Iodothyronine-5'-deiodinase activity in progenies of hypothyroid rats

Iodothyronine-5'-deiodinase activity (I-5'DA) was measured in the progenies of control rats, hypothyroid (Tx) rats, and hypothyroid treated with ovine GH (Tx + GH) during gestation. The enzyme was measured in cerebral cortex and cerebellum at 22 days gestation and at 5, 10, 30 and 60 days postpartum. In addition, the pituitary I-5'-DA was assessed in the postnatal animals. The experiments were undertaken because the tissues of the progenies of rats that were hypothyroid during pregnancy appeared in many ways to resemble those of hypothyroid animals, even at ages when serum thyroxine (T4) and triiodothyronine (T3) levels were normal. It was found that the progenies of Tx mothers had low liver 5'-deiodinase activities. This is a likely cause of the low serum T3 levels with normal T4 levels seen in these progenies in the neonatal period. Cerebral and cerebellar 5'-deiodinase activities were low in these progenies during the thyroid hormone-dependent perinated period of brain development. The progenies of GH-treated Tx dams had higher enzyme activities than the progenies of untreated Tx dams. These pups from GH-treated Tx mothers have been shown previously to have significantly less neurological impairment than the progenies of untreated Tx mothers. As most of the brain intracellular T3 is produced in situ, a functional thyroid deficiency could result from such a 5'-deiodinase deficiency. As the deiodinase deficiency was still seen in the progenies of Tx mothers at 60 days of age, such a deficiency could explain why, even though serum T4 and T3 levels were normal, brain metabolism was in many ways characteristic of hypothyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)     

EFFECT OF THYROID DEFICIENCY ON THE LEVELS OF SEVERAL ENZYMES IN RAT BRAIN

—Activities of acid phosphatase, alkaline phosphatase and β-glucuronidase have been estimated in the brain tissues, using various subcellular particles, in growing thyroidectomized rats and also using cytoplasmic extracts free from debris and nuclear fraction in young hypothyroid animals. Hepatic glucose-6-phosphate dehydrogenase activity was markedly reduced after thyroidectomy but the enzyme was brought back to normal levels by thyroxine treatment. There was no change, however, in the activity of neural glucose-6-phosphate dehydrogenase after thyroidectomy. In the thyroidectomized animals an increase only in the free acid phosphatase activity in the neural synaptosomes was found and this increase in activity was not counteracted by administration of thyroxine. In the hypothyroid young animal β-glucuronidase, acid phosphatase and alkaline phosphatase activities were found to be affected during development.     

Effects of altered thyroid status on beta-adrenergic actions on skeletal muscle glycogen metabolism

The effects of hypothyroidism on glycogen metabolism in rat skeletal muscle were studied using the perfused rat hindlimb preparation. Three weeks after propylthiouracil treatment, serum thyroxine was undetectable and muscle glycogen and Glc-6-P were decreased. Basal and epinephrine-stimulated phosphorylase a and phosphorylase b kinase activities were also significantly reduced, as were epinephrine-stimulated cAMP accumulation and cAMP-dependent protein kinase activity. Conversely, basal and epinephrine-stimulated glycogen synthase I activities were significantly higher while the Ka of the enzyme for Glc-6-P was lower in hypothyroid animals. Propylthiouracil-treated rats also had increased phosphoprotein phosphatase activities towards phosphorylase and glycogen synthase and decreased activity of phosphatase inhibitor 1. beta-Adrenergic receptor binding and basal and epinephrine-stimulated adenylate cyclase activities were reduced in muscle particulate fractions from hypothyroid rats. Administration of triiodothyronine to rats for 3 days after 3 weeks of propylthiouracil treatment restored the altered metabolic parameters to normal. It is proposed that the decreased beta-adrenergic responsiveness of the enzymes of glycogen metabolism in hypothyroid rat skeletal muscle is due to increased activity of phosphoprotein phosphatases and to reduced beta-adrenergic receptors and adenylate cyclase activity.     

Ontogenic pattern of dopamine, acetylcholine, and acetylcholinesterase in the brains of normal and hypothyroid rats.

