Pharmacological modulation of paracannabinoid tone in peripheral and central alterations associated with maladaptive eating behaviors

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 signalling 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 signalling differentially influences adipose–liver metabolic pathways.