Abstract
Diets rich in carbohydrate and saturated fat contents, when combined with a sedentary lifestyle, contribute to the development of obesity and metabolic syndrome (MetS), which subsequently increase palmitic acid (PA) levels. At high concentrations, PA induces lipotoxicity through several mechanisms involving endoplasmic reticulum (ER) stress, mitochondrial dysfunction, inflammation and cell death. Nevertheless, there are endogenous strategies to mitigate PA-induced lipotoxicity through its unsaturation and elongation and its channeling and storage in lipid droplets (LDs), which plays a crucial role in sequestering oxidized lipids, thereby reducing oxidative damage to lipid membranes. While extended exposure to PA promotes mitochondrial reactive oxygen species (ROS) generation leading to cell damage, acute exposure of ß-cells to PA increases glucose-stimulated insulin secretion (GSIS), through the activation of free fatty acid receptors (FFARs). Subsequently, the activation of FFARs by exogenous agonists has been suggested as a potential therapeutic strategy to prevent PA-induced lipotoxicity in ß cells. Moreover, some saturated fatty acids, including oleic acid, can counteract the negative impact of PA on cellular health, suggesting a complex interaction between different dietary fats and cellular outcomes. Therefore, the challenge is to prevent the lipid peroxidation of dietary unsaturated fatty acids through the utilization of natural antioxidants. This complexity indicates the necessity for further research into the function of palmitic acid in diverse pathological conditions and to find the main therapeutic target against its lipotoxicity. The aim of this review is, therefore, to examine recent data regarding the mechanism underlying PA-induced lipotoxicity in order to identify strategies that can promote protection mechanisms against lipotoxicity, dysfunction and apoptosis in MetS and obesity.