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.

Abstract	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.
Authors	S Brun, M C Carmona, T Mampel, O Viñas, M Giralt, R Iglesias, F Villarroya
Journal	Diabetes (Diabetes) Vol. 48 Issue 6 Pg. 1217-22 (Jun 1999) ISSN: 0012-1797 [Print] United States
PMID	10342807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Carrier Proteins DNA-Binding Proteins Fatty Acids, Nonesterified Hypolipidemic Agents Ion Channels Leptin Mitochondrial Proteins Peroxisome Proliferators Proteins Pyrimidines RNA, Messenger Receptors, Cytoplasmic and Nuclear Recombinant Proteins Thiazoles Thiazolidinediones Transcription Factors Ucp3 protein, mouse Uncoupling Protein 3 Rosiglitazone pirinixic acid Clofibrate Bezafibrate
Topics	Animals Bezafibrate (pharmacology) Carrier Proteins (biosynthesis, genetics) Clofibrate (pharmacology) DNA-Binding Proteins (metabolism) Eating Fatty Acids, Nonesterified (blood) Female Gene Expression Regulation, Developmental (drug effects) Hypolipidemic Agents (pharmacology) Ion Channels Leptin Male Mice Mitochondria, Muscle (drug effects, metabolism) Mitochondrial Proteins Muscle Development Muscle, Skeletal (drug effects, growth & development) Peroxisome Proliferators (pharmacology) Proteins (genetics, pharmacology) Pyrimidines (pharmacology) RNA, Messenger (metabolism) Receptors, Cytoplasmic and Nuclear (agonists, metabolism) Recombinant Proteins (pharmacology) Rosiglitazone Thiazoles (pharmacology) Thiazolidinediones Transcription Factors (agonists, metabolism) Transcriptional Activation Uncoupling Protein 3

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