Intracellular conversion of thyroxine to triiodothyronine is required for the optimal thermogenic funciton of brown adipose tissue

The effect of thyroxine (T₄) and triiodothyronine (T₃) on the expression of uncoupling protein (UCP) in rat brown adipose tissue (BAT) has been examined. Thyroidectomzied rats have a threefold reduction in basal UCP levels. When exposed to cold, they become hypothermic and show a fivefold lower response of UCP than euthyroid controls. T₃ augments the basal levels and the response of UCP and its mRNA to cold in a dose-dependent manner. However, to normalize the response of UCP, T₃ has to be given in a dosage that produces systemic hyperthyroidism. Mere T₃ replacement corrects the systemic hypothyroidism but not the hypothermia or the low levels of UCP. In contrast, replacement doses of T₄ prevent the hypothermia and correct the UCP level. Both effects of T₄ are blocked by preventing T₄ to T₃ conversion in BAT. Thus, the optimal UCP response to cold and protection against hypothermia require a high BAT T₃ concentration, which is attained from euthyroid levels of T₄ via the activation of the BAT T₄ 5' deiodinase during cold exposure, but not from euthyroid plasma T₃ levels.