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Food Intake Regulates Oleoylethanolamide Formation And THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 282, NO. 2, pp. 1518–1528, January 12, 2007 © 2007 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A. Food Intake Regulates Oleoylethanolamide Formation and Degradation in the Proximal Small Intestine* Received for publication, August 15, 2006, and in revised form, October 26, 2006 Published, JBC Papers in Press, November 22, 2006, DOI 10.1074/jbc.M607809200 Jin Fu‡1, Giuseppe Astarita‡1, Silvana Gaetani§, Janet Kim‡, Benjamin F. Cravatt¶, Ken Mackieʈ, and Daniele Piomelli‡2 From the ‡Department of Pharmacology and Center for Drug Discovery, University of California, Irvine, California 92697, §Department of Human Physiology and Pharmacology, University of Rome “La Sapienza”, Piazzale Aldo Moro 5, 00185 Roma, Italy, ¶Department of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, California 92037, and ʈDepartment of Anesthesiology, University of Washington, Seattle, Washington 98195 Oleoylethanolamide (OEA) is a lipid mediator that inhibits lin have attracted the most attention (1), but recent evidence food intake by activating the nuclear receptor peroxisome indicates that lipid-derived messengers such as oleoylethanol- Downloaded from proliferator-activated receptor-␣. In the rodent small intes- amide (OEA) may also be involved (2). OEA is synthesized in tine OEA levels decrease during food deprivation and the small intestine of various vertebrate species, where its increase upon refeeding, suggesting that endogenous OEA levels decrease during food deprivation and increase upon may participate in the regulation of satiety. Here we show that refeeding (3–5). The possibility that these fluctuations rep- feeding stimulates OEA mobilization in the mucosal layer of resent a satiety signal is suggested by experiments in rodents rat duodenum and jejunum but not in the serosal layer from which show that pharmacological administration of OEA www.jbc.org the same intestinal segments in other sections of the gastro- delays meal initiation and prolongs the interval between suc- intestinal tract (stomach, ileum, colon) or in a broad series of cessive meals, resulting in a persistent inhibition of food internal organs and tissues (e.g. liver, brain, heart, plasma). intake (3, 6–8). These anorexiant effects are strikingly dif- Feeding also increases the levels of other unsaturated fatty ferent from those elicited by traditional satiety factors such at The Scripps Research Institute on March 5, 2007 acid ethanolamides (FAEs) (e.g. linoleoylethanolamide) with- as CCK, which reduce meal size without affecting the inter- out affecting those of saturated FAEs (e.g. palmitoylethanol- val between meals (9). Moreover, the hypophagic actions of amide). Feeding-induced OEA mobilization is accompanied OEA differ from those exerted by glucagon-like peptide-1 by enhanced accumulation of OEA-generating N-acylphos- (10) and corticotropin-releasing factor (11) in that they are phatidylethanolamines (NAPEs) increased activity and not accompanied by behavioral signs of malaise and anxiety expression of the OEA-synthesizing enzyme NAPE-phospho- or by changes in circulating corticosterone levels (3, 12). lipase D, and decreased activity and expression of the OEA- The molecular mechanism through which OEA inhibits degrading enzyme fatty acid amide hydrolase. Immuno- feeding has been partially elucidated. In vitro studies have staining studies revealed that NAPE-phospholipase D and shown that OEA is a high affinity agonist of peroxisome fatty acid amide hydrolase are expressed in intestinal entero- proliferator-activated receptor-␣ (PPAR-␣) (13), a nuclear cytes and lamina propria cells. Collectively, these results receptor present in the small intestine and implicated in the indicate that nutrient availability controls OEA mobilization regulation of energy balance and lipid metabolism (14–17). in the mucosa of the proximal intestine through a concerted OEA binds to the purified ligand binding domain of PPAR-␣ regulation of OEA biosynthesis and degradation. ϳ with a KD of 40 nM and activates this receptor in cell-based assays with a half-maximal effective concentration (EC50)of 120 nM (13). Furthermore, in vivo experiments have revealed The gastrointestinal tract controls key aspects of feeding that genetic deletion of PPAR-␣ abrogates the anorexiant behavior through both neuronal and humoral mechanisms. effects of OEA without altering those evoked by CCK-8 and Among the regulatory signals released by the gut, peptides such 3 fenfluramine (13). Finally, it has been shown that synthetic as cholecystokinin (CCK), glucagon-like peptide-1, and ghre- PPAR-␣ agonists, but not agonists of PPAR-␦ and PPAR-␥, produce a hypophagic response that is behaviorally