Palmitoylethanolamide, a lipid mediator, controls feeding behaviour and restores leptin sensitivity in ovariectomized obese rats.

G Mattace Raso, A Santoro, R Simeoli, R Russo, G D\'Agostino, A Calignano, R Meli. University of Naples Federico II, Department of Experimental Pharmacology Naples 80131, Italy

Recently it has been suggested a role of fatty acid ethanolamides (FAEs) in the control of feeding behaviour (1). Among FAEs, it is clear that oleylethanolamide (OEA), produces satiety, reduces body weight gain in mice involving the peripheral regulation of feeding (2). Conversely, palmitoylethanolamide (PEA), a well characterized anti-inflammatory and anti-nociceptive compound, has never been directly implicated in appetite regulation.

The aim of the present study was to investigate whether PEA treatment is able to modulate feeding behaviour and weight gain through the modification of leptin level and hormone central signaling. To this purpose, we used a rat model of mild obesity induced by ovariectomy. Five weeks after surgery (under general anaesthesia by ketamine 100 mg/kg and xilazina 10mg/kg, i.p.), the ovariectomized rats (n=6 each group; Wistar female rats; 200±5 g) were divided in two groups one receiving vehicle alone (OVX), the second treated with palmitoylethanolamide (PEA; 30 mg/kg/daily s.c.). Sham operated rats (SHAM), subjected to the same general surgical procedure except that ovarian excision, were used as control. PEA and vehicle treatments were performed for five weeks. Here, we show that in ovariectomized rats repeated administration of PEA causes a gradual reduction of food intake and body weight. Moreover, PEA significantly lowered leptin gene transcription in subcutaneous adipose tissue (P<0.05), that were strongly up-regulated in ovariectomized rats vs sham-animals (p<0.001). To evaluate the re-establishment of leptin signaling sensitivity we first determined leptin receptor expression in the hypothalamus which was increased by PEA treatment (P<0.05 vs OVX). Subsequently, the improvement by PEA on leptin sensitivity was showed by the reduction of suppressor of cytokine signaling 3 (SOCS3) and the protein tyrosine phosphatase 1B (PTP1B). In addition, we also demonstrated that PEA treatment reduces the phosphorylation of AMP-activated protein kinase (AMPK)-alpha in the hypotalamus. Behind its peripherical function of fuel-sensing enzyme, the modification of AMPK phosphorilation in the hypothalamus regulates food intake modulating orexigenic and anorexigenic neuropeptides.

The above findings imply a delicate interaction between PEA and leptin, suggesting that the anorexic and leptin-reducing effects of PEA are a result of increased leptin sensitivity.

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