Targeted enhancement of oleoylethanolamide production in proximal small intestine induces across-meal satiety in rats

Abstract

Pharmacological administration of the natural lipid amide, oleoylethanolamide (OEA), inhibits food intake in free-feeding rodents by prolonging latency to feed and postmeal interval. This anorexic effect is mediated by activation of type-α peroxisome proliferator-activated receptors (PPAR-α). Food intake stimulates mucosal cells in duodenum and jejunum to generate OEA, suggesting that this lipid-derived messenger may act as a local satiety hormone. As a test of this hypothesis, here, we examined whether targeted enhancement of OEA production in the small intestine affects feeding behavior in rats. We constructed an adenoviral vector (Ad-NPLD) that directs overexpression of the enzyme N-acylphosphatidylethanolamine (NAPE)-phospholipase D (PLD), which catalyzes the hydrolysis of NAPE to generate OEA. Intraduodenal injection of the Ad-NPLD vector resulted in a time-dependent increase in NAPE-PLD expression and OEA production, which was restricted to the proximal small intestine. No such effect was observed after administration of a control adenoviral vector. Enhanced OEA production in Ad-NPLD-injected animals was temporally associated with increased expression of two PPAR-α target genes (PPAR-α and CD36) and with decreased food intake. The hypophagic phenotype of Ad-NPLD-injected rats was attributable to increase feeding latency and postmeal interval, rather than decreased meal size. The results suggest that localized changes in OEA production in the small intestine, such as those produced by food intake, are sufficient to induce in rats a state of across-meal satiety similar to that elicited by systemic administration of exogenous OEA.

Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma

“…For example, our DHA-enriched diet signifi cantly decreased circulating levels of both the anorectic lipid OEA as well as AG, an endocannabinoid that promotes eating ( 15,52,53 ). Our observation that acute dietary DHA supplementation did not infl uence either food consumption or weight gain may refl ect a counterbalancing effect between the coordinate, DHAinduced decreases in circulating OEA and AG that allowed maintenance of homeostatic feeding behavior.…”

“…Our observation that acute dietary DHA supplementation did not infl uence either food consumption or weight gain may refl ect a counterbalancing effect between the coordinate, DHAinduced decreases in circulating OEA and AG that allowed maintenance of homeostatic feeding behavior. Alternatively, because a local OEA increase in the small intestine is suffi cient to suppress appetite to an extent similar to that elicited by systemic OEA administration ( 15,(52)(53)(54), changes in plasma/brain OEA per se (vs. changes in small intestine OEA) may not be reliable correlates to or indices of food consumption, which is a complex process involving multiple, interactive nutritional, bioenergetic, and metabolic signaling pathways ( 55,56 ).…”

G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

“…Lysophospholipids may also be agonistic at GPR119 since a range of lysophosphatidycholine species having oleoly, steroyl or palmitoyl derivatives at the C-1 position were all able to raise cAMP in cells expressing GPR119; as were lysophosphatidylethanolamine and lysophosphatidylinositol [107]. It remains uncertain which (if any) of these can serve as a physiological ligand but OEA is a strong candidate since this molecule is produced in the intestine and may also be present in blood as well as, locally, within other tissues [108][109][110][111].…”

Oleoylethanolamide-induced anorexia in rats is associated with locomotor impairment

“…2006; Fu et al. 2007, 2008; Schwartz et al 2008). OEA has been shown to potently reduce food intake in rodents after peripheral administration (Rodriguez de Fonseca et al.…”