New avenues in appetite reduction

The recent discovery of receptors that bind to ligands found outside the body — derivatives of hemp (Cannabis sativa) known as cannabinoids — as well as inside the body (fatty acid ethanolamides) has illuminated a new drug development path in the realm of appetite control.

Fatty acid ethanolamides are derivatives of N-substituted fatty acid ethanolamines, which enzymatically liberate the ethanolamides. The latter are defined by the fatty acid they are comprised of: arachidonic acid, for instance, yields arachidonoylethanolamide (anandamide), which binds to a cannabinoid receptor in the central nervous system.

Substituting with linoleic and oleic (unsaturated) fatty acids, hence, yields linoleoylethanolamide (LEA) and oleoylethanolamide (OEA), respectively. Interestingly, these derivatives do not bind to cannabinoid receptors. LEA and OEA are present in small amounts (mcg/g) in cocoa and dark chocolate, soybeans, oatmeal, millet, and hazelnuts, and as such do not appear to exert cannabinoidlike psychotropic effects.1,2

One of the hallmark behavioral effects of anandamide and the exocannabinoids found in hemp is increased appetite and food consumption behavior.3 This led researchers to pursue the effects of the anandamide analogue OEA, which has oleic acid substituted for arachidonic acid, upon food consumption and body weight. Injection of synthetic OEA into adult male rats, both acutely (after a 24-hour fast) and subacutely (seven days), led to substantial reductions in food intake.4 During the one-week period, body weight gain was significantly curtailed in the OEA group.

Different mechanism
The lack of OEA binding to cannabinoid receptors suggested it exerted its anorexic effects through a different mechanism. Because oleic acid is a ligand that binds to peroxisome proliferator-activated receptor-alpha (PPARa), which regulates lipid metabolism and thus body weight, researchers explored the interaction of OEA with PPARa.5 Daily injections over four weeks of OEA into mice lacking PPARa had no effect on food consumption or weight gain, while those with PPARa showed results similar to the earlier rat study. Additionally, OEA lowered blood lipids in the mice and in genetically obese rats.5 Different studies by the same group found OEA administration to promote fat breakdown via PPARa.6

Recently, two independent studies have shown that oral administration of OEA can influence food intake.7,8 The first compared an OEA solution to OEA contained in enteric-coated capsules (released at pH 6 in the upper small intestine).7 The capsules effected the same reduction in food intake over a 24-hour period as a four-fold higher dose. Unfortunately, the effects of non-enteric-coated capsules were not reported.

The second study administered solutions of ?cold? or radioactively labeled (?hot?) OEA and monitored 24-hour food intake in 24-hour-fasted rats.8 Food intake was dose-dependently reduced by OEA. Interestingly, hot OEA exhibited a distance-dependent breakdown.

There do not appear to be animal studies assessing the effects of fatty acid ethanola-mides on food intake. Moreover, the lack of human studies on fatty acid ethanolamides, or OEA or its parent N-oleoylethanolamide on body weight paint a picture of unfulfilled promise. Future research merits the exploration of comparisons between fatty acid ethanolamides, the chronic regulation of their production in the gut during dieting and overfeeding,9 and OEA?s immunosuppressive/anti-inflammatory activity.10

Anthony Almada, MSc, is president and chief scientific officer of IMAGINutrition Inc.

1. Di Tomaso E, et al. Brain cannabinoids in chocolate. Nature 1996; 382:677-8.
2. Di Marzo V. Trick or treat from food endocannabinoids? Nature 1998; 396:636-7.
3. Williams CM and Kirkham TC. Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacology 1999; 143:315-7.
4. Rodr?guez de Fonseca F, et al. An anorexic lipid mediator regulated by feeding. Nature 2001; 414:209-12.
5. Fu J, et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 2003; 425:90-3.
6. Guzm?n M, et al. Oleoylethanolamide stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-alpha). J Biol Chem 2004; 279:27849-54.
7. Oveisi F, et al. Oleoylethanolamide inhibits food intake in free-feeding rats after oral administration. Pharmacol Res 2004; 49:461-6.
8. Nielsen MJ, et al. Food intake is inhibited by oral oleoylethanolamide. J Lipid Res 45; 2004:1027-9.
9. Gaetani S, et al. Feeding regulates levels of the satiety mediator oleoylethanolamide in rat small intestine. Society for Neuroscience annual meeting, 2004, Program No. 427.11.
10. Degn M, et al. Immune inhibitory effects of N-oleoylethanolamine. Society for Neuroscience annual meeting, 2004, Program No. 273.14.

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