Cerebral Cortex Responds Rapidly to Thyroid Hormones

Leonard, Jack L.; Kaplan, M M; Tj, Visser; Je, Silva; Larsen, P. Reed

doi:10.1126/science.7291997

Cited by 208 publications

(92 citation statements)

References 25 publications

(17 reference statements)

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“…They observed an increase in T4 5'-deiodination by rat hemipituitaries by 24 h (but not 4-6 h) after thyroidectomy, with further increases at 7 and 14 d. We have reported such a rapid increase for cerebral cortex 5'-deiodinase after thyroidectomy (29). Our present results for the time course of the increase of PTUinsensitive rT3 5'-deiodination and T4 5'-deiodination in pituitary tissue are similar ( Fig.…”

Section: Discussionsupporting

confidence: 74%

Evidence for Two Pathways of Iodothyronine 5′-Deiodination in Rat Pituitary That Differ in Kinetics, Propylthiouracil Sensitivity, and Response to Hypothyroidism

Tj¹,

Kaplan²,

Leonard³

et al. 1983

J. Clin. Invest.

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195

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A B S T R A C T We have studied 5'-deiodination of thyroxine (T4) and 3,3',5'-triiodothyronine (rT3) in rat pituitary tissue in vitro, with respect to substrate specificity, reaction kinetics, effects of 6-n-propyl-2-thiouracil (PTU), and the time course of effects of thyroid hormone depletion and repletion. Removal of one phenolic iodine or both tyrosyl iodines from the T4 molecule resulted in compounds that were not deiodinated, but alterations in the alanine side chain had little effect.5'-Deiodination of 2 nM rT3 by pituitary microsomes from euthyroid rats was inhibited >90% by 1 mM PTU, but was inhibited <10% by 100 nM T4. The apparent Michaelis constant (K.n) and maximum velocity (Vll~ax) for rT3 at 20 mM dithiothreitol (DTT) were 33 nM and 84 pmol/mg protein per h. This reaction followed ping-pong type reaction kinetics when concentrations of DTT sitive rT3 5'-deiodination (K, = 1.3 nM). T4 5'-deiodination by hypothyroid microsomes was not affected by PTU, was competitively inhibited by rT3 (Ki, 1.7 nM), and exhibited sequential type reaction kinetics with DTT as cosubstrate. When T4 5'-deiodination was measured in euthyroid and hypothyroid microsomes, respectively, the apparent Km and Vma. for T4 at 20 mM DTT, were 0.9 nM and 0.55 pmol/mg protein per h (euthyroid), and 0.8 nM and 6.9 pmol/mg protein per h (hypothyroid).The T4 5'-deiodination rate and the PTU-insensitive, but not total, rT3 5'-deiodination rate (i.e. measured in the presence and the absence of 1 mM PTU, respectively) in pituitary homogenates were significantly elevated 24 h after thyroidectomy. PTU-insensitive activity continued to increase until at .30 d after thyroidectomy it was 11 times the PTU-insensitive activity in controls. At the latter time, PTU-sensitive rT3 5'-deiodinase activity appeared to be decreased. The increase in PTU-insensitive T4 and rT3 5'-deiodination observed 48

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Section: Discussionsupporting

confidence: 74%

Evidence for Two Pathways of Iodothyronine 5′-Deiodination in Rat Pituitary That Differ in Kinetics, Propylthiouracil Sensitivity, and Response to Hypothyroidism

Tj¹,

Kaplan²,

Leonard³

et al. 1983

J. Clin. Invest.

Self Cite

195

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“…7). As previously reported, the deiodinase in the cerebral cortex reached the levels seen in long-term thyroidectomized rats in -2 d (36). In addition, this result contrasted with the rapid dissipation of the suppressive effects of T4 on the stimulation of the enzyme induced by cold stress (Fig.…”

Section: Methodscontrasting

confidence: 47%

Interrelationships among thyroxine, growth hormone, and the sympathetic nervous system in the regulation of 5'-iodothyronine deiodinase in rat brown adipose tissue.