The influence of neonatal thyroidectomy (Tx) on developmental changes in dopamine (DA), acetylcholine (ACh), and acetylcholinesterase (AChE) was studied in the whole brain of rats. In control animals, brain levels of ACh gradually increased and attained adult values at the 70th day. In contrast, AChE activity showed a rapid increase between the 7th and 30th days. Levels of DA were low during the early postnatal life but markedly increased to reach adult values of 1.47 mug/g at the 30th day, after which no further enhancement was noted. Neonatal Tx interfered with the normal growth of the animals, decreased brain weights, and markedly influenced the developmental pattern of both DA and ACh in the brain. The concentration of DA in 30-day-old hypothyroid rats was 46% of the control values. In contrast, brain ACh levels in Tx rats were consistently above those seen in controls, being significantly higher, by 49 and 64%, at 15 and 30 days, respectively. Activity of AChE in brains of hypothyroid animals was not significantly different from that in controls. Treatment of Tx rats with thyroid hormone virtually restored the levels of DA and ACh to values in control animals.     

Thyroid hormones and the precocious induction of hepatic glucokinase in the neonatal rat

1. Oral intubation of glucose is more effective than intraperitoneal injection in inducing the premature appearance of hepatic glucokinase in suckling rats. 2. The inducing effect of glucose is enhanced by treatment of the animals 12 h or more earlier with 1 microgram triiodothyronine/g body weight. 3. Low but significant activities of glucokinase appear at the normal time of development in hypothyroid neonatal rats. Intubation of glucose into 13-day-old and 24-day-old hypothyroid results in the rapid appearance of glucokinase similar to that in normal animals treated likewise. 4. The enhancing effect of thyroid hormones on glucokinase induction by glucose does not necessarily mean that the normal postnatal increase in plasma thyroid hormones is essential for the normal appearance of glucokinase activity at the time of weaning. Other possible explanations are discussed.     

Angiotensinase activity in hypothalamus and pituitary of hypothyroid, euthyroid and hyperthyroid adult male rats.

A local renin-angiotensin system (RAS) that may be involved in their regulatory functions has been identified in hypothalamus and pituitary. Altered thyroid status induces modifications in the secretory function of hypothalamus and pituitary. However, few studies have analyzed the role of the RAS in hypothalamus and, to our knowledge, there is no data on the pituitary RAS during thyroid dysfunction. In the present study, angiotensinase activities (glutamyl, aspartyl and alanyl aminopeptidase: GluAP, AspAP and AlaAP, respectively) were studied in hypothalamus and in the anterior and posterior lobes of pituitary of euthyroid, hypothyroid and hyperthyroid adult male rats. In the anterior pituitary, compared with euthyroid and hyperthyroid rats, hypothyroid animals showed a highly significant increase of GluAP and AspAP activities; the percentage increase in GluAP was markedly higher than the percentage increase in AspAP. This suggests an increased metabolism of angiotensin (Ang) I and Ang II to des-Asp 1-Ang I and Ang III, respectively. We also observed an increase of Ang III-degrading activity (AlaAP) in the hypothalamus of hyperthyroid rats in soluble fraction. Increased Ang I and Ang II metabolism in the anterior pituitary of hypothyroid rats and increased metabolism of Ang III in the hypothalamus of hyperthyroid animals may be related to alterations in the secretory function of hypothalamus and pituitary in these thyroid dysfunctions.     

Modulation by thyroid status of cyclic AMP-dependent and Ca2+-dependent mechanisms of hormone action in rat liver cells. Possible involvement of two different transduction mechanisms in alpha 1-adrenergic action

The actions of hormones which are associated to cAMP-dependent and calcium-dependent mechanisms of signal transduction were studied in hepatocytes obtained from rats with different thyroid states. In cells from euthyroid and hyperthyroid rats, the metabolic actions of epinephrine were mediated mainly through alpha 1-adrenoceptors; beta-adrenoceptors seem to be functionally unimportant. In contrast, both alpha 1- and beta-adrenoceptors mediate the actions of epinephrine in hepatocytes from hypothyroid animals. Phosphatidylinositol labeling was strongly stimulated by epinephrine, vasopressin and angiotensin II in cells from eu-, hyper- or hypothyroid rats. However, metabolic responsiveness to vasopressin and angiotensin II was markedly impaired in the hypothyroid state. The glycogenolytic response to the calcium ionophore A-23187 was also impaired, suggesting that hepatocytes from hypothyroid rats are less sensitive to calcium signalling. The persistence of alpha 1-adrenergic responsiveness in the hypothyroid state suggests that the mechanism of signal transduction for alpha 1-adrenergic amines is not identical to that of the vasopressor peptides. alpha 1-Adrenergic stimulation of cyclic AMP accumulation was not detected in cells from hypothyroid rats. These data suggest that factors besides calcium and besides cAMP are probably involved in alpha 1-adrenergic actions. Metabolic responses to glucagon and to the cAMP analogue dibutyryl cAMP were not markedly changed during hypothyroidism, although cAMP accumulation produced by glucagon and beta-adrenergic agonists was enhanced. In hyperthyroidism, cell responsiveness to epinephrine, vasopressin, angiotensin II and glucagon was decreased, but sensitivity to cAMP was not markedly altered. The factors involved in this hyposensitivity to hormones during hyperthyroidism are unclear.     

