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Central mechanisms mediating the hypophagic effects of oleoylethanolamide and N-acylphosphatidylethanolamines: different lipid signals?

Romano A, Tempesta B, Provensi G, Passani MB, Gaetani S - Front Pharmacol (2015)

Bottom Line: Similarly to NAEs, NAPE (with particular reference to the N16:0 species) levels were shown to be regulated by the fed state and this finding was initially interpreted as fluctuations of NAE precursors.Indirect observations suggest that the hypophagic action of NAPEs might involve central mechanisms, although the molecular target remains unknown.The present paper reviews the role that OEA and NAPEs play in the mechanisms that control food intake, further supporting this group of phospholipids as optimal candidate for the development of novel anti-obesity treatments.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome , Rome,Italy.

ABSTRACT
The spread of "obesity epidemic" and the poor efficacy of many anti-obesity therapies in the long-term highlight the need to develop novel efficacious therapy. This necessity stimulates a large research effort to find novel mechanisms controlling feeding and energy balance. Among these mechanisms a great deal of attention has been attracted by a family of phospholipid-derived signaling molecules that play an important role in the regulation of food-intake. They include N-acylethanolamines (NAEs) and N-acylphosphatidylethanolamines (NAPEs). NAPEs have been considered for a long time simply as phospholipid precursors of the lipid mediator NAEs, but increasing body of evidence suggest a role in many physiological processes including the regulation of feeding behavior. Several observations demonstrated that among NAEs, oleoylethanolamide (OEA) acts as a satiety signal, which is generated in the intestine, upon the ingestion of fat, and signals to the central nervous system. At this level different neuronal pathways, including oxytocinergic, noradrenergic, and histaminergic neurons, seem to mediate its hypophagic action. Similarly to NAEs, NAPE (with particular reference to the N16:0 species) levels were shown to be regulated by the fed state and this finding was initially interpreted as fluctuations of NAE precursors. However, the observation that exogenously administered NAPEs are able to inhibit food intake, not only in normal rats and mice but also in mice lacking the enzyme that converts NAPEs into NAEs, supported the hypothesis of a role of NAPE in the regulation of feeding behavior. Indirect observations suggest that the hypophagic action of NAPEs might involve central mechanisms, although the molecular target remains unknown. The present paper reviews the role that OEA and NAPEs play in the mechanisms that control food intake, further supporting this group of phospholipids as optimal candidate for the development of novel anti-obesity treatments.

No MeSH data available.


Related in: MedlinePlus

The synthesis of oleoylethanolamide (OEA) is mediated by two concerted reactions: The first one is the N-acylation of phosphatidylethanolamine (PE) from the phospholipid bilayer of the cell membrane, mediated by a N-acyltransferase (NAT) to form N-oleoylphosphatidylethanolamine (NOPE) and the second one is the phospholipase D (PLD)-mediated hydrolysis of NOPE. Similar enzymatic reactions take place also during the synthesis of other NAEs, so that NAPEs are synthesized by acylation of the free amine group of ethanolamine-containing glycerophospholipids (both those containing diacyl and those containing alkenyl-acyl bound fatty acids) and transformed into the respective NAEs by NAPE-dependent PLD.
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Figure 1: The synthesis of oleoylethanolamide (OEA) is mediated by two concerted reactions: The first one is the N-acylation of phosphatidylethanolamine (PE) from the phospholipid bilayer of the cell membrane, mediated by a N-acyltransferase (NAT) to form N-oleoylphosphatidylethanolamine (NOPE) and the second one is the phospholipase D (PLD)-mediated hydrolysis of NOPE. Similar enzymatic reactions take place also during the synthesis of other NAEs, so that NAPEs are synthesized by acylation of the free amine group of ethanolamine-containing glycerophospholipids (both those containing diacyl and those containing alkenyl-acyl bound fatty acids) and transformed into the respective NAEs by NAPE-dependent PLD.

