Identification and characterization of PPARα ligands in the hippocampus

Peroxisome proliferator-activated receptor alpha (PPARα) regulates hepatic fatty acid catabolism and mediates the metabolic response to starvation. Recently, we have found that PPARα is constitutively activated in nuclei of hippocampal neurons and controls plasticity via direct transcriptional activation of CREB. Here, three endogenous ligands of PPARα, 3-hydroxy-(2,2)-dimethyl butyrate, hexadecanamide, and 9-octadecenamide were discovered in mouse brain hippocampus. Mass spectrometric detection of these compounds in mouse hippocampal nuclear extracts, in silico interaction studies, time-resolved FRET analyses, and thermal shift assay clearly indicated that these three compounds served as ligands of PPARα. Site-directed mutagenesis studies further revealed that PPARα Tyr 464 and Tyr 314 were involved in binding these hippocampal ligands. Moreover, these ligands activated PPARα and upregulated synaptic function of hippocampal neurons. These results highlight the discovery of hippocampal ligands of PPARα capable of modulating synaptic functions.