Differential 3,5,3'-triiodothyronine-mediated regulation of uncoupling protein 3 transcription: role of Fatty acids.
T(3) 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 T(3) rendered it a possible molecular determinant of the action of T(3) on energy metabolism, but data are controversial. This controversy may in part be attributable to discrepancies observed between the regulation by T(3) of UCP3 expression in rats, humans, and mice. To clarify this issue, we studied 1) the induction kinetics of the UCP3 gene by T(3) in rat skeletal muscle, 2) the influence of fatty acids, and 3) the structure and regulation of the various UCP3 promoters by T(3). 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 delta (PPARdelta) (within 24 h) and PPAR target gene expression (after 24 h). This T(3)-induced early UCP3 expression depended on fatty acid-PPAR signaling because depleting serum fatty acid levels abolished its expression, restorable by administration of the PPARdelta 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 T(3) and L165,041 together in the presence of MyoD, thyroid hormone receptor beta1 (TRbeta1), PPARdelta, or PPARdelta plus the TR dimerization partner retinoid X receptor alpha. 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.
de Lange
Pieter
P
Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, Via Vivaldi 43, 81100 Caserta, Italy.
Feola
Anna
A
Ragni
Maurizio
M
Senese
Rosalba
R
Moreno
Maria
M
Lombardi
Assunta
A
Silvestri
Elena
E
Amat
Ramon
R
Villarroya
Francesc
F
Goglia
Fernando
F
Lanni
Antonia
A
D000085:Acetates / Q000494:pharmacology; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D005091:Exons / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007037:Hypothyroidism / Q000188:drug therapy / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology; D017570:MyoD Protein / Q000235:genetics; D047494:PPAR delta / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D010170:Palmitoyl-CoA Hydrolase / Q000235:genetics; D010636:Phenols / Q000494:pharmacology; D010642:Phenoxyacetates; D011401:Promoter Regions, Genetic / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D047490:Retinoid X Receptor alpha / Q000235:genetics; D013045:Species Specificity; D037042:Thyroid Hormone Receptors beta / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D014284:Triiodothyronine / Q000378:metabolism* / Q000494:pharmacology*; D000071247:Uncoupling Protein 3; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; D000085:Acetates; D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017570:MyoD Protein; D047494:PPAR delta; D010636:Phenols; D010642:Phenoxyacetates; D047490:Retinoid X Receptor alpha; D037042:Thyroid Hormone Receptors beta; C000604392:UCP3 protein, human; C000604393:Ucp3 protein, mouse; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D014284:Triiodothyronine; D002334:Carnitine O-Palmitoyltransferase; D010170:Palmitoyl-CoA Hydrolase