Dottorato in FARMACOLOGIA E TOSSICOLOGIA

Titolo della tesi: Pre-clinical evaluation of novel pharmacological targets for the treatment of obesity and eating disorders: focus on Oleoylethanolamide and the oxytocinergic system

Obesity and anorexia nervosa (AN) represent contrasting yet debilitating conditions within the spectrum of disordered eating behaviors, each posing significant challenges to public health. The pathophysiology of these conditions involves complex interactions between genetic, environmental, and neurobiological factors. Understanding the metabolic changes at the beginning of obesity development can help find strategies to avoid the onset of obesity-related pathological consequences. Oleoylethanolamide (OEA), a natural occurring lipid mediator, is widely studied for its positive effect on food intake and lipid metabolism. In the present study, we investigated the effect of OEA on cardiac and skeletal muscle metabolism in young rats after a period of exposure to a high fat diet (HFD). Young male Wistar rats were exposed to a HFD for seven weeks, followed by daily treatment with either a vehicle or OEA for two weeks. Various analyses were conducted to evaluate morphological changes, lipid content, molecular pathways related to insulin signalling, and ATP production in the heart and gastrocnemius muscles. Rats exposed to the HFD exhibited increased body weight, triacylglycerol levels in skeletal muscle, and histological changes indicating fibrosis in both muscle tissues. Additionally, compromised ATP production and altered Akt and AMPK signalling pathways were observed, along with increased mitochondrial biogenesis in skeletal muscle. However, pharmacological treatment with OEA reversed many of these effects. These findings suggest a potential role for OEA in correcting metabolic abnormalities associated with early-onset obesity, offering insights into potential therapeutic interventions for obesity-related metabolic diseases. The second study delves into the neurobiological basis of anorexia nervosa (AN), a psychiatric disorder marked by distorted body image and severe food restriction. Recent research implicates hypothalamic neuropeptides, including oxytocin (OXY), in AN pathogenesis. Using the anx/anx mouse model of anorexia, the study examines OXY and OXY receptor expression in brain regions associated with eating behavior and olfaction, as well as OXY plasma levels. Additionally, the study profiles the RNA-transcriptome of hypothalamic nuclei mainly involved in OXY synthesis, the paraventricular and supraoptic ones. Our data show an overall alteration of the oxytocinergic signalling in brain areas related to olfaction, as well as differential expression in genes involved in neuronal plasticity and microglia activation in both PVN and SON. The findings derived from this investigation offer additional support for the dysregulation of the oxytocinergic system in AN and emphasize the significance of advancing our comprehension of these mechanisms to facilitate the emergence of novel therapeutic approaches targeted at enhancing the management of this complex disorder. In conclusions, the results reported in this work have the potential to unravel new targets for the development of pharmacological treatments for obesity and AN, two major health problems worldwide.