Mentions: N-acylethanolamines have been the most widely characterized. They include anandamide that was the most studied among them for its ability to act as endogenous cannabinoid ligand (D’Addario et al., 2014). Besides cannabinoid receptors, it has been gradually demonstrated that, depending on the nature of the N-linked acyl chain, NAEs can interact with different receptors in animals, including also vanilloid receptors and peroxisome proliferator activated-receptors (PPAR), and to be involved in many physiological processes (Fu et al., 2003; Nielsen et al., 2004; Terrazzino et al., 2004; Diep et al., 2011). With regard to the role played in the regulation of food intake, the most studied NAE was the monounsaturated analog of anandamide, oleoylethanolamide (OEA). Produced primarily in the small intestine, upon the absorption of dietary fat, OEA was demonstrated to act as a satiety signal in rodents by prolonging the interval between meals (Fu et al., 2003; Gaetani et al., 2003; Karimian Azari et al., 2014; Romano et al., 2014a). OEA endogenous mobilization is under the control of the sympathetic nervous system (LoVerme et al., 2006a; Fu et al., 2011) and is mediated by two concerted reactions. The first one is the transfer of an oleic group from the stereospecific numbering-1 (sn-1) position of a membrane phospholipid (for example phosphatidylcholine) to the amine group of a second membrane phospholipid, namely phosphatidylethanolamine (PE; Figure 1). This reaction is catalyzed by an enzyme, which remains to be molecularly identified, and whose N-acyltransferase activity seems to be calcium-dependent. The products of this reaction form a chemically heterogeneous family of N-oleoylphosphatidylethanolamines (NOPEs), which, depending on the specific PE precursor involved, may differ in the substituents at sn-1 and sn-2 position of PE (Figure 1). The sn-1 position is most often esterified by a saturated fatty acid or can contain an alkyl or alkenyl ether moiety; while the sn-2 position usually binds an unsaturated or polyunsaturated fatty acid (Coulon et al., 2012). Similar enzymatic reactions take place also during the synthesis of other NAEs, so that NAPEs are synthesized by acylation of the free amine group of ethanolamine-containing glycerophospholipids (both those containing diacyl and those containing alkenyl-acyl bound fatty acids; Natarajan et al., 1982; Schmid et al., 1990). This mechanism for NAEs formation was described some time ago and suggested that NAPEs merely act as unstable intermediate metabolites quickly converted into NAEs. However, novel evidence suggested that rather than simply precursors to NAEs, NAPEs can be defined as signaling lipids, able to control important biological functions on their own (Mora et al., 2002; Wellner et al., 2013). For example, it was recently demonstrated that among NAPEs, N-palmitoyl-phosphatidylethanolamine (N16:0 NAPE) can be involved in the gut-to brain axis that regulates food intake (Gillum et al., 2008; Fu et al., 2011).


Central mechanisms mediating the hypophagic effects of oleoylethanolamide and N-acylphosphatidylethanolamines: different lipid signals?

Romano A, Tempesta B, Provensi G, Passani MB, Gaetani S - Front Pharmacol (2015)

The synthesis of oleoylethanolamide (OEA) is mediated by two concerted reactions: The first one is the N-acylation of phosphatidylethanolamine (PE) from the phospholipid bilayer of the cell membrane, mediated by a N-acyltransferase (NAT) to form N-oleoylphosphatidylethanolamine (NOPE) and the second one is the phospholipase D (PLD)-mediated hydrolysis of NOPE. Similar enzymatic reactions take place also during the synthesis of other NAEs, so that NAPEs are synthesized by acylation of the free amine group of ethanolamine-containing glycerophospholipids (both those containing diacyl and those containing alkenyl-acyl bound fatty acids) and transformed into the respective NAEs by NAPE-dependent PLD.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4481858&req=5

