Peroxisome Proliferator-activated Receptor α Activates Transcription of the Brown Fat Uncoupling Protein-1 Gene

Abstract

High expression of the peroxisome proliferator-activated receptor α (PPARα) differentiates brown fat from white, and is related to its high capacity of lipid oxidation. We analyzed the effects of PPARα activation on expression of the brown fat-specific uncoupling protein-1 (ucp-1) gene. Activators of PPARα 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 PPARα co-transfection in a dose-dependent manner and this activation was potentiated by Wy 14,643 and retinoid X receptor α. The coactivators CBP and PPARγ-coactivator-1 (PGC-1), which is highly expressed in brown fat, also enhanced the PPARα-dependent regulation of the ucp-1 gene. Deletion and point-mutation mapping analysis indicated that the PPARα-responsive element was located in the upstream enhancer region of the ucp-1 gene. This −2485/−2458 element bound PPARα and PPARγ from brown fat nuclei. Moreover, this element behaved as a promiscuous responsive site to either PPARα or PPARγ activation, and we propose that it mediates ucp-1 gene up-regulation associated with adipogenic differentiation (via PPARγ) or in coordination with gene expression for the fatty acid oxidation machinery required for active thermogenesis (via PPARα).