UNCOUPLING PROTEIN-3 IS A MEDIATOR OF THERMOGENESIS REGULATED BY THYROID-HORMONE, BETA-3-ADRENERGIC AGONISTS, AND LEPTIN

Mitochondrial uncoupling proteins (UCPs) are transporters that are imp ortant for thermogenesis, The net result of their activity is the exot hermic movement of protons through the inner mitochondrial membrane, u ncoupled from ATP synthesis, We have cloned a third member of the UCP family, UCP3. UCP3 is expressed at high levels in muscle and rodent br own adipose tissue, Overexpression in yeast reduced the mitochondrial membrane potential, showing that UCP3 is a functional uncoupling prote in, UCP3 RNA levels are regulated by hormonal and dietary manipulation s, In contrast, levels of UCP2, a widely expressed UCP family member, showed little hormonal regulation, In particular, muscle UCP3 levels w ere decreased 3-fold in hypothyroid rats and increased B-fold in hyper thyroid rats, Thus UCP3 is a strong candidate to explain the effects o f thyroid hormone on thermogenesis. White adipose UCP3 levels were gre atly increased by treatment with the beta 3-adrenergic agonist, CL2146 13, suggesting another pathway for increasing thermogenesis, UCP3 mRNA levels were also regulated by dexamethasone, leptin, and starvation, albeit differently in muscle and brown adipose tissue. Starvation caus ed increased muscle and decreased BAT UCP3, suggesting that muscle ass umes a larger role in thermoregulation during starvation, The UCP3 gen e is located close to that encoding UCP2, in a chromosomal region impl icated in previous linkage studies as contributing to obesity.