PhD Niels Wellner – University of Copenhagen

PhD Niels Wellner

Faculty of Pharmaceutical Sciences

Affiliated with UNIK project no. 11

Title of thesis: N-Acylphosphatidylethanolamines as New Intestinal Hormones in the Regulation of Appetite?

Thesis summary: N-acylphosphatidylethanolamines (NAPEs) are phospholipid precursors of the endocannabinoid anandamide and other N-acylethanolamnes (NAEs). NAEs have been associated with a range of biological effects, including anti-inflammatory properties and regulation of food intake by auto- or paracrine effects in the small intestine. Recently, NAPE was discovered also to be a hormone, involved in controlling energy homeostasis. NAPE is formed in the small intestine by the enzyme N-acyltransferase as a response to ingested fat, is released for lympthatic and subsequent systemic circulation, and has been suggested to exert its effect in the hypothalamus of the brain. The receptor for NAPE is as yet unknown.

The work presented in this dissertation investigates the anorectic effect of NAPE and related phospholipid metabolites and precursors, when administered by different administration routes.

The earlier published anorectic effect of NAPE was replicated by injecting male C57BL6 mice intraperitoneally with a 500mg/kg dose of NAPE, and monitoring food intake, water intake and activity of the mice for 12 hours. The phospholipids phosphatidylethanolamine, phosphatidylcholine (PC), phosphatidic acid and a stable diether-NAPE analogue were injected in equimolar doses in the same manner, and all but PC were found to inhibit food intake. White precipitatons were found in the peritoneal cavity of the animals post mortem, suggesting that this formulation or method of injection were unsuitable for high-dose phospholipid administration.

Instead, NAPE and the diether-NAPE analogue were formulated as liposomes suitable for intravenous injection. The liposomes were characterized and administered in a 300nmol dose in the tail vein to similar mice, but this had no effect on food intake.

In another study, the water soluble metabolite of NAPE, glycero-phospho-N-acylethanolamine (GP-NAE), was injected intraperitoneally in male C57BL6 mice, and again food intake was monitored. Doses of 25mg/kg-100mg/kg were found to significantly inhibit food intake in a dose-dependent manner, but observations of the mice revealed this effect to be toxic. GP-NAE was injected intrathecally to avoid the toxic effects seen after peripheral administration of the compound, but in this study no effect on food intake was observed.

The data presented in this dissertation suggest that the effect of the phospholipid hormone NAPE is not mediated by the metabolite GP-NAE, and that the effect of intraperitoneally administered NAPE could be unspecific, due to the positive outcome of several negative controls. Overall, the results question the hormonal action of NAPE, although much data still support this hypothesis.


Articles in PubMed


Niels Wellner at LinkedIn