Cold Exposure Stimulates Synthesis of the Bioactive Lipid Oleoylethanolamide in Rat Adipose Tissue

Abstract

Oleoylethanolamide (OEA) is an endogenous lipid mediator that inhibits feeding and stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activating receptor-␣. Little is known about the physiological regulation of this compound outside of the gastrointestinal tract, where its production is regulated by feeding. Here we show that cold exposure increases OEA levels in rat white adipose tissue but not in liver or intestine. This change is accompanied by parallel elevations in the activity of N-acyltransferase, a key enzyme responsible for OEA synthesis, without concomitant changes in fatty acid amide hydrolase, an enzyme responsible for OEA degradation. Moreover, cold stimulates the production of two species of N-oleoylphosphatidylethanolamine OEA precursors. The changes in OEA biosynthesis are reversed by pretreatment with the ␤-receptor antagonist propranolol, suggesting a role for ␤-adrenoreceptors in this response. In agreement with these findings, the ␤-agonists noradrenaline and isoproterenol stimulate OEA production in isolated adipocytes, an effect that is mimicked by the adenylyl cyclase activator forskolin. Collectively, these results identify cold exposure as a natural stimulus for OEA formation in white fat and suggest a role for the sympathetic nervous system in regulating OEA biosynthesis. The fatty acid ethanolamide (FAE)2 family of lipid mediators includes polyunsaturated species such as anandamide (1) and saturated or monounsaturated species such as oleoylethanolamide (OEA) (2, 3). Anandamide is an endogenous ligand for G-protein-coupled cannabinoid receptors (1), while OEA exerts a number of pharmacological effects, which include inhibition of feeding behavior (4) and stimulation of fatty acid mobilization and oxidation (5). These effects are thought to be mediated, at least in part, by activation of the nuclear receptor peroxisome proliferator-activating receptor type-␣ (PPAR-␣), because they are absent in PPAR-␣ null mice and are mimicked by synthetic PPAR-␣ agonists (5, 6). Despite the potential physiological significance of OEA, little is known about the natural stimuli that trigger the biosynthesis of this compound in vivo. In the small intestine of rodents (4, 6) and reptiles (7), OEA levels change in response to nutrient status: they are lower in fooddeprived than free-feeding animals and return to base-line values upon re-feeding (2,4,6,8). Moreover, in the brain (9) and white adipose tissue (WAT) (2), OEA levels fluctuate diurnally, although the physiological significance of these oscillations remains unknown.The biosynthesis of OEA, like that of other FAEs, is thought to occur through two sequential biochemical steps. The first consists in the transfer of a fatty acid residue from the sn-1 position of phosphatidylcholine to the free amine group of phosphatidylethanolamine (PE). This reaction is catalyzed by a Ca 2ϩ and cyclic AMP-regulated N-acyltransferase (NAT) activity, which yields a family of N-acylphosphatidylethanolamine (NAPE) species (1). The second rea...

Non-targeted human plasma metabolomics reveals the changes in oleoylethanolamide, a lipid-derived signaling molecule, by acute exposure of electric field

“…ACOX1, CYP4A11, ACSL3, and FAT/CD36 are reportedly involved in lipid metabolism genes induced by a PPAR-α agonist [27]. Guzman et al reported an increased gene expression of FAT/CD36, fatty acidbinding protein, uncoupling protein-2, and PPAR-α in the adipose tissue of rats after OEA administration [22]. In our study, the response of OEA on ACOX1 mRNA expression was inhibited by the PPAR-α antagonist GW6471.…”

“…Our findings also clarified that EF exposure elicits an increase in plasma OEA, a fatty acid ethanolamide. In contrast, LoVerme et al reported that cold exposure increased the OEA content in white adipose tissue, but not plasma [22]. Therefore, it is possible that the physiology differs is different between cold exposure and EF exposure.…”

“…Voltagesensing is reportedly coupled to protein phosphatase which is an enzyme responsible for the generation of arachidonoyl ethanolamide (anandamide) from its phosphorylated precursor [22][23][24][25]. Thus, the increase in OEA after exposure of EF is conceivable.…”

Ginger Phenylpropanoids Inhibit IL-1β and Prostanoid Secretion and Disrupt Arachidonate-Phospholipid Remodeling by Targeting Phospholipases A2

“…In contrast, PEA levels were not affected by ginger phenylpropanoids. Its biosynthesis mainly relies on N-acyltransferases, N-acylphosphatidylethanolamine phospholipase D, and fatty acid amide hydrolases, and only to a minor extent on lyso-phospholipase D and sPLA 2 , but not on other PLA 2 classes (88,89). Consequently, our data indicate selectivity toward i/cPLA 2 of the ginger extract and its main constituents and exclude unspecific perturbation of lipid homeostasis.…”

Plasma lipidomics reveals potential prognostic signatures within a cohort of cystic fibrosis patients

“…An increase in OEA could be due to either increased NAPE-PLD or to decreased fatty-acid amide hydrolase (FAAH), the catabolizing enzyme. Synthesis takes place mainly in the liver and adipose tissue and is increased in starvation and cold exposure ( 46 ), while nothing is known about its potential synthesis or metabolism in the lung. Therefore, it can be argued that in severe CF a harsh stress-like scenario may lead to an increase of OEA in plasma.…”