indistin- * This research was supported by grants from the National Institute on Drug guishable from that elicited by OEA and is absent in mutant Abuse (to K. M. and D. P.). The costs of publication of this article were mice lacking PPAR-␣ (13). A parsimonious interpretation of defrayed in part by the payment of page charges. This article must there- fore be hereby marked “advertisement” in accordance with 18 U.S.C. Sec- these results is that OEA regulates food intake in rodents by tion 1734 solely to indicate this fact. selectively activating intestinal PPAR-␣. Notably, OEA can 1 These authors contributed equally to this study. also activate the G protein-coupled receptor, GPR119 (8), 2 To whom correspondence should be addressed: Dept. of Pharmacology, 360 MSRII, University of California, Irvine, CA 92697-4625. Tel.: 949-824- and the vanilloid receptor channel, TRPV1 (18), albeit at 6180; Fax: 949-824-6305; E-mail: [email protected]. micromolar concentrations. However, the contribution of 3 The abbreviations used are: CCK, cholecystokinin; EC50, half-maximal effective concentration; FAE, fatty acid ethanolamide; FAAH, fatty-acid amide hydrolase; NAPE, N-acyl phosphatidylethanolamine; NAPE-PLD, NAPE-specific phospholipase D; OEA, oleoylethanolamide; PEA, palmi- some proliferator-activated receptor-␣; LC, liquid chromatography; MS, toylethanolamide; PBS, phosphate-buffered saline; PPAR-␣, peroxi- mass spectroscopy. 1518 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 282•NUMBER 2•JANUARY 12, 2007 Oleoylethanolamide Mobilization in Small Intestine process have not been fully elucidated. In the present study we show that food intake promotes OEA mobilization in the mucosal layer of the rodent proximal intestine through a con- certed regulation of NAPE biosynthesis, NAPE-PLD activity, and OEA hydrolysis. EXPERIMENTAL PROCEDURES Animals—Adult male Wistar rats (250–300 g) were pur- chased from Charles River (Wilmington, MA). FAAHϪ/Ϫ and NAPE-PLDϪ/Ϫ mice were generated and bred as described (23, 24). A 12-hour light/dark cycle was set with lights on at 5:30 a.m. Water and standard chow pellets (Pro- lab RMH 2500; PMI Nutrition International, Brentwood, MO) were available ad libitum, except when animals were food-deprived. Food deprivation was conducted for 24 h in bottom-wired cages to prevent coprophagia. All procedures Downloaded from met the National Institutes of Health guidelines for the care and use of laboratory animals and were approved by the Institutional Animal Care and Use Committee of the Univer- sity of California, Irvine. Chemicals—Fatty acid chlorides were purchased from Nu-Chek Prep (Elysian, MN), 1,2-Dipalmitoyl-sn-glycero-3- www.jbc.org phosphoethanolamine was from Sigma-Aldrich, and tetra- hydrolipstatin was from ChemPacific (Baltimore, MD). N-Cyclohexanecarbonylpentadecylamine was a kind gift at The Scripps Research Institute on March 5, 2007 from Dr. Natsuo Ueda (Kagawa University, Kagawa, Japan). Chemical Syntheses—URB597 was synthesized as described (25). OEA and other FAEs were prepared by the reaction of fatty acid chlorides with a 10-fold molar excess of ethanolamine (Sig- 2 ma-Aldrich) or [ H4]ethanolamine (Cambridge Isotope Labo- ratories, Andover, MA). Reactions were conducted in dichlo- romethane at 0–4 °C for 15 min with stirring. The products were washed with water, dehydrated over sodium sulfate, fil- FIGURE 1. Proposed route of OEA formation and degradation in verte- tered, and dried under N2. They were characterized by liquid brate tissues. PE, phosphatidylethanolamine; PC, phosphatidylcholine; PA, chromatography/mass spectrometry (LC/MS) and 1H nuclear phosphatidic acid; NAT, N-acyltransferase; NAAA, N-acylethanolamine-hydro- magnetic resonance spectroscopy. Purity was Ͼ98% by LC/MS. lyzing acid amidase. NAPEs were prepared by the reaction of fatty acid chlorides with a 2-fold molar excess of 1,2-dipalmitoyl-sn-glycero-3- these receptors to the satiety-inducing effects of OEA is still phosphoethanolamine. Reactions were conducted in dichlo- undefined. romethane at 25 °C for 2 h using triethylamine (Sigma-Aldrich) The enzyme pathway considered responsible for OEA for- as a catalyst. The products were washed with water, fraction- mation and deactivation in mammalian tissues is illustrated in ated by silica gel thin-layer chromatography (chloroform/ Fig. 1. Its first step is the transfer of a fatty acid residue from the methanol/ammonia, 80:20:2, v/v/v), and characterized by sn-1 position of phosphatidylcholine to the free amine group of LC/MS coupled to tandem mass spectrometry (LC/MSn). phosphatidylethanolamine. This reaction is catalyzed by an Purity was Ͼ95%. N-acyltransferase, which remains to be molecularly identified, Lipid Extractions—Rats were sacrificed with halothane, and yields
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