Tissue-Specific 5′ Heterogeneity of PPARα Transcripts and Their Differential Regulation by Leptin

The genes encoding nuclear receptors comprise multiple 5' untranslated exons, which give rise to several transcripts encoding the same protein, allowing tissue-specific regulation of expression. Both human and mouse peroxisome proliferator activated receptor (PPAR) alpha genes have multiple promoters, although their function is unknown. Here we have characterised the rat PPAR alpha promoter region and have identified three alternative PPAR alpha transcripts, which have different transcription start sites owing to the utilisation of distinct first exons. Moreover these alternative PPAR alpha transcripts were differentially expressed between adipose tissue and liver. We show that while the major adipose (P1) and liver (P2) transcripts were both induced by dexamethasone, they were differentially regulated by the PPAR alpha agonist, clofibric acid, and leptin. Leptin had no effect on the adipose-specific P1 transcript, but induced liver-specific P2 promoter activity via a STAT3/Sp1 mechanism. Moreover in Wistar rats, leptin treatment between postnatal day 3-13 led to an increase in P2 but not P1 transcription in adipose tissue which was sustained into adulthood. This suggests that the expression of the alternative PPAR alpha transcripts are in part programmed by early life exposure to leptin leading to persistent change in adipose tissue fatty acid metabolism through specific activation of a quiescent PPAR alpha promoter. Such complexity in the regulation of PPAR alpha may allow the expression of PPAR alpha to be finely regulated in response to environmental factors.