Brown fat thermogenesis in cold-acclimated rats is not abolished by the suppression of thyroid function

The effects of long-term cold exposure on brown adipose tissue (BAT) thermogenesis in hypothyroid rats have been examined. Thyroid ablation was performed in normal rats after 2 mo of exposure to 4 degrees C, when BAT hypertrophy and thermogenic activity were maximal. After ablation, hypothyroid and normal controls remained in the cold for 2 additional months. At the end of the 4-mo cold exposure, all untreated hypothyroid rats were alive, had normal body temperature, and had gained an average 12.8% more weight than normal controls. Long-term cold exposure of hypothyroid rats markedly increased BAT weight, mitochondrial proteins, uncoupling protein (UCP)-1, mRNA for UCP-1, and oxygen consumption to levels similar to those seen in cold-exposed normal rats. The results indicate that thyroid hormones are required for increased thermogenic capacity to occur as an adaptation to long-term cold exposure. However, cold adaptation can be maintained in the absence of thyroid hormone.     

Involvement of an NAD(P)H oxidase as a pO2 sensor protein in the rat carotid body.

Selenium (Se) deficiency for 5 weeks in rats produced changes in the activity of a number of hepatic, renal and plasma enzymes. In animals whose food intake was restricted to 75% of normal for 2 weeks, Se deficiency produced significant increases in the activity of hepatic cytosolic 'malic' enzyme and mitochondrial alpha-glycerophosphate dehydrogenase (GPD), two enzymes that are particular sensitive to the thyroid-hormone concentrations in tissue. Propylthiouracil-induced hypothyroidism produced significant decreases in 'malic' enzyme and GPD activities. The effect of hypothyroidism on the activity of 'malic' enzyme, GPD and other enzymes studied in liver and plasma was often opposite to that seen in Se deficiency. Glutathione S-transferase (GST) activity was increased by both Se deficiency and hypothyroidism, but in hypothyroid animals further significant increases in GST were produced by Se deficiency. These data suggest that the changes in enzyme expression observed in Se deficiency are not caused by decreased tissue exposure to thyroid hormones.     

Effect of hypothyroidism on mitochondrial energy metabolism and nuclear synthesis of RNA in the liver of Cynomolgus monkeys

The effects of hypothyroidism and of replacement therapy with T4 or T3 were studied on the enzymatic activities of liver subcellular fractions isolated from Cynomolgus monkeys. Animals were sacrificed 20 days after thyroidectomy. In mitochondria, thyroidectomy decreased significantly the respiratory chain activity (succinate cytochrome c-reductase), the transfer of cytosolic reducing equivalents (glycerol-3-phosphate dehydrogenase) and the phosphorylating capacity (oligomycin-sensitive ATPase and state 3 respiratory rate). The activity of nucleolar and nucleoplasmic RNA polymerases dropped by about 50% in hypothyroid monkeys. In T4 (2.5 micrograms/kg/d) or T3 (1 microgram/kg/d) treated thyroidectomized animals, the iodothyronine concentrations and the activity of mitochondria and nuclei enzymes were halfway between normal and hypothyroid values. Thus, the mitochondrial effects of thyroidectomy in monkey are, as in rat, at least partly secondary to a decrease in nucleocytoplasmic protein synthesis.     

Effect of thyroid hormone on the turnover of rat liver pyruvate carboxylase and pyruvate dehydrogenase.

