Peroxisome proliferator-activated receptor-alpha is required for the neurotrophic effect of oleic acid in neurons

Oleic acid synthesized by astrocytes behaves as a neurotrophic factor for neurons, up-regulating the molecular markers of axonal and dendritic outgrowth, growth-associated protein 43 and microtubule-associated protein 2. In this work, the nature of the receptor involved in this neurotrophic effect was investigated. As oleic acid has been reported to be a ligand and activator of the peroxisome proliferator-activated receptor (PPAR), we focus on this family of receptors. Our results show that PPAR alpha, beta/delta, and gamma are expressed in neurons in culture. However, only the agonists of PPAR alpha, Wy14643, GW7647 and oleoylethanolamide, promoted neuronal differentiation, while PPAR beta/delta and gamma agonists did not modify neuronal differentiation. Consequently, we investigated the involvement of PPAR alpha (Nr1c1) in oleic acid-induced neuronal differentiation. Our results indicate that oleic acid activates PPAR alpha in neurons. In addition, the effect of oleic acid on neuronal morphology, growth-associated protein 43 and microtubule-associated protein 2 expression decreases in neurons after PPAR alpha has been silenced by small interfering RNA. Taken together, our results suggest that PPAR alpha could be the receptor for oleic acid in neurons, further broadening the range of functions attributed to this family of transcription factors. Although several works have reported that PPAR alpha could be involved in neuroprotection, the present work provides the first evidence suggesting a role of PPAR alpha in neuronal differentiation.