Differential 3,5,3′-triiodothyronine-mediated regulation of uncoupling protein 3 transcription: Role of fatty acids

T3 regulates energy metabolism by stimulating metabolic rate and decreasing metabolic efficiency. The discovery of mitochondrial uncoupling protein 3 (UCP3), its homology to UCP1, and regulation by T3 rendered it a possible molecular determinant of the action of T3 on energy metabolism, but data are controversial. This controversy may in part be attributable to discrepancies observed between the regulation by T3 of UCP3 expression in rats, humans, and mice. To clarify this issue, we studied 1) the induction kinetics of the UCP3 gene by T3 in rat skeletal muscle, 2) the influence of fatty acids, and 3) the structure and regulation of the various UCP3 promoters by T3. Within 8 h of single-dose T 3 administration, hypothyroid rats showed a rise in serum fatty acid levels concomitant with a rapid increase in UCP3 expression in gastrocnemius muscle, followed by inductions of peroxisome proliferator activated receptor δ (PPARδ) (within 24 h) and PPAR target gene expression (after 24 h). This T3-induced early UCP3 expression depended on fatty acid-PPAR signaling because depleting serum fatty acid levels abolished its expression, restorable by administration of the PPARδ agonist L165,041 (4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]acetic acid). In transfected rat L6 myoblasts, only the rat UCP3 promoter positively responded to T3 and L165,041 together in the presence of MyoD, thyroid hormone receptor β1 (TRβ1), PPARδ, or PPARδ plus the TR dimerization partner retinoid X receptor α. All promoters share a response element common to TR and PPAR (TRE 1), but the observed species differences may be attributable to different localizations of the MyoD response element, which in the rat maps to exon 1. Copyright © 2007 by The Endocrine Society.