Palmitoylethanolamide counteracts hepatic metabolic inflexibility modulating mitochondrial function and efficiency in diet‐induced obese mice

Peroxisome proliferator‐activated receptor (PPAR)‐α activation controls hepatic lipid homeostasis, stimulating fatty acid oxidation, and adapting the metabolic response to lipid overload and storage. Here, we investigate the effect of palmitoylethanolamide (PEA), an endogenous PPAR‐α ligand, in counteracting hepatic metabolic inflexibility and mitochondrial dysfunction induced by high‐fat diet (HFD) in mice. Long‐term PEA administration (30 mg/kg/die per os) in HFD mice limited hepatic lipid accumulation, increased energy expenditure, and markedly reduced insulin resistance. In isolated liver mitochondria, we have demonstrated PEA capability to modulate mitochondrial oxidative capacity and energy efficiency, leading to the reduction of intracellular lipid accumulation and oxidative stress. Moreover, we have evaluated the effect of PEA on mitochondrial bioenergetics of palmitate‐challenged HepG2 cells, using Seahorse analyzer. In vitro data showed that PEA recovered mitochondrial dysfunction and reduced lipid accumulation in insulin‐resistant HepG2 cells, increasing fatty acid oxidation. Mechanistic studies showed that PEA effect on lipid metabolism was limited by AMP‐activated protein kinase (AMPK) inhibition, providing evidence for a pivotal role of AMPK in PEA‐induced adaptive metabolic setting. All these findings identify PEA as a modulator of hepatic lipid and glucose homeostasis, limiting metabolic inflexibility induced by nutrient overload.