Peroxisome proliferator-activated receptor α 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 (PPAR alpha) differentiates brown fat from white, and is related to its high capacity of lipid oxidation, We analyzed the effects of PPAR alpha activation 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 assays indicated that the (-4551)UCP1-CAT construct, containing the 5'-regulatory region of the rat ucp-1 gene, was activated by PPAR alpha co-transfection in a dose-dependent manner and this activation was potentiated by Wy 14,643 and retinoid X receptor alpha, The coactivators CBP and PPAR gamma -coactivator-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 element 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. Moreover, this element behaved as a promiscuous responsive site to either PPAR alpha or PPAR gamma activation, and we propose that it mediates ucp-1 gene up-regulation associated with adipogenic differentiation (via PPAR gamma) or in coordination with gene expression for the fatty acid oxidation machinery required for active thermogenesis (via PPAR alpha).