Developmental and tissue-specific involvement of peroxisome proliferator-activated receptor-α in the control of mouse uncoupling protein-3 gene expression

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 alpha 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.