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Differential 3,5,3'-Triiodothyronine-Mediated Regulation of Uncoupling Protein 3 Transcription: Role of Fatty Acids

Dipartimento di Scienze della Vita (P.d.L., A.F., M.R., R.S., A.La.), Seconda Università degli Studi di Napoli, 81100 Caserta, Italy; Dipartimento di Scienze Biologiche ed Ambientali (M.M., E.S., F.G.), Università degli Studi del Sannio, 82100 Benevento, Italy; Dipartimento delle Scienze Biologiche (A.Lo.), Sezione Fisiologia ed Igiene, Università degli Studi di Napoli "Federico II," 80134 Napoli, Italy; and Departament de Bioquímica i Biologia Molecular (R.A., F.V.). Universitat de Barcelona, and CIBER Fisiopatologia de la Obesidad y Nutrición, Instituto de Salud Carlos III, 08028 Barcelona, Spain

Address all correspondence and requests for reprints to: Antonia Lanni, Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, Via Vivaldi 43, 81100 Caserta, Italy. E-mail: antonia.lanni{at}unina2.it.

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 T₃ 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 (PPAR) (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 PPAR 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 ß1 (TRß1), PPAR, or PPAR plus the TR dimerization partner retinoid X receptor . 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.

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