PPARalpha activation by Wy 14643 induces transactivation of the rat UCP-1 promoter without increasing UCP-1 mRNA levels and attenuates PPARgamma-mediated increases in UCP-1 mRNA levels induced by rosiglitazone in fetal rat brown adipocytes.

Rodent brown adipocytes express peroxisome proliferator activated receptor-alpha (PPARalpha) and PPARgamma and while the rodent uncoupling protein-1 (UCP-1) gene contains a putative peroxisome proliferator response element (PPRE), only PPARgamma activation by thiazolidinediones increase UCP-1 mRNA levels. We have investigated this phenomenon in foetal rat brown adipocytes (FBA) and show that although transactivation occurs in FBA containing a plasmid encoding 4.5kb of the 5'-flanking region of the rat UCP-1 promoter ((-4551)-UCP-1-CAT) treated with either the selective PPARgamma agonist rosiglitazone (1.0 microM) or the selective PPARalpha agonist Wy 14643 (10.0 microM), only rosiglitazone induced transcription of UCP-1 mRNA. Furthermore, Wy 14643 (10 and 100.0 microM) abolished rosiglitazone-induced UCP-1 mRNA induction in spite of a transactivation event occurring with the combination treatment. Thus in FBA PPARalpha-activation with Wy 14643 elicits a "blind" transactivation of the UCP-1 promoter which can prevent PPARgamma-mediated UCP-1 mRNA transcription either by competition for the PPRE or by an unidentified post-transcriptional event. Copyright 1999 Academic Press.