Immunochemical techniques have been utilized to study the effect of thyroid status on the content and rates of synthesis and degradation of pyruvate carboxylase and pyruvate dehydrogenase in rat liver. Liver from hyperthyroid rats had twice the pyruvate carboxylase activity of normal rats while thyroidectomized rats had about two-thirds of normal activity. Pyruvate dehydrogenase complex activity was unchanged in the hyperthyroid state but was significantly reduced (by a third) in hypothyroid rats. Changes in catalytic activity during altered thyroid status were by immunochemical means to be closely related to the amount of the hepatic enzymes present. Isotopic studies showed that the changes in the content of pyruvate carboxylase and pyruvate dehydrogenase reflected alterations in the rate of the synthesis of the enzymes with the degradation rates little affected by thyroid status. The half-life for pyruvate carboxylase was 4.6 days, and that for pyruvate dehydrogenase, 8.1 days. In both cases, the turnover time was slower than that of the average mitochondrial protein (t1/2 = 3.8 days) for the control animals.     

Thyroid hormone regulation of flavocoenzyme biosynthesis

The means by which thyroid hormone regulates flavocoenzyme biosynthesis was studied in hyper-, eu-, and hypothyroid rats by determining the activities of flavocoenzyme-forming enzymes, viz., flavokinase and FAD synthetase, as well as those of flavocoenzyme-degrading enzymes, viz., FMN phosphatase and FAD pyrophosphatase. Flavokinase activity was increased in hyperthyroid animal and decreased in hypothyroid animals. Correspondence of flavokinase activity with the amount of a high-affinity flavin-binding protein quantitated immunologically in hypo-, eu-, and hyperthyroid rats indicated that the thyroid response is caused by an increased amount of enzyme; moreover, the concomitant decrease in a low-affinity flavin-binding protein suggests an inactive precursor form of flavokinase. FAD synthetase activity showed a similar but less pronounced trend than flavokinase. Activities of FMN phosphatase and FAD pyrophosphatase were not influenced by thyroid hormone. Overall results indicate that the mechanism of thyroid hormone regulation of flavocoenzyme level is in the steps of biosynthesis, especially at flavokinase, rather than in degradation steps.     

The lipoprotein lipase activity of brown adipose tissue during early post-natal development of the normal and hypothyroid rat.

The heparin-releasable LP lipase activity of BAT (brown adipose tissue), and the TG (triglyceride) content of plasma were determined in normal and hypothyroid rats during early post-natal development. The TG content of plasma increased sharply after the onset of suckling and decreased during the weaning period in normal rats, while it stayed at a high level in hypothyroid rats. LP lipase activity was maximal during the perinatal period and decreased later, being practically undetectable in one month old control animals; in contrast, LP lipase activity was still present in cretin rats at this age. The effects of several forms of treatment were also tested in weaned rats: a high-fat diet was not able to maintain the high LP lipase activity of suckling rats, but the activity was high if the animals were bred at a cold temperature. Thyroxine injections had no effect. These results are discussed in terms of the possible factors regulating the LP lipase activity in BAT.     

Poly(ADP-ribose) polymerase activity in regenerating liver of hypothyroid rats

The role of PARP, a nuclear enzyme involved in DNA synthesis, repair and cell transformation, was studies during liver regeneration in hypothyroid animals. Hypothyroidism was induced by in vivo administration of propylthiouracil. In regenerating euthyroid animals PARP activity is stimulated showing an early and significant increase at 1.5 h with a maximum at 6 h after partial hepatectomy. Such an increase returns to control values within 18 h preceding the onset of DNA synthesis. A markedly different behavior, with respect to euthyroids, has been evidenced in hypothyroid rats. At first, liver PARP level was about 2-fold higher in non regenerating hypothyroid rats with respect to control euthyroids. During regeneration, PTU-treated animals show a net decrease in PARP activity, with a minimum at 6-9 h after partial hepatectomy. The activity returns to control levels within 24 days. The minimum in PARP activity anticipates, also in this case, the onset of DNA synthesis, which exhibits a maximum at 15-18 h. During liver regeneration PARP activity shows modifications related to the beginning of de novo DNA synthesis. Furthermore, these variations in turn undergo the effects of hypothyroidism.     

