Activators of peroxisome proliferator-activated receptor-alpha induce the expression of the uncoupling protein-3 gene in skeletal muscle: a potential mechanism for the lipid intake-dependent activation of uncoupling protein-3 gene expression at birth.
The recently identified uncoupling protein-3 (UCP-3) gene, predicted to encode a new member of the family of uncoupling proteins, is preferentially expressed in skeletal muscle and has been related to phenotypes of obesity and type 2 diabetes. We have established that during mouse ontogeny, the expression of the UCP-3 gene is switched on in skeletal muscle just after birth. The induction of UCP-3 gene expression is dependent on the initiation of suckling and particularly on lipid intake. Treatment of newborn mice with activators of peroxisome proliferator-activated receptors (PPARs), such as clofibrate, bezafibrate, or (4-chloro-6-(2,3-xylidine)-pirimidinylthio)acetic acid (WY 14,643), mimics the action of food intake on UCP-3 gene expression. The specific ligand of PPAR-alpha WY 14,643 induces UCP-3 gene expression in a time- and dose-dependent manner, whereas the thiazolidinedione BRL 49653, specific for PPAR-gamma, has no effect. These treatments act without altering circulating free fatty acids. During development, skeletal muscle expresses constitutive levels of PPAR-delta mRNA, whereas expression of the PPAR-gamma gene is undetectable. PPAR-alpha gene expression is developmentally regulated in muscle as it is first expressed at birth, just before UCP-3 gene induction occurs. The induction of UCP-3 gene expression by WY 14,643 is impaired in skeletal muscle of premature neonates, which do not express PPAR-alpha. It is proposed that the UCP-3 gene is predominantly regulated in neonatal muscle by PPAR-alpha activation.
Brun
S
S
Department of Biochemistry and Molecular Biology, University of Barcelona, Spain.
Carmona
M C
MC
Mampel
T
T
Viñas
O
O
Giralt
M
M
Iglesias
R
R
Villarroya
F
F
D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002994:Clofibrate / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004435:Eating; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007473:Ion Channels; D020738:Leptin; D008297:Male; D051379:Mice; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000187:drug effects / Q000254:growth & development*; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D015533:Transcriptional Activation; D000071247:Uncoupling Protein 3
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005230:Fatty Acids, Nonesterified; D000960:Hypolipidemic Agents; D007473:Ion Channels; D020738:Leptin; D024101:Mitochondrial Proteins; D020025:Peroxisome Proliferators; D011506:Proteins; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; D000077154:Rosiglitazone; C006253:pirinixic acid; D002994:Clofibrate; D001629:Bezafibrate