Peroxisome proliferator-activated receptor alpha activates transcription of the brown fat uncoupling protein-1 gene - A link between regulation of the thermogenic and lipid oxidation pathways in the brown fat cell

High expression of the peroxisome proliferator-activated receptor alpha (PP AR alpha) differentiates brown fat from white, and is related to its high c apacity of lipid oxidation, We analyzed the effects of PPAR alpha activatio n on expression of the brown fat-specific uncoupling protein-1 (ucp-1) gene . Activators of PPAR alpha increased UCP-1 mRNA levels severalfold both in primary brown adipocytes and in brown fat in vivo. Transient transfection a ssays indicated that the (-4551)UCP1-CAT construct, containing the 5'-regul atory region of the rat ucp-1 gene, was activated by PPAR alpha co-transfec tion in a dose-dependent manner and this activation was potentiated by Wy 1 4,643 and retinoid X receptor alpha, The coactivators CBP and PPAR gamma -c oactivator-1 (PGC-1), which is highly expressed in brown fat, also enhanced the PPAR alpha -dependent regulation of the ucp-1 gene. Deletion and point -mutation mapping analysis indicated that the PPAR alpha -responsive elemen t was located in the upstream enhancer region of the ucp-1 gene. This -2485 /-2458 element bound PPAR alpha and PPAR gamma from brown fat nuclei. Moreo ver, this element behaved as a promiscuous responsive site to either PPAR a lpha or PPAR gamma activation, and we propose that it mediates ucp-1 gene u p-regulation associated with adipogenic differentiation (via PPAR gamma) or in coordination with gene expression for the fatty acid oxidation machiner y required for active thermogenesis (via PPAR alpha).