Poly(ADP-ribose) polymerase is affected early by thyroid state during liver regeneration in rats

Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme involved in DNA synthesis, DNA repair, and cell replication and transformation, also plays a role in the early steps of liver regeneration induced by partial hepatectomy (PH). PARP and DNA topoisomerase I (Topo I) activities and de novo DNA synthesis were studied during liver regeneration in rats with altered thyroid state. Hepatic PARP activity, evaluated as [(32)P]NAD incorporated into isolated liver nuclei, was inhibited in hyperthyroid rats and increased in hypothyroid animals. In both euthyroid and hyperthyroid rats PARP activity was rapidly stimulated, peaking 6 h after PH. In hypothyroid animals, an early decrease in activity was found, at a minimum of 6 h after PH, followed by an early onset of DNA synthesis. An inverse relationship between PARP and Topo I activities was a shared feature among euthyroid, hypothyroid, and hyperthyroid rats. Together these data show that, in replicating hepatocytes, thyroid hormones exert a regulatory role on PARP activity, which reflects the control of a number of nuclear proteins involved in DNA metabolism.     

Role of Thyroid Hormone and Nerve Growth Factor in the Development of Choline Acetyltransferase and Other Cell-Specific Marker Enzymes in the Basal Forebrain of the Rat

The effects of treatment with L-thyroxine (subcutaneously 0.3 microgram/g body weight daily from birth, i.e., day 1) and 2.5S nerve growth factor (NGF; intraventricularly 2 micrograms on 1, 3, 5, 7, and 9 postnatal days), separately and together, were studied on the biochemical development of different cell types in the basal forebrain of 10-day-old rats. The development of cholinergic, gamma-aminobutyric acid-ergic (GABAergic), and glutamatergic neurons was monitored respectively in terms of choline acetyltransferase (ChAT), glutamate decarboxylase (GAD), and glutaminase activities, whereas glutamine synthetase (GS) and 2',3'-cyclic nucleotide-3'-phosphohydrolase (CNPase) activities were used to judge the maturation of astroglial and oligodendroglial cells. Treatment with either thyroid hormone or NGF from birth significantly increased the expression of ChAT activity in the basal forebrain of neonatal rats. When both agents were administered to the same animal, in agreement with our earlier in vitro findings, the stimulation in ChAT activity was much greater than the sum of the individual effects. In hypothyroid rats, significant effects of NGF at the low doses used were not detectable, although the increase of ChAT activity induced by thyroxine was potentiated by NGF in these animals. Under the present experimental conditions neither thyroxine nor NGF treatment had an appreciable effect on the activities of glutaminase, GS, and lactate dehydrogenase. However, the administration of thyroxine markedly increased CNPase activity in normal rats, whereas in hypothyroid rats the effect on both CNPase and GAD was also significant. Similar elevations in CNPase and GAD activities were not observed after NGF treatment, suggesting that the effect of NGF was specific to the cholinergic cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma homocysteine is decreased in the hypothyroid rat

Recent clinical studies have indicated that plasma homocysteine was significantly increased in hypothyroid patients. Since hyperhomocysteinemia is an independent risk factor for cardiovascular disease we investigated homocysteine metabolism in hypothyroid rats. Hypothyroidism was induced in one study by addition of propylthiouracil (PTU) to the drinking water for 2 weeks. In a second study, thyroidectomized and sham-operated rats were used with thyroid hormone replacement via mini-osmotic pumps. Unlike the human hypothyroid patients, both groups of hypothyroid rats exhibited decreased total plasma homocysteine (30% in PTU rats, 50% in thyroidectomized rats) versus their respective controls. Thyroid replacement normalised homocysteine levels in the thyroidectomized rat. Increased activities of the hepatic trans-sulfuration enzymes were found in both models of hypothyroidism. These results provide a possible explanation for the decreased plasma homocysteine concentrations. The hypothyroid rat cannot be used as a model to study homocysteine metabolism in hypothyroid patients.     

Hormonal control of pulmonary surfactant synthesis

The specific activities of palmitoyl-CoA synthetase, phospholipase A2, and lysophosphatidylcholine acyltransferase enzymes were low in the lungs of diabetic and hypophysectomized rats as compared to those found in the normal controls. Administration of triiodothyronine (T3), to the diabetic and hypophysectomized rats restored the normal activities of these enzymes. Stimulation of the enzyme activities were also observed when normal rats were injected with the above hormone. The enhancement of the enzyme activities was also found to be dependent on the dose and duration of the hormonal treatment. Optimum levels were achieved at a dose of about 100 micrograms/100 g body weight of T3, 3-4 days after the administration of this hormone. Actinomycin D or cycloheximide abolished the hormone-mediated stimulation of these enzymes in diabetic and hypophysectomized rats. Reduced rate of in vivo palmitoyl-CoA synthetase synthesis was observed in the lungs of diabetic and hypophysectomized animals. Administration of T3 stimulated the rate of synthesis of this enzyme indicating increasing synthesis of this enzyme and not of activation of the pre-existing inactive species. Reduced phospholipid contents, specially decreased amount of lecithin and dipalmitoyl lecithin (DPL) were observed in the lungs of the diabetic and hypophysectomized animals as compared to those in the normal animals. T3 also increased the lecithin and DPL content of the normal rat lungs. These results provide evidence for the involvement of the thyroid hormones in the control of the pulmonary surfactant. The results further suggest that T3 was capable of inducing the enzymes of the "deacylation-reacylation" pathway involved in palmitate incorporation into phosphatidylcholine thereby contributing to the stimulation of dipalmitoyl phosphatidylcholine biosynthesis.     

