Long-chain saturated fatty acids at the interface between mitochondrial dysfunction and OxInflammation: implications for metabolic health

Skeletal muscle oxinflammation and mitochondrial dysfunction are tightly linked by a bidirectional relationship and have both been implicated in the pathogenesis of insulin resistance. Oxidative stress and NFκB signaling contribute to mitochondrial dysfunction, which, in turn, further fuels oxinflammation. Dietary lipid overload appears to be a major driver of this vicious cycle, however the ability of fatty acids to trigger oxinflammation may depend on their chain length and saturation. Thus, the aim of this study was to evaluate the impact of different fatty acids on skeletal muscle inflammation, mitochondrial dysfunction and the repercussion on insulin signaling. Using a human primary myotube cell model, we compared the effects of palmitic acid (PA) and lauric acid (LA), respectively a long and a medium-chain saturated fatty acid, on inflammation, mitochondrial dynamics and function. While PA activated NFκB signaling, promoted mitochondrial fragmentation and impaired mitochondrial membrane potential, these effects were absent in myotubes treated with LA. Furthermore, the effects of PA were prevented by the anti-inflammatory eicosapentaenoic acid, which rescued mitochondrial function, inflammation and insulin signaling. Thus, the quality, rather than the quantity of dietary fatty acids represents a pivotal discriminant in modulating the pathophysiological mechanisms fueling oxinflammation and underpinning skeletal muscle insulin resistance.