Opposite effects of saturated and unsaturated free fatty acids on intracellular signaling and metabolism in neuronal cells

Elevated levels of plasma saturated free fatty acids are a major pathogenic factor in diabetes, cardiovascular and liver diseases. Growing evidence suggests a link between sFFA-induced metabolic impairments and neurodegeneration. Excessive sFFAs in the brain circulation may trigger neuroinflammation and insulin resistance, however the underlying signaling changes have not been clarified in neuronal cells. We recently reported the effects of FFAs on intracellular signaling and metabolism in neuronal cells. We found that palmitate induced both insulin resistance and mitochondrial dysfunction while promoting phosphorylation and nuclear translocation of NF-κB p65 in neuronal cells. The latter is a key event in the inflammatory cascade. Oleate pre-exposure and then removal was sufficient to completely block subsequent palmitate-induced intracellular signaling and metabolic derangements. Interestingly, oleate also prevented ceramide-induced insulin resistance and cytotoxicity. Protein kinase A and triglyceride accumulation were implicated in the mechanism of oleate action. This is the first demonstration showing that oleate has beneficial properties against sFFA and ceramide models of neuronal injury. The lasting effect following oleate removal on preventing palmitate- or ceramide- induced cell damage was striking.