Silva¹,

Larsen²

1986

J. Clin. Invest.

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Thyroxine (T4) and reverse triiodothyronine are potent inhibitors of brown adipose T4 5'-deiodinase (BAT 5D). This effect does not require protein synthesis and is due to an acceleration of the rate of disappearance of the enzyme. Growth hormone (GH) also inhibits BAT 5'D but by a mechanism mediated through a long-lived messenger that correlates with growth rate. This explains the failure of BAT 5D to increase abruptly after thyroidectomy as does the type II 5'-deiodinase in pituitary and central nervous system or the BAT 5'D itself after hypophysectomy. Although virtually inactive when given acutely, triiodothyronine replacement partially reduces BAT 5D in hypophysectomized and thyroidectomized (Tx) animals probably as a result of improvement of systemic hypothyroidism and an increase in GH levels in the Tx rats. The fine balance between these inhibitory factors and the stimulatory effects of the sympathetic nervous system suggests an important physiologic role for the enzyme in this tissue.

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“…D2 prefers T 4 as substrate; its K m is in the nM range and is insensitive to inhibition by 6-N-propyl-2-thiouracil (PTU). D2 is present in the brain, pituitary and brown adipose tissue (BAT) (Leonard et al 1981, Silva & Larsen 1983, Visser et al 1983, the pineal gland and the maternal side of the placenta (Kaplan & Shaw 1984, Rubio et al 1991 and in man is also present in heart, skeletal muscle and thyroid gland (Croteau et al 1996, Salvatore et al 1996. D2 is upregulated in hypothyroidism (Silva & Leonard 1985, Silva & Larsen 1986a and by a number of factors, such as adrenergic agents, cAMP, growth factors and insulin (Silva & Larsen 1983, 1986b, Courtin et al 1988.…”

Section: Introductionmentioning

confidence: 99%

Insulin increases the adrenergic stimulation of 5′ deiodinase activity and mRNA expression in rat brown adipocytes; role of MAPK and PI3K

Martinez-deMena

Obregón

2005

Journal of Molecular Endocrinology

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Type II 58 deiodinase (D2) activity produces triiodothyronine (T 3 ) from thyroxine (T 4 ) and is induced by cold and norepinephrine (NE) in brown adipose tissue. T 3 is required for and amplifies the adrenergic stimulation of D2 activity and mRNA in cultured brown adipocytes. D2 is upregulated by insulin and decrease in fasting. We now study the regulation by insulin of the adrenergically induced D2 activity and mRNA in primary cultures of rat brown adipocytes. Insulin alone does not increase D2 activity or mRNA. Insulin-depleted cells show a reduction in the adrenergically induced D2 activity, which is proportional to the length of insulin depletion and is restored after insulin addition. IGFs mimic this effect at higher doses. ERK 1/2 MAPK activity (p44/p42), stimulated by insulin, serum and NE, is an absolute requirement for the adrenergic stimulation of D2 activity and mRNA. PI3K is stimulated by insulin and serum, and NE increases the effect of insulin. The action of insulin on D2 is not due to changes in D2 half-life or in the proteasome-mediated degradation of D2, but it seems to modulate the transcriptional induction mediated by NE. D2 mRNA expression, induced by NE plus T 3 , is reduced when insulin is withdrawn at early differentiation stages. Insulin or IGF-I promotes increases in D2 mRNA. Insulin is required for the induction of D2 mRNA by T 3 . In conclusion, MAPK signaling is required for the adrenergic stimulation of D2 activity and mRNA, and insulin stimulates D2 activity via MAPK and PI3K and enhances the adrenergic pathways.

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Cerebral Cortex Responds Rapidly to Thyroid Hormones

Cited by 208 publications

References 25 publications

Evidence for Two Pathways of Iodothyronine 5′-Deiodination in Rat Pituitary That Differ in Kinetics, Propylthiouracil Sensitivity, and Response to Hypothyroidism

Evidence for Two Pathways of Iodothyronine 5′-Deiodination in Rat Pituitary That Differ in Kinetics, Propylthiouracil Sensitivity, and Response to Hypothyroidism

Interrelationships among thyroxine, growth hormone, and the sympathetic nervous system in the regulation of 5'-iodothyronine deiodinase in rat brown adipose tissue.

Insulin increases the adrenergic stimulation of 5′ deiodinase activity and mRNA expression in rat brown adipocytes; role of MAPK and PI3K

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