Abstract
Prader-Willi syndrome (PWS), the leading genetic cause of obesity, is characterized by a striking hyperphagic behavior that can lead to obesity, type-2 diabetes, cardiovascular disease and death. The molecular mechanism underlying impaired satiety in PWS is unknown. Oleoylethanolamide (OEA) is a lipid mediator involved in the control of feeding, body weight and energy metabolism. OEA produced by small-intestinal enterocytes during dietary fat digestion activates type-α peroxisome proliferator-activated receptors (PPAR-α) to trigger an afferent signal that causes satiety. Emerging evidence from genetic and human laboratory studies suggests that deficits in OEA-mediated signaling might be implicated in human obesity. In the present study, we investigated whether OEA contributes to feeding dysregulation in Magel2m+/p− (Magel2 KO) mice, an animal model of PWS. Fasted/refed male Magel2 KO mice eat more than do their wild-type littermates and become overweight with age. Meal pattern analyses show that hyperphagia in Magel2 KO is due to increased meal size and meal duration rather than to lengthening of the intermeal interval, which is suggestive of a defect in mechanisms underlying satiation. Food-dependent OEA accumulation in jejunum and fasting OEA levels in plasma are significantly greater in Magel2 KO mice than in wild-type controls. Together, these findings indicate that deletion of the Magel2 gene is accompanied by marked changes in OEA signaling. Importantly, intraperitoneal administration of OEA (10mg/kg) significantly reduces food intake in fasted/refed Magel2 KO mice, pointing to a possible use of this natural compound to control hunger in PWS.
Highlights
Prader-Willi syndrome (PWS) is the leading genetic cause of obesity
Previous work has shown that mice carrying a deletion of the Magel2 gene, which is frequently mutated in persons with PWS, display a deficit in the ability to regulate food intake [1,2,3]
Consistent with those data, we found that Magel2 KO mice that had been deprived of food for 24 h consumed significantly more food than did their wild-type littermates (Fig. 1A)
Summary
Prader-Willi syndrome (PWS) is the leading genetic cause of obesity. Children with PWS develop a striking hyperphagic behavior that leads, if left unchecked, to morbid obesity, type-2 diabetes, Abbreviations: PWS, Prader–Willi syndrome; OEA, oleoylethanolamide; PC, phosphatidylcholine; PE, phosphatidylethanolamine; NAT, N-acyl transferase; NAPE, N-acyl-phosphatidylethanolamine; NOPE, N-oleoylphosphatidylethanolamine; NAPE-PLD, N-acylphosphatidylethanolamine-selective phospholipase D; FAAH, fatty acid amide hydrolase; NAAA, N-acylethanolamine acid amidase; PPAR-␣, peroxisome proliferator activated receptor-␣; PEA, palmitoylethanolamide; FAE, fatty acid ethanolamide; LC–MS, liquid chromatography-mass spectrometry; SIM, selected ion monitoring; ANOVA, analysis of variance.cardiovascular disease and premature death. Children with PWS develop a striking hyperphagic behavior that leads, if left unchecked, to morbid obesity, type-2 diabetes, Abbreviations: PWS, Prader–Willi syndrome; OEA, oleoylethanolamide; PC, phosphatidylcholine; PE, phosphatidylethanolamine; NAT, N-acyl transferase; NAPE, N-acyl-phosphatidylethanolamine; NOPE, N-oleoylphosphatidylethanolamine; NAPE-PLD, N-acylphosphatidylethanolamine-selective phospholipase D; FAAH, fatty acid amide hydrolase; NAAA, N-acylethanolamine acid amidase; PPAR-␣, peroxisome proliferator activated receptor-␣; PEA, palmitoylethanolamide; FAE, fatty acid ethanolamide; LC–MS, liquid chromatography-mass spectrometry; SIM, selected ion monitoring; ANOVA, analysis of variance. Its first step is the transfer of a fatty acid, oleic acid, from phosphatidylcholine (PC) to phosphatidylethanolamine (PE). This reaction is catalyzed by the N-acyl transferase PLA2G4E [10] and produces various forms of N-acyl-phosphatidylethanolamine (NAPE), including the OEA precursor N-oleoyl-phosphatidylethanolamine (NOPE)
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