Abstract
High expression of the peroxisome proliferator-activated receptor alpha (PPARalpha) differentiates brown fat from white, and is related to its high capacity of lipid oxidation. We analyzed the effects of PPARalpha activation on expression of the brown fat-specific uncoupling protein-1 (ucp-1) gene. Activators of PPARalpha 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 PPARalpha 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 PPARgamma-coactivator-1 (PGC-1), which is highly expressed in brown fat, also enhanced the PPARalpha-dependent regulation of the ucp-1 gene. Deletion and point-mutation mapping analysis indicated that the PPARalpha-responsive element was located in the upstream enhancer region of the ucp-1 gene. This -2485/-2458 element bound PPARalpha and PPARgamma from brown fat nuclei. Moreover, this element behaved as a promiscuous responsive site to either PPARalpha or PPARgamma activation, and we propose that it mediates ucp-1 gene up-regulation associated with adipogenic differentiation (via PPARgamma) or in coordination with gene expression for the fatty acid oxidation machinery required for active thermogenesis (via PPARalpha).
Highlights
High expression of the peroxisome proliferator-activated receptor ␣ (PPAR␣) differentiates brown fat from white, and is related to its high capacity of lipid oxidation
This ؊2485/؊2458 element bound PPAR␣ and PPAR␥ from brown fat nuclei. This element behaved as a promiscuous responsive site to either PPAR␣ or PPAR␥ activation, and we propose that it mediates ucp-1 gene up-regulation associated with adipogenic differentiation or in coordination with gene expression for the fatty acid oxidation machinery required for active thermogenesis
Exposure to Wy 14,643 led to a dose-dependent increase in uncoupling protein (UCP)-1 mRNA expression (Fig. 2A) and maximum induction was attained at 10 M, a concentration at which it selectively activates PPAR␣ [4], whereas at 100 M it activates all three PPAR subtypes [10]
Summary
High expression of the peroxisome proliferator-activated receptor ␣ (PPAR␣) differentiates brown fat from white, and is related to its high capacity of lipid oxidation. We analyzed the effects of PPAR␣ activation on expression of the brown fat-specific uncoupling protein-1 (ucp-1) gene. Activation of PPAR␥ promotes HIB-1B brown adipocyte differentiation [17], and up-regulates ucp-1 gene expression [18].
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