The Endocannabinoid-Like Derivative Oleoylethanolamide at the Gut–Brain Interface: A “Lipid Way” to Control Energy Intake and Body Weight

Abstract

In the last three decades, we witnessed a concomitant major increase in lifespan and a worldwide increasing incidence of chronic diseases such as obesity and type 2 diabetes. Disruption of energy homeostasis and systemic inflammation appear as common traits of these epidemic human diseases. The conventional endocannabinoid (eCB) system encompasses two G-protein-coupled receptors (GPCRs), their endogenous ligands (anandamide and 2-AG), and the enzymes essential for eCB biosynthesis and hydrolytic inactivation. Nonetheless, the family of eCB-like derivatives is growing constantly including other N-acylethanolamines (NAEs) and 2-monoacylglycerols (2-MAGs) that do not bind canonical CB receptors rather other orphan G-protein-coupled receptors or peroxisome proliferator-activated nuclear receptors (PPARs). Here, we focus on the recent knowledge gathered on one such PPAR endocannabinoid ligand, oleoylethanolamide (OEA), from the identification of its synthesis in the small intestine to its anorexiant function with particular emphasis on our discovery of the main brain neurotransmitters system involved in its satiating effects.

The Endocannabinoids-Microbiota Partnership in Gut-Brain Axis Homeostasis: Implications for Autism Spectrum Disorders

“…In support of the idea of a mutual interconnection between endocannabinoids and microbiota, especially in the regulation of energy metabolism (Cani et al, 2016), it has been pointed out that human microbiota can encode N-acyl amides (i.e., eCBs congeners) that can bind G-protein-coupled receptors (GPCRs), thus modulating the intestinal function by the way of the GPR119 (Cohen et al, 2017). Dietary habits and composition are the most important modifiers of the intestinal microbial community (Rinninella et al, 2019), and the eCB machinery is high susceptible to changes in food composition and dietary patterns (Bisogno and Maccarrone, 2014;Passani and Coccurello, 2016;Chianese et al, 2017). In turn, food-induced changes in the eCB system can be paralleled by changes in gut microbiota composition.…”

“…If ASD is a NDD accompanied by comorbid GI disorders and intestine inflammation, then we also know that eCBs and diet are reciprocally and metabolically linked and that the eCB system may be modulated not only by dietary factors and lifestyles (Bisogno and Maccarrone, 2014;Passani and Coccurello, 2016;Coccurello and Maccarrone, 2018), but also by gut microorganisms and selected bacterial taxa that can change circulating eCBs and regulate immune function and adaptive immunity (Castonguay-Paradis et al, 2020;Zheng et al, 2020). The eCB system is widely distributed all along the GI tract (Izzo et al, 2015) and the eCBs of the intestinal epithelium are functionally involved in the control of gut-brain signaling, thus influencing and being influenced by gut microbiota composition.…”

Different Routes to Inhibit Fatty Acid Amide Hydrolase: Do All Roads Lead to the Same Place?

“…The efficacy of FAAH inhibitors has demonstrated also in gastrointestinal, neurological and psychiatric conditions, such as inflammatory bowel disease, multiple sclerosis, Parkinson’s disease, epilepsy, anxiety and depression [13,14,15,16,17]. Notably, FAAH inhibition also enhances the levels of other N -acyl-ethanolamines (NAEs) such as N -palmitoylethanolamine (PEA) and N -oleoylethanolamine (OEA), for which anti-inflammatory, analgesic, neuroprotective and anti-obesity effects have been reported [18,19,20]. The family of FAAH inhibitors is continuously increasing, as confirmed by the interest of several pharmaceutical companies (e.g., Eli Lilly, Pfizer, Bial-Portela & Ca.…”