As judged by the response of uncoupling protein and key enzymes, brown adipose tissue (BAT) is highly dependent upon the local generation of T3 catalyzed by the tissue type II T4 5′-deiodinase (5′D-II). In hypothyroid rats treated with T3 or T4, the capacity to withstand cold seems better correlated with the normalization of BAT responses than with the liver thyroid status. 5′D-II is activated by cold via sympathetic nervous system (SNS) stimulation, and the activation generates enough T3 to nearly saturate BAT nuclear T3 receptors (NTR) in euthyroid rats. In hypothyroidism, 5′D-II is highly stimulated by the SNS and hypothyroxinemia. In the present studies we have taken advantage of this situation to test 1) the capacity of 5′D-II to maintain nuclear T3 in rats with various degrees of hypothyroxinemia, and 2) the hypothesis that thyroid hormone-dependent BAT-facultative thermogenesis, rather than the effect of thyroid hormone on obligatory thermogenesis (basal metabolic rate), is the basic mechanism by which thyroid hormone confers protection against acute cold exposure. We treated methimazole-blocked rats (undetectable plasma T4 and T3) for a week with either subreplacement doses of T4 (0.5, 1, 2, and 4 μg/kg·day) or replacement doses of T4 or T3 (8 or 3 μg/kg·day, respectively). Sources and content of BAT nuclear T3 were studied at 25 C and after 48 h at 4 C by labeling the plasmaborne T3 (T3[T3]) with [131I]T3 and the locally generated T3 (T3[T4]) with [125I]T4. Neither the kinetics of nuclear-plasma exchange of T3[T3], the time of appearance of T3[T4] in BAT nuclei, nor NTR maximal binding capacity (0.71 ng T3/mg DNA) was affected by hypothyroidism. Kinetic analyses indicated a maximal BAT NTR occupancy of 40% at euthyroid serum T3 concentrations if T4 is not present. Replacement with T4 normalized both serum T4 and T3, while replacement with T3 normalized serum T3; for all other doses of T4, serum T4 and T3 concentrations were predictably related to the dose. 5′D-II activity decreased with increasing doses of T4, but for each dose of T4, this activity was 2-4 times greater at 4 C than at 25 C. BAT NTR occupancy normalized with 2 μg T4/kg in rats maintained at 25 C and with 4 μg T4/kg in cold-exposed rats, although in neither condition were serum T4 and T3 normalized nor more than 30% of NTR occupied by plasma T3. The thermogenic response to cold, measured as an increase in oxygen consumption (QO2), was significantly greater in T4-replaced than in T3-replaced rats. Two micrograms of T4/kg/day sufficed to normalize the response of QO2 to cold. Prazosin, which blunts the adrenergic-induced stimulation of 5′D-II, caused a marked reduction in T3[T4] and blunted the T4-dependent increase in QO2. We conclude that the protective effect of thyroid hormone against cold-induced hypothermia is largely the result of the stimulation of facultative thermogenesis in BAT, stimulation in which the adrenergic activation of BAT 5′D-II plays an essential role. This enzyme is, furthermore, of adaptive value in hypothyroidism by allowing a normal thermogenic response to cold in the face of substantial reductions in plasma T4.
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