Improvement of follicular development rather than gonadotrophin secretion by thyroxine treatment in infertile immature hypothyroid rdw rats

Despite extensive study of reproductive abnormalities in female hypothyroid animals, little is known of folliculogenesis and gonadotrophin secretion in spontaneously hypothyroid animals, especially in response to exogenous hormone treatment. In this study, follicular development and plasma hormone concentrations in the presence or absence of thyroxine and eCG treatment were investigated in infertile immature spontaneously hypothyroid rdw rats. Administration of thyroxine once a day from day 21 to day 29 after birth resulted in increases in body weight (P < 0.001) and ovary mass on day 30 (P < 0.01). Similar populations of both healthy and atretic antral follicles ranging from 101 to 400 micrometer in diameter were observed in control rdw and normal rats. In rdw rats, thyroxine treatment markedly increased the number of healthy antral uniovular follicles 101-400 or > 550 micrometer in diameter in the absence or presence of eCG, respectively. Combined treatment of thyroxine and eCG in rdw rats also markedly increased the number of healthy antral biovular follicles. Thyroxine treatment did not affect the population of atretic antral follicles, but resulted in decrease in the number of atretic large antral follicles (> 400 microm) in the presence of eCG. Plasma oestradiol concentrations in rdw rats given both thyroxine and eCG were significantly higher than they were in rdw rats given eCG alone (P < 0.001). There were no significant differences in plasma FSH concentrations on day 28 between rdw (10.7 +/- 1.6 ng ml(-1)) and normal rats (12.0 +/- 1.4 ng ml(-1); P > 0. 05). Although there were no significant differences in plasma LH concentrations between control rdw (1.9 +/- 0.1 ng ml(-1)) and normal rats on day 30 (1.8 +/- 0.1 ng ml(-1); P > 0.05), eCG treatment increased plasma LH to a peak concentration 52 h after injection in normal (24.9 +/- 2.4 ng ml(-1)) but not in rdw rats treated with thyroxine (4.8 +/- 0.3 ng ml(-1); P < 0.05). In conclusion, the results of the present study indicate that thyroxine treatment improves follicular development but does not rescue the defect of the preovulatory surge of LH in eCG-primed rdw rats.     

ENHANCED CEREBRAL PROTEIN SYNTHESIS IN DEVELOPING HYPOTHYROID RATS: EVIDENCE FOR DELAYED MATURATION

(1) Neonatal hypothyroidism resulted in a 40% increase in the incorporation of [¹⁴C]leucine into protein by cerebral cortical slices from 25-day-old rats. The uptake of the [¹⁴C]-labelled amino acid into the acid-soluble free amino acid pool was similar in hypothyroid and control groups which excluded the possibility that transport differences contributed to the observed differences in incorporation. (2) The conversion of [¹⁴C]leucine in the free amino acid pool to other metabolites was substantially greater in the hypothyroid state compared to euthyroid controls. (3) The correction of the incorporation data for radioactivity associated with [¹⁴C]leucine in the precursor pool, provided an estimate of cerebral protein synthetic rate which was markedly higher in thyroid hormone-deficient-rats compared to litter mate controls. (4) The administration of L-thyroxine to hypothyroid animals for two successive days essentially returned the accelerated metabolism of the precursor pool leucine to normal but failed to ameliorate the increased incorporation into protein. (5) Incubations conducted in the presence of high exogenous leucine levels, to eliminate possible differences in intracellular free amino acid pool size, provided additional evidence for an increased rate of cerebral protein synthesis in 25-day-old hypothyroid rats compared to controls. (6) The results are compatible with a retardation in the normal developmental decline in the rate of cerebral protein synthesis associated with hypothyroidism.