Titolo della tesi: Pharmacological modulation of paracannabinoid tone in peripheral and central alterations associated with maladaptive eating behaviours
Abstract 1: Overweight and obesity are metabolic conditions characterized by peripheral adaptations involving white adipose tissue remodelling and alterations in hepatic pathways regulating intracellular lipid homeostasis. In both conditions, adipose tissue undergoes changes in lipid signaling profiles, while hepatic mechanisms, including autophagy-related processes, contribute to the regulation of systemic metabolic balance. Endocannabinoid-related mediators and N-acylethanolamides participate in the control of adipose lipid metabolism and may influence liver adaptive responses. Although overlapping in several metabolic features, overweight and established obesity may differ in the magnitude and organization of peripheral adaptations. Oleoylethanolamide (OEA), an endogenous N-acylethanolamide and agonist of peroxisome proliferator-activated receptor alpha (PPARα), has been implicated in the modulation of peripheral metabolic pathways. However, whether its effects differ between overweight and established obesity remains insufficiently characterized. This chapter investigates the impact of sub-chronic OEA administration in two distinct metabolic conditions: an early-onset obese phenotype and an established obese phenotype. Through targeted LC–MS/MS lipidomic profiling of epididymal adipose tissue and the assessment of hepatic autophagy-related markers by Western blot analysis, the study aims to characterize peripheral adaptations in both conditions and to determine whether pharmacological modulation of paracannabinoid signaling differentially influences adipose–liver metabolic pathways. Abstract 2: Obesity induced by chronic consumption of energy-dense, palatable diets is associated with hypothalamic neuroinflammation and glial activation, contributing to dysregulation of energy balance. The endocannabinoid system, particularly N-acylethanolamides (NAEs), regulates metabolic and inflammatory processes. Since these mediators are degraded by fatty acid amide hydrolase (FAAH), their pharmacological inhibition may enhance endogenous anti-inflammatory signaling. This study evaluated whether chronic administration of the FAAH inhibitor PF-3845 (10 mg/kg, s.c.) modulates astrocytic activation in rats exposed to a cafeteria (CAF) diet. Male Wistar rats were fed either chow or CAF diet, followed by treatment with PF-3845 or vehicle. Glial fibrillary acidic protein (GFAP) expression was assessed in the paraventricular nucleus (PVN) and lateral hypothalamus (LH). While PF-3845 did not significantly affect body weight or food intake, it reduced GFAP expression in the LH of CAF-fed rats, with no significant changes observed in the PVN. These findings indicate a region-specific attenuation of hypothalamic astrocytic activation following FAAH inhibition, suggesting that enhancement of endogenous NAE signaling may modulate neuroinflammation associated with Cafeteris-diet obesity.