“ANTI-OBESITY EFFECTS OF OLEOYLETHANOLAMIDE IN A RODENT MODEL OF DIET INDUCED OBESITY”

Oleoylethanolamide (OEA) is an endogenous satiety signal produced by enterocytes upon the ingestion of dietary fat. Although OEA is a structural analog of anandamide, it does not show any affinity for cannabinoid receptors, but rather activates the peroxisome-proliferator activated receptor-α (PPAR-alpha). Through this activation, OEA is able to reduce food intake and body weight gain (BWG) in both lean and obese rodents and has emerged as a potential novel pharmacological target for the treatment of aberrant eating behaviors. In the present study we investigated the anti-obesity effects of OEA in a rat model of diet-induced obesity (DIO), not only focusing on the regulation of feeding behavior and BWG, but also on the composition of the gut-microbiota, and on the expression of genes involved in the control of feeding behavior in key regions of the central nervous system, such as the brainstem and the hypothalamus. DIO rats were obtained by exposing male rats to a high fat diet (HFD: 60% of the Kcal from fats) for 11 weeks. During the same time-window control rats received a low fat diet (LFD: 10% of the Kcal from fats). Then, part of DIO rats were shifted to the LFD (SLFD) for the following 2 weeks, during which all the animals were chronically treated either with OEA (10 mg/kg, i.p.) or with vehicle. Vehicle-treated animals were maintained either of a free-feeding regiment or a pair-feeding regimen, in which they were offered the same amount of food on average consumed by OEA-treated rats within the same diet-group. Body weight and food intake were measured throughout the experiment, and, after the sacrifice, brains and cecal content were collected for gene expression and microbiota analyses, respectively. Our results demonstrate that OEA treatment significantly reduced BWG in DIO rats and this effect was not strictly dependent from the inhibition of caloric intake since it was significantly higher than the decrease of BWG observed in pair-feeding rats. Moreover, the reduction of caloric intake after OEA treatment was not immediately observed in DIO rats, as expected, but it rather became significant at the end of the first week of treatment. These observation suggest that both the behavioural and metabolic effects of OEA can be evident in DIO rats with a long-time HFD exposure only after an adequate adaptation time. We hypothesize that this adaptation includes rearrangements of the gut microbiota and brain expression of key-genes that might be involved in the effects produced by OEA. In accordance with our hypothesis, we found a decreased number of total bacteria and a lower diversity of gut bacteria in the samples collected from DIO rats, as compared to those harvested from LFD-exposed rats. The results obtained from the analysis of the gene expression revealed that the treatment with OEA is able to significantly increase the expression of the early-gene c-fos (marker of neuronal activation) within the brainstem of animals exposed to HFD respect to those exposed to LFD. Interestingly this latter effect is completely abolished by the dietary shift. The same effects was observed regarding the expression of PPAR-alpha gene. As far as the hypothalamus, here OEA treatment is able to significantly increase the expression of melanocortin 4 receptor in both HFD-fed and SFLD animals compared to the LFD-fed animals. Overall, our study provides important new information on the therapeutic potential of OEA for the treatment of obesity.