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The anorectic N-acylethanolamines (NAEs), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and linoleoylethanolamide (LEA) are generated in the small intestine where they may function as a homeostatic signal, which contributes to regulating the amount and type of food ingested (1, 2). Their mechanism of action involves activation of PPARalpha and of the vagus nerve (2). We have previously shown that a prolonged intake of a diet high in fat (45E% fat) will decrease the intestinal levels of these signaling lipids in a time and dose-dependent manner (3,4), suggesting that this effect may contribute to the hyperphagic effect of dietary fat. Male C57BL/6 mice were fed with either chow (minced Altromin) (n=8 from Taconic and n=8 from Charles River) or chow mixed with supplemented 0.5 wt% Fenofibrate (n=8 from Taconic and n=8 from Charles River) for seven days, and intestinal levels of NAEs were measured by LC-MS as previously described (3,4). The levels of PEA and LEA were significantly decreased (23-64%) in both strain of mice , while the decrease in OEA only reached significance in Charles river mice. There was no difference in levels of anandamide in any strain of mice. This suggests that PPARalpha may be the fat-sensing receptor in the intestine being responsible for the fat-induced decrease in the level of anorectic OEA, PEA and LEA.

BACKGROUND AND AIMS: Oleoylethanolamide and several other N-acylethanolamines (NAEs), e.g. linoleoylethanolamide and palmitoylethanolamide, have anorectic properties in rats, and prolonged intake of a high-fat diet decreases the levels of the anorectic NAEs in jejunum. Jejunal anorectic NAEs are thought to add to the control of food intake via activation of PPARalpha and the vagus nerve. The fat-induced decrease may explain part of the hyperphagic effect of high-fat diets. In the present study, we investigated 1) whether the reduced levels of anorectic NAEs were reversible in rats, 2) whether mice respond to dietary fat (olive oil) by reducing levels of anorectic NAEs, and 3) whether dietary non-esterified oleic acid also can decrease levels of anorectic NAEs in mice. We are searching for the fat sensor in the intestine, which mediates the decreased levels of anorectic NAEs.METHODS: Male rats and mice were fed diets high (45 energy% fat) in either triacylglycerol or free fatty acids for 7-14 days, and jejunal NAE and N-acylphosphatidylethanolamine (NAPE) levels were determined by liquid-chromatography mass spectrometry.RESULTS: In rats, reduced levels of anorectic NAEs could be reversed after 3 days from changing the diet from high-fat to chow. Corresponding NAPE levels tended to show the same changes. In mice, jejunal levels of anorectic NAEs were also reduced when fed a high-fat diet. In addition, we found that non-esterified oleic acid were also able to reduce levels of anorectic NAEs in mice.CONCLUSIONS: These results suggest that the down-regulation of the jejunal level of anorectic NAEs by dietary fat is not restricted to rats, and that the fatty acid component oleic acid, in dietary olive oil may be sufficient to mediate this regulation. Thus, a fatty acid sensor may mediate this effect of dietary fat.

