As bstract. Local 5'-deiodination of serum thyroxine (T4) is the main source of triiodothyronine (T3) for the brain. Since we noted in previous studies that the cerebral cortex of neonatal rats tolerated marked reductions in serum T4 without biochemical hypothyroidism, we examined the in vivo T4 and T3 metabolism in that tissue and in the cerebellum of euthyroid and hypothyroid 2-wk-old rats. We also assessed the contribution of enhanced tissue T4 to T3 conversion and decreased T3 removal from the tissues to the T3 homeostasis in hypothyroid brain. Congenital and neonatal hypothyroidism was induced by adding methimazole to the drinking water. Serum, cerebral cortex (Cx), cerebellum (Cm), liver (L) and kidney (R) concentrations of 1251-T4, '25I-T3(T4), and 13'I-T3 were measured at various times after injecting '251-T4 and 13'I-T3. The rate of T3 removal from the tissues was measured after injecting an excess of anti-T3-antibody to rats previously injected with tracer T3. In euthyroid rats, fractional turnover rates of T3 per hour were: Cx, 0.26±0.02 (SE); Cm, 0.20±0.02; L, 0.98±0.07; R, 0.97±0.12; and the calculated unidirectional plasma T3 clearance by these tissues were, in milliliters per gram per hour: Cx = 0.38, Cm = 0.32, L = 5.0, and R = 5.6. In hypothyroidism, the fractional removal rates and clearances were reduced in all tissues, in cortex and cerebellum by 70%, and in liver and kidney ranging from 30 to 50%. While >80% May 24, 1984. of the '25I-T3(T4) in the brain tissues of euthyroid rats was locally produced, in hypothyroid cerebral cortex and cerebellum the integrated concentrations of 1251. T3(T4) were 2.7-and 1.5-fold greater than in euthyroid rats. In the Cx, this response resulted from an approximately sixfold increase in fractional conversion and an approximately fourfold decrease in T3 removal rate hampered by a decreased uptake of T4 from plasma, whereas in Cm the response resulted only from the reduced T3 removal rate. In euthyroid rats, the calculated production rate of T3 in nanograms per gram per hour by the Cx was 0.96 and 0.89 by the Cm, which on a per organ basis equals 15 and 2%, respectively, of the extrathyroidal production rate as assessed in the body pool exchanging with plasma. Several conclusions can be drawn: (a) Production of T3 by developing brain is a very active process in agreement with the need of thyroid hormones during this period. (b) The brainplasma exchange of T3 is slow compared with that of L or R. (c) This, along with the active local production, explains the predominant role of the latter as a source of T3 for the brain. (d) In hypothyroidism, the Cx is protected by an increase in the efficiency of T4 to T3 conversion and a prolonged residence time of T3 in the tissue, whereas the Cm is protected only by the latter. Because of the large fraction of the tissue T3 produced locally and the active turnover rate of T3 in the brain, reductions in T3 removal rate are of utmost importance for T3 homeostasis in these tissues.

We have examined the uncoupling (UCP) protein gene expression in euthyroid and hypothyroid rats. UCP mRNA levels were estimated by northern blot analysis of total RNA from brown adipose tissue (BAT). Stimuli were endogenous (cold) and exogenous norepinephrine (NE), isoproterenol, T3, and T4. While the euthyroid rats UCP mRNA levels increase 2- to 3-fold by 2 h after NE or overnight cold exposure, these stimuli and isoproterenol are ineffective in hypothyroid rats. One single dose of T4, equal to the daily production rate, brings about a normal response in hypothyroid rats exposed to cold overnight. Hypothyroid rats recover their responsiveness to NE approximately 4 h after a receptor saturating dose of T3. On the other hand, such a dose of T3 induces a 3- to 4-fold increase in UCP mRNA levels in hypothyroid rats without the need of exogenous NE, and this response is not reduced by raising ambient temperature to thermoneutrality (28 C). However, the following evidence indicates that T3 requires adrenergic input to stimulate the accumulation of UCP mRNA: first, euthyroid animals maintained at 28 C do not respond to such a treatment. Second, when T3 was injected to hypothyroid rats with unilaterally denervated BAT, only the intact side responded to T3 with an elevation of the UCP mRNA levels, but both sides remained responsive to T3 + NE.(ABSTRACT TRUNCATED AT 250 WORDS)

Earlier studies have shown larger increments in serum T3 in 2-week-old congenitally hypothyroid rats than in euthyroid controls after injections of small doses of T4. Since hepatic and renal 5'-deiodination of T4 to T3 in vitro (5' D-I) is reduced during the neonatal period and in hypothyroidism, those results suggest that there may be major changes in the distribution and metabolism of T3 or that an alternative enzymatic pathway is the predominant source of extrathyroidally produced T3 in these rats. The alternative pathway, 5' D-II, is a relatively minor source of serum T3 in adult euthyroid rats, but the contribution of this pathway to the extrathyroid T3 pool during the neonatal period and in hypothyroxinemia is not known. Consequently, we studied [125I]T4 and [131I]T3 kinetics and fractional T4 to T3 conversion in 2-week-old euthyroid and hypothyroid rats and then explored the source of circulating T3 by manipulating 5' D-I activity with propylthiouracil and that of 5' D-II with thyroid hormone. The plasma clearance rate of T4 was increased in hypothyroid rats, a difference entirely accounted for by the faster fractional rate of irreversible removal in the hypothyroid pups. Plasma clearance rate of T3 was reduced in hypothyroid rats owing to the reduced volume of distribution of T3. Fractional T4 to T3 conversion was 2- to 3-fold higher in euthyroid or hypothyroid neonates than in adult rats. In euthyroid rats the serum concentration of T4 was 36 +/- 1 (SEM) ng/ml and that of T3 0.61 +/- 0.03 ng/ml, and the production rates were 432 and 159 ng day-1 30 g-1 BW for T4 and T3, respectively. About 80% of the T3 in euthyroid neonates was produced extrathyroidally . These findings are inconsistent with hepatic and renal 5' D-I being the main source of serum T3 in 2-week-old rats. In fact, liver and kidney 5' D-I activities were 40% and 65% of the corresponding adult values in euthyroid neonates, and in hypothyroid pups were further reduced to 15% and 17%. In contrast, 5' D-II, previously reported to be high in central nervous tissue and pituitary, was 7-10-fold higher in brown adipose tissue (BAT) of hypothyroid pups than in that of euthyroid ones.(ABSTRACT TRUNCATED AT 400 WORDS)