THE EFFECTS OF THE BETA(3)-ADRENOCEPTOR AGONIST BRL-35135 ON UCP ISOFORM MESSENGER-RNA EXPRESSION

The mitochondrial uncoupling protein UCP-1 uncouples respiration from ATP synthesis in brown adipose tissue (BAT) and thus energy is dissipa ted as heat. Recently two further isoforms have been identified which may play a similar role in other tissues. We have determined the effec ts of the rodent-selective beta(3)-adrenoceptor (beta(3)-AR) agonist B RL 35135, on beta(3)-AR and UCP mRNA levels in tissues from lean and o bese (fa/fa) Zucker rats. beta(3)-AR mRNA levels were reduced in fa/fa white (WAT) and brown (BAT) adipose tissue relative to levels in lean littermates. BRL 35135 treatment increased expression levels of beta( 3)-AR mRNA in both genotypes. UCP-2 and UCP-3 mRNA levels in BAT, WAT and skeletal muscle were reduced by 2-3 fold in the fa/fa rats relativ e to the lean rats. We confirm that BRL 35135 increases BAT UCP-1 mRNA in lean rats, and and that BAT UCP-3 mRNA was reduced 3.2 fold, with no changes in UCP-2 expression. In WAT BRL 35135 increased UCP-2 and U CP-3 expression 2-3 fold in both lean and fa/fa rats. In lean rats, sk eletal muscle UCP-3 mRNA was increased 2.3 fold by BRL 35135 whereas U CP-2 was reduced by 2.2 fold. BRL 35135 had no effects on UCP-2 and UC P-3 expression in skeletal muscle of the fa/fa rats. Our results demon strate that mechanisms regulating UCP isoform synthesis in fa/fa rats are impaired and that WAT could be involved in the thermogenic respons e of BRL 35135. (C) 1998 Academic Press.