Figure 1: The synthesis of oleoylethanolamide (OEA) is mediated by two concerted reactions: The first one is the N-acylation of phosphatidylethanolamine (PE) from the phospholipid bilayer of the cell membrane, mediated by a N-acyltransferase (NAT) to form N-oleoylphosphatidylethanolamine (NOPE) and the second one is the phospholipase D (PLD)-mediated hydrolysis of NOPE. Similar enzymatic reactions take place also during the synthesis of other NAEs, so that NAPEs are synthesized by acylation of the free amine group of ethanolamine-containing glycerophospholipids (both those containing diacyl and those containing alkenyl-acyl bound fatty acids) and transformed into the respective NAEs by NAPE-dependent PLD.
Mentions: N-acylethanolamines have been the most widely characterized. They include anandamide that was the most studied among them for its ability to act as endogenous cannabinoid ligand (D’Addario et al., 2014). Besides cannabinoid receptors, it has been gradually demonstrated that, depending on the nature of the N-linked acyl chain, NAEs can interact with different receptors in animals, including also vanilloid receptors and peroxisome proliferator activated-receptors (PPAR), and to be involved in many physiological processes (Fu et al., 2003; Nielsen et al., 2004; Terrazzino et al., 2004; Diep et al., 2011). With regard to the role played in the regulation of food intake, the most studied NAE was the monounsaturated analog of anandamide, oleoylethanolamide (OEA). Produced primarily in the small intestine, upon the absorption of dietary fat, OEA was demonstrated to act as a satiety signal in rodents by prolonging the interval between meals (Fu et al., 2003; Gaetani et al., 2003; Karimian Azari et al., 2014; Romano et al., 2014a). OEA endogenous mobilization is under the control of the sympathetic nervous system (LoVerme et al., 2006a; Fu et al., 2011) and is mediated by two concerted reactions. The first one is the transfer of an oleic group from the stereospecific numbering-1 (sn-1) position of a membrane phospholipid (for example phosphatidylcholine) to the amine group of a second membrane phospholipid, namely phosphatidylethanolamine (PE; Figure 1). This reaction is catalyzed by an enzyme, which remains to be molecularly identified, and whose N-acyltransferase activity seems to be calcium-dependent. The products of this reaction form a chemically heterogeneous family of N-oleoylphosphatidylethanolamines (NOPEs), which, depending on the specific PE precursor involved, may differ in the substituents at sn-1 and sn-2 position of PE (Figure 1). The sn-1 position is most often esterified by a saturated fatty acid or can contain an alkyl or alkenyl ether moiety; while the sn-2 position usually binds an unsaturated or polyunsaturated fatty acid (Coulon et al., 2012). Similar enzymatic reactions take place also during the synthesis of other NAEs, so that NAPEs are synthesized by acylation of the free amine group of ethanolamine-containing glycerophospholipids (both those containing diacyl and those containing alkenyl-acyl bound fatty acids; Natarajan et al., 1982; Schmid et al., 1990). This mechanism for NAEs formation was described some time ago and suggested that NAPEs merely act as unstable intermediate metabolites quickly converted into NAEs. However, novel evidence suggested that rather than simply precursors to NAEs, NAPEs can be defined as signaling lipids, able to control important biological functions on their own (Mora et al., 2002; Wellner et al., 2013). For example, it was recently demonstrated that among NAPEs, N-palmitoyl-phosphatidylethanolamine (N16:0 NAPE) can be involved in the gut-to brain axis that regulates food intake (Gillum et al., 2008; Fu et al., 2011).

Bottom Line: Similarly to NAEs, NAPE (with particular reference to the N16:0 species) levels were shown to be regulated by the fed state and this finding was initially interpreted as fluctuations of NAE precursors.Indirect observations suggest that the hypophagic action of NAPEs might involve central mechanisms, although the molecular target remains unknown.The present paper reviews the role that OEA and NAPEs play in the mechanisms that control food intake, further supporting this group of phospholipids as optimal candidate for the development of novel anti-obesity treatments.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome , Rome,Italy.

ABSTRACT
The spread of "obesity epidemic" and the poor efficacy of many anti-obesity therapies in the long-term highlight the need to develop novel efficacious therapy. This necessity stimulates a large research effort to find novel mechanisms controlling feeding and energy balance. Among these mechanisms a great deal of attention has been attracted by a family of phospholipid-derived signaling molecules that play an important role in the regulation of food-intake. They include N-acylethanolamines (NAEs) and N-acylphosphatidylethanolamines (NAPEs). NAPEs have been considered for a long time simply as phospholipid precursors of the lipid mediator NAEs, but increasing body of evidence suggest a role in many physiological processes including the regulation of feeding behavior. Several observations demonstrated that among NAEs, oleoylethanolamide (OEA) acts as a satiety signal, which is generated in the intestine, upon the ingestion of fat, and signals to the central nervous system. At this level different neuronal pathways, including oxytocinergic, noradrenergic, and histaminergic neurons, seem to mediate its hypophagic action. Similarly to NAEs, NAPE (with particular reference to the N16:0 species) levels were shown to be regulated by the fed state and this finding was initially interpreted as fluctuations of NAE precursors. However, the observation that exogenously administered NAPEs are able to inhibit food intake, not only in normal rats and mice but also in mice lacking the enzyme that converts NAPEs into NAEs, supported the hypothesis of a role of NAPE in the regulation of feeding behavior. Indirect observations suggest that the hypophagic action of NAPEs might involve central mechanisms, although the molecular target remains unknown. The present paper reviews the role that OEA and NAPEs play in the mechanisms that control food intake, further supporting this group of phospholipids as optimal candidate for the development of novel anti-obesity treatments.

No MeSH data available.


Related in: MedlinePlus