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 alipid 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 (10 mg/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.

Obesity management in Prader–Willi syndrome: current perspectives

“…New evidence suggests that intraperitoneal administration of oleoylethanolamide (a lipid messenger, produced by small-intestinal enterocytes, that controls feeding, body weight, and energy metabolism) in Magel2KO mice is able to reduce food intake, probably acting through mechanisms underlying satiety control. 23 These results, combined with imaging studies showing both an increased functional response of the hypothalamus to food stimuli, 24 the involvement of the amygdala, 25 and the reduced coupling of the ventral striatum with limbic structures for basic internal homeostasis, 26 suggest a crucial role of several brain areas in the abnormal regulation of food intake in PWS.…”

Mast Cell-Derived Histamine Regulates Liver Ketogenesis via Oleoylethanolamide Signaling

“…Third, viral-mediated enhancement of OEA production in rat jejunum reduces food intake and concomitantly increases local expression of PPAR-a target genes (Fu et al, 2008). Finally, OEA levels in small intestine from various vertebrate species, including fish, snakes, and rodents, rise from %50 nM in the fasting state to R250 nM after feeding (Astarita et al, 2006b;Fu et al, 2007;Tinoco et al, 2014;Igarashi et al, 2017), a concentration range that is compatible with PPAR-a activation (Fu et al, 2003;Astarita et al, 2006a). In sum, the available data indicate that OEA is a physiologically relevant endogenous agonist for small-intestinal PPAR-a, which participates in the control of satiety .…”

N-Palmitoylethanolamine Maintains Local Lipid Homeostasis to Relieve Sleep Deprivation–Induced Dry Eye Syndrome

“…PEA and OEA are both involved in the regulation of lipid metabolism (Ueda et al, 2010). OEA is a satiety factor that suppresses feeding and stimulates lipolysis by activating PPAR-a receptors and in turn engaging vagal sensory afferent nerves (Hankir et al, 2017;Igarashi et al, 2017). However, there is not enough evidence to confirm the effects of PEA on appetite regulation and weight gain.…”