composition modulate the activity of enzymes involved in NAE biosynthesis, including cytosolic phospholipase A2 ε (cPLA2ε) and phospholipase A and acyltransferase (PLAAT).
NAEs can also undergo oxidative metabolism by enzymes such as cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450 enzymes, producing additional lipid mediators, including prostaglandin ethanolamides (prostamides) and other oxidized derivatives.
Pharmacological inhibition of FAAH, the primary enzyme that breaks down AEA within the brain, increases endogenous NAE levels. Because FAAH inhibition elevates multiple NAEs simultaneously, it has been investigated as a strategy to enhance endocannabinoid and NAE signaling. Although FAAH inhibitors remain under investigation, no therapies targeting this pathway are currently widely approved due to safety considerations observed in earlier clinical trials.
Together, dietary interventions and enzyme-targeted pharmacological strategies highlight the translational potential of NAEs as modulators of metabolic health and healthy aging.1,2,3
Challenges and future directions
To date, most studies investigating the mechanisms underlying NAE activity have been conducted in animal models, limiting the generalizability of these findings to other species. Thus, additional research conducted among human cohorts is needed to clarify tissue-specific regulation, compensatory pathways, as well as the long-term safety and efficacy of targeting NAE metabolism.1,3
Importantly, the presence of multiple parallel biosynthetic and metabolic pathways for NAEs complicates experimental interpretation and highlights the need for more selective pharmacological tools to manipulate specific components of the NAE signaling network.
Conclusions
NAEs are versatile endogenous lipid mediators that integrate nutrient sensing, inflammation, appetite regulation, and energy metabolism through tightly regulated biosynthetic and degradative pathways. Significant translational challenges remain; however, NAEs are potential molecular targets for therapeutic, nutritional, and lifestyle strategies to improve metabolic health and promote healthy aging.
Ongoing research into NAE biosynthesis, receptor signaling, and metabolic regulation continues to reveal new opportunities for targeting lipid signaling networks in metabolic, inflammatory, and neurological disorders.
References
- Uyama, T., Sasaki, S., Okada-Iwabu, M., & Murakami, M. (2025). Recent Progress in N-Acylethanolamine Research: Biological Functions and Metabolism Regulated by Two Distinct N-Acyltransferases: cPLA2ε and PLAAT Enzymes. International Journal of Molecular Sciences 26(7). DOI: 10.3390/ijms26073359. https://www.mdpi.com/1422-0067/26/7/3359
- Tyrtyshnaia, A., Konovalova, S., Ponomarenko, A., et al. (2022). Fatty Acid-Derived N-acylethanolamines Dietary Supplementation Attenuates Neuroinflammation and Cognitive Impairment in LPS Murine Model. Nutrients 14(18). DOI: 10.3390/nu14183879. https://www.mdpi.com/2072-6643/14/18/3879
- 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. DOI: 10.1016/j.plipres.2022.101194. https://www.sciencedirect.com/science/article/pii/S0163782722000492
- Tsuboi, K., Uyama, T., Okamoto, Y., & Ueda, N. (2018). Endocannabinoids and related N-acylethanolamines: biological activities and metabolism. Inflammation and Regeneration 38(28). DOI: 10.1186/s41232-018-0086-5. https://link.springer.com/article/10.1186/s41232-018-0086-5
Further Reading
Last Updated: Mar 12, 2026