Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor α in the adult rodent heart

Relatively little is known concerning the regulation of uncoupling proteins (UCPs) in the heart. We investigated in the adult rodent heart 1) whether changes in workload, substrate supply, or cytokine (TNF-alpha) administration affect UCP-2 and UCP-3 expression, and 2) whether peroxisome proliferator-activated receptor alpha (PPAR alpha) regulates the expression of either UCP-2 or UCP-3. Direct comparisons were made between cardiac and skeletal muscle. UCP-2, UCP-3, and PPAR alpha expression were reduced when cardiac workload was either increased (pressure overload by aortic constriction) or decreased (mechanical unloading by heterotopic transplantation). Similar results were observed during cytokine administration. Reduced dietary fatty acid availability resulted in decreased expression of both cardiac UCP-2 and UCP-3. However, when fatty acid (the natural ligand for PPAR alpha) supply was increased thigh-fat feeding, fasting, and STZ-induced diabetes), cardiac UCP-3 but not UCP-2 expression increased. Comparable results were observed in rats treated with the specific PPAR alpha agonist WY-14,643, The level of cardiac UCP-3 but not UCP-2 expression was severely reduced (20-fold) in PPAR alpha (-/-) mice compared to wild-type mice. These results suggest that in the adult rodent heart, UCP-3 expression is regulated by PPAR alpha, In contrast, cardiac UCP-2 expression is regulated in part by a fatty acid-dependent, PPAR alpha -independent mechanism.