N-acyletanolaminer (NAEs) er en gruppe lipider, som i de sidste årtier har vist sig at være involveret i flere biologiske funktioner ikroppen. De findes overalt i kroppen, inklusivt i hjernen, fedtvævet og fordøjelseskanalen. Anandamide var den første NAE, man identificerede med en biologisk funktion. Den blev identificeret som et endocannabinoid med evne til at aktivere de cannabinoide receptorer, og udøve effekter såsom smertelindring, kvalmestillende, og kan derudover inducere hypermotilitet og hypothermia. Palmitoylethanolamide (PEA) blev efterfølgende identificeret som værende antiinflammatorisk, hvor PEA bliver opreguleret i forbindelse med iskæmiske tilstande i kroppen. Oleoylethanolamide (OEA) har vist sig at være involveret i regulering af energihomeostasen, appetiten, mavesækkens motilitet og lipolyse. I denne Ph.D afhandling er der fokuseret på NAEerne i tyndtarmen og hvordan indtagelsen af kostens fedt påvirker NAE niveauerne. Sprague-Dawley hanrotter blev fodret med en fedtholdig diæt i variende længder og med forskellige mængder af fedt i diæten. NAEerne i tyndtarmen blev dernæst oprenset og målt ved hjælp af massespektrometri. Niveauerne af PEA, linoleoylethanolamide (LEA) og til dels OEA var reduceret efter fedtfodring. En dag med fedtholdig kost (45E% fedt) resulterede i signifikant reduceret niveauer af NAEerne, som forblev reduceret gennem de 7 dage hvor forsøget stod på. Mindre fedtholdig kost var også i stand til at reducere de anorektiske NAEer (OEA, PEA og LEA), men rotterne skulle fodres i flere dage, før en reduktion blev observeret. De fysiologiske konsekvenser af det nedsatte niveau af de anorektiske NAEer blev undersøgt ved brug af et automatiseret overvågningssystem, MANIFeed systemet, som meget præcist måler foder- og vandindtag. Kalorieintaget var forøget med øget energitæthed i foderet. NAE niveauerne var nedsat uanset energidensiteten i fodret. Den isokaloriske diæt, som energitætheds-mæssigt er identisk med, N-acylethanolamines (NAEs) are a group of lipids, which during the course of the last decades have shown to have multiple biological functions. They are widely distributed in the body, e.g. in the brain, adipose tissue and gastroinstetinal tract. Anandamide was the first NAE discovered to have a biological function. It was first identified as an endocannabinoid, with the ability to activate the cannabinoid receptors, and exert effects such as analgesia, anti-emetic, induce hypermotility and hypothermia, respectively. Palmitoylethanolamide (PEA) was subsequently discovered as an anti-inflammatory agent, being upregulated during inflammation and shown to be protective in the brain followed ischemic events. Oleoylethanolamide (OEA) has shown to be involved in energy homeostasis regulating food intake, gastric motility and lipolysis. In this Ph.D. dissertation focus has been on NAE levels in the small intestine and the effects of dietary fat consumption on intestinal NAE levels. Male Sprague-Dawley rats were fed a high-fat diet for varying length and with varying energy percentages of fat in the diet. The intestinal NAE levels were extracted and measured by liquid chromatography mass spectrometry. Levels of PEA, linoleoylethanolamide (LEA) and partially OEA were reduced followed the high fat diet regime. After one day of high fat diet (45 energy percentage (E%) from fat) these NAE levels were significantly reduced, a reduction which persisted throughout the 7 days of experimetally feeding the rats. Less energy-dense diets were also able to reduce the levels of the anorectic NAEs (OEA, PEA and LEA), however longer exposure time was needed to elicit a reduction. The physiological implications of the reduced anorectic NAE levels were investigated by using the MANIFeed system, which carefully monitored food- and water intake. Caloric consumption increased with increasing energy density in the food. NAE levels were reduced regardle

Endocannabinoids bind to cannabinoid, vanilloid, and peroxisome proliferator-activated receptors. The biological actions of these polyunsaturated lipids are controlled by key agents responsible for their synthesis, transport and degradation, which together form an endocannabinoid system (ECS). In the past few years, evidence has been accumulated for a role of the ECS in regulating food intake and energy balance, both centrally and peripherally. In addition, up-regulation of the ECS in the gastrointestinal tract has a potential impact on inflammatory bowel diseases. In this review, the main features of the ECS are summarized in order to put in better focus our current knowledge of the nutritional relevance of endocannabinoid signaling and of its role in obesity, cardiovascular pathologies, and gastrointestinal diseases. The central and peripheral pathways that underlie these effects are discussed, as well as the possible exploitation of ECS components as novel drug targets for therapeutic intervention in eating disorders.

Udgivelsesdato: 2009-Sep-15, Anandamide and the other N-acylethanolamines, e.g. oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and linoleoylethanolamide (LEA), may be formed by several enzymatic pathways from their precursors, which are the N-acylated ethanolamine phospholipids. The exact enzymatic pathways involved in their biosynthesis in specific tissues are not clarified. It has been suggested that endogenous anandamide could stimulate food intake by activation of cannabinoid receptors in the brain and/or in the intestinal tissue. On the other hand, endogenous OEA and PEA have been suggested to inhibit food intake by acting on receptors in the intestine. At present, there is no clear role for endogenous anandamide in controlling food intake via cannabinoid receptors, neither centrally nor in the gastrointestinal tract. However, OEA, PEA and perhaps also LEA may be involved in regulation of food intake by selective prolongation of feeding latency and post-meal interval. These N-acylethanolamines seem to be formed locally in the intestine, where they can activate PPARalpha located in close proximity to their site of synthesis. The rapid onset of OEA response and its reliance on an intact vagus nerve suggests that activation of PPARalpha does not result in formation of a transcription-dependent signal but must rely on an unidentified non-genomic signal that translates to activation of vagal afferents. Whether GPR119, TRPV1 and/or intestinal ceramide levels also contribute to the anorectic and weight-reducing effect of exogenous OEA is less clear. Prolonged intake of dietary fat (45 energy%) may promote over-consumption of food by decreasing the endogenous levels of OEA, PEA and LEA in the intestine.