Identification and characterization of PPARα ligands in the hippocampus

Peroxisome proliferator-activated receptor-alpha (PPAR alpha) regulates hepatic fatty acid catabolism and mediates the metabolic response to starvation. Recently we found that PPAR alpha is constitutively activated in nuclei of hippocampal neurons and controls plasticity via direct transcriptional activation of CREB. Here we report the discovery of three endogenous PPAR alpha ligands3- hydroxy-(2,2)-dimethyl butyrate, hexadecanamide, and 9-octadecenamide-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 results clearly indicated that these three compounds served as ligands of PPAR alpha. Site-directed mutagenesis studies further revealed that PPAR alpha Y464 and Y314 are involved in binding these hippocampal ligands. Moreover, these ligands activated PPAR alpha and upregulated the synaptic function of hippocampal neurons. These results highlight the discovery of hippocampal ligands of PPAR alpha capable of modulating synaptic functions.