title: Dysfunctional oleoylethanolamide signaling in a mouse model of Prader-Willi syndrome.
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.
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA.
authors.forename: Miki
authors.initials: M
authors.lastname: Igarashi
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA.
authors.forename: Vidya
authors.initials: V
authors.lastname: Narayanaswami
authors.affiliation: Department of Pediatrics, University of California, Irvine, CA, 92697, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Kimonis
authors.affiliation: Department of Pediatrics, University of California, Irvine, CA, 92697, USA.
authors.forename: Pietro M
authors.initials: PM
authors.lastname: Galassetti
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA.
authors.forename: Fariba
authors.initials: F
authors.lastname: Oveisi
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA.
authors.forename: Kwang-Mook
authors.initials: KM
authors.lastname: Jung
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA; Department of Biological Chemistry, University of California, Irvine, CA, 92697, USA; Department of Pharmacology, University of California, Irvine, CA, 92697, USA. Electronic address: piomelli@uci.edu.
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D004195:Disease Models, Animal; D004435:Eating / Q000502:physiology; D063388:Endocannabinoids / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009829:Oleic Acids / Q000378:metabolism*; D011218:Prader-Willi Syndrome / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins
chemical_list: D000951:Antigens, Neoplasm; D063388:Endocannabinoids; D009829:Oleic Acids; D011506:Proteins; C403091:Magel2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins; C488250:oleoylethanolamide
keywords: Feeding behavior; Hyperphagia; Magel2(m+/p−); Mice; Oleoylethanolamide (OEA); Peroxisome proliferator-activated receptor-α (PPAR-α)