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 enc ode a new member of the family of uncoupling proteins, is preferentially ex pressed in skeletal muscle and has been related to phenotypes of obesity an d type 2 diabetes. We have established that during mouse ontogeny, the expr ession 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 a ctivators of peroxisome proliferator-activated receptors (PPARs), such as c lofibrate, bezafibrate, or (4-chloro-6-(2,3-xylidine)-pirimidinylthio)aceti c acid (WY 14,643), mimics the action of food intake on UCP-3 gene expressi on. The specific ligand of PPAR-alpha WY 14,643 induces UCP-3 gene expressi on 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 th e PPAR-gamma gene is undetectable. PPAR-gamma gene expression is developmen tally regulated in muscle as it is first expressed at birth, just before UC P-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 expr ess PPAR-a. It is proposed that the UCP-3 gene is predominantly regulated i n neonatal muscle by PPAR-alpha activation.