Differential regulation of mouse uncoupling proteins among brown adipose tissue, white adipose tissue, and skeletal muscle in chronic beta 3 adrenergic receptor agonist treatment.

Uncoupling proteins (UCPs) are inner mitochondrial membrane transporters that dissipate the proton gradient, releasing stored energy as heat, without coupling to other energy-consuming processes. Therefore, the UCPs are thought to be important determinants of the metabolic efficiency. To elucidate relationships between the UCPs expressions and insulin sensitivity improvement, we treated KK-Ay mice with beta 3 adrenergic receptor agonist for 21 days and examined the changes of the UCPs mRNA expressions in various tissues. Chronic treatment of a specific beta 3 adrenergic receptor agonist, CL316,243 (0.2 mg/kg body weight/day s.c.) markedly increased the expressions of uncoupling protein 1 (UCP1), uncoupling protein 2 (UCP2), and uncoupling protein 3 (UCP3) by 14-fold, 6-fold, and 16-fold, respectively, in the brown adipose tissue (BAT). The UCP1 and UCP3 mRNA expressions in the white adipose tissue (WAT) were also increased by 12-fold and 9-fold, respectively, but the UCP2 mRNA expression was not changed in this tissue. Interestingly, the UCP2 and UCP3 mRNA expressions were strikingly decreased in the skeletal muscle and heart. Particularly, the UCP3 mRNA expression level in the skeletal muscle was dropped to 10% of that of the saline-treated control mice, indicating that the UCPs mRNA expressions are regulated in tissue-specific ways. The concentrations of plasma insulin and circulating free fatty acid (FFA) were significantly decreased, suggesting that they correlate with the reductions of the UCP2 and UCP3 mRNA expressions in the skeletal muscle and heart. It has been thought that the UCP1 and UCP3 mRNA expressions in the BAT and WAT are mainly controlled by the hypothalamus via the sympathetic nervous system, while the levels of insulin, FFA or both may play important roles in the control of the UCP2 and UCP3 mRNA expressions in the skeletal muscle an heart.