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Endocrinology, doi:10.1210/en.2006-0226
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Endocrinology Vol. 147, No. 10 4695-4704
Copyright © 2006 by The Endocrine Society

Developmental and Tissue-Specific Involvement of Peroxisome Proliferator-Activated Receptor-{alpha} in the Control of Mouse Uncoupling Protein-3 Gene Expression

Neus Pedraza1, Meritxell Rosell1, Joan Villarroya, Roser Iglesias, Frank J. Gonzalez, Gemma Solanes and Francesc Villarroya

Departament de Bioquímica i Biologia Molecular (N.P., M.R., J.V., R.I., G.S., F.V.), Universitat de Barcelona, E-08028 Barcelona, Spain; and Laboratory of Metabolism (F.J.G.), National Cancer Institute, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. G. Solanes, Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Avda Diagonal 645, E-08028 Barcelona, Spain. E mail: gsolanes{at}ub.edu.

Uncoupling protein-3 (UCP3) is a member of the mitochondrial carrier family expressed preferentially in skeletal muscle and heart. It appears to be involved in metabolic handling of fatty acids in a way that minimizes excessive production of reactive oxygen species. Fatty acids are powerful regulators of UCP3 gene transcription. We have found that the role of peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) on the control of UCP3 gene expression depends on the tissue and developmental stage. In adults, UCP3 mRNA expression is unaltered in skeletal muscle from PPAR{alpha}-null mice both in basal conditions and under the stimulus of starvation. In contrast, UCP3 mRNA is down-regulated in adult heart both in fed and fasted PPAR{alpha}-null mice. This occurs despite the increased levels of free fatty acids caused by fasting in PPAR{alpha}-null mice. In neonates, PPAR{alpha}-null mice show impaired UCP3 mRNA expression in skeletal muscle in response to milk intake, and this is not a result of reduced free fatty acid levels. The murine UCP3 promoter is activated by fatty acids through either PPAR{alpha} or PPAR{delta} but not by PPAR{gamma} or retinoid X receptor alone. PPAR{delta}-dependent activation could be a potential compensatory mechanism to ensure appropriate expression of UCP3 gene in adult skeletal muscle in the absence of PPAR{alpha}. However, among transcripts from other PPAR{alpha} and PPAR{delta} target genes, only those acutely induced by milk intake in wild-type neonates were altered in muscle or heart from PPAR{alpha}-null neonates. Thus, PPAR{alpha}-dependent regulation is required for appropriate gene regulation of UCP3 as part of the subset of fatty-acid-responsive genes in neonatal muscle and heart.




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