Targeted disruption of peroxisomal proliferator-activated receptor beta (delta) results in distinct gender differences in mouse brain phospholipid and esterified FA levels.

The peroxisomal proliferator-activated receptor beta (delta) (PPARbeta) is a nuclear hormone receptor that is ubiquitously expressed and that regulates the transcription of genes involved in lipid metabolism. A homozygous PPARbeta-null mouse has been developed in which the ligand-binding domain of the PPARbeta receptor is disrupted. Analysis of brains from these animals shows that female null mice have 24 and 17% increases in plasmenylethanolamine and phosphatidylserine and a 9% decrease in the level of phosphatidylinositol when compared to controls. The phospholipid changes found in female null mice were associated with increased levels of esterified 18:1n-9, 20:1n-9, 20:4n-6, and 22:5n-3 FA in plasmenylethanolamine, 20:1n-9 in phosphaticlylinositol, and 18:0, 18:1n-9, 18:3n-6, 20:1 n-9, and 20:4n-6 in phosphatidylserine. Increased levels of esterified 18:1n-9, 18:2n-6, 18:3n-6, and 20:1n-9 were also found in the phosphatidylethanolamine fraction despite its cellular content remaining unchanged. Brain phospholipid content in male PPARbeta-null mice did not differ from controls, but increased levels of 20:1n-9 in the phosphatidylinositol and 18:1n-9 in the phosphatidylserine fractions were observed. No changes were found in the content of brain cholesterol, TAG, and FFA in either female or male PPARbeta-null mice. These data suggest that PPARbeta is involved in maintaining FA and phospholipid levels in adult female mouse brain and provide strong evidence that suggests a role for PPARbeta in brain peroxisomal acyl-CoA utilization.