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Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine (L.A.B., J.P.), Pittsburgh, Pennsylvania 15261; and the Department of Medicine and Physiology, Dartmouth Medical School (D.L.S.G.), Lebanon, New Hampshire 03756
Address all correspondence and requests for reprints to: Dr. Lynn A. Burmeister, Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The type 2 iodothyronine 5'-deiodinase (D2) appears to be an important factor in the ability of the central nervous system to adapt to alterations in thyroid hormone status. This enzyme, which is present in the anterior pituitary gland and brown adipose tissue as well as in several regions of the brain (8, 9, 10), deiodinates T4 at the 5'-position to form T3 and appears to be the principal source of intracellular T3 in these tissues (3, 4, 5, 7, 11). D2 activity is rapidly and markedly altered by changes in thyroid hormone levels; hypothyroidism results in enhanced activity, whereas the opposite effect occurs in hyperthyroidism (9, 12, 13). Furthermore, it has recently been reported that 90% of T3 production in hypothyroid rats occurs in slowly exchanging tissues, such as brain and brown adipose tissue (BAT), where D2 predominates as the enzyme catalyzing T4 to T3 conversion (14).
Several lines of evidence strongly suggest that posttranslational mechanisms are involved in the regulation of D2 activity by thyroid hormone (15, 16, 17, 18, 19, 20, 21, 22). Specifically, thyroid hormones have been observed both in vivo in rodents and in several cell culture systems to induce a decrease in D2 activity that is more rapid than that observed when gene transcription or protein synthesis is blocked with actinomycin D or cycloheximide, respectively (15, 18, 19). In addition, T4 and rT3 are considerably more potent that T3 in inducing inactivation of D2 when administered acutely to hypothyroid animals (16, 18, 23, 24). Given that transcriptional regulation by thyroid hormone is primarily, if not exclusively, mediated by T3 binding to its nuclear receptors (25), the greater potency of T4 and rT3 in acutely inhibiting D2 activity is further evidence that this process involves extranuclear metabolic events such as alterations in the rate of D2 protein turnover or translocation of the enzyme between various cellular compartments (19, 20, 21, 26).
In the present studies, we sought to determine whether the regulation of D2 in cerebral cortex might involve pretranslational as well as posttranslational mechanisms. A direct assessment of this possibility has only recently become feasible with the cloning of complementary DNAs (cDNAs) for this enzyme from several species (13, 27). Indeed, initial studies in rats have demonstrated significant changes in D2 messenger RNA (mRNA) levels in BAT and the anterior pituitary gland in response to alterations in thyroid hormone status (13). To assess the pretranslational regulation of D2 in the cerebral cortex by thyroid hormone, D2 mRNA and activity levels were compared in euthyroid and hypothyroid rats and in animals treated with graded doses of L-T3 or L-T4.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-32P]deoxy-CTP,
[125I]rT3, and Gene Screen
membranes were purchased from New England Nuclear (Boston, MA).
Decaprime II oligolabeling kits were purchased from Ambion (Austin,
TX). L-T4,
L-T3, and methimazole (MMI) were
purchased from Sigma Chemical Co. (St. Louis, MO). Reagents for
determining protein concentration were obtained from Bio-Rad
Laboratories (Richmond, CA).
Animals and treatments
All treatments were approved and in compliance with the
requirements of the animal care and use committee of the University of
Pittsburgh or Dartmouth Medical School. Male Sprague-Dawley rats,
weighing 175–200 g, were purchased from Zivic Miller (Zelienople, PA),
Harlan Sprague-Dawley (Indianapolis, IN), or Charles River Laboratories
(Burlington, MA). Rats had free access to water and food at all times
during the study. Hypothyroidism was induced by the addition of MMI
(0.025% or 0.05%) to the drinking water. Hypothyroidism was assessed
clinically by failure to gain weight at the expected rate and could be
observed within 2 weeks of beginning MMI treatment.
In an initial study, the experimental groups (n = 6 rats/group) included euthyroid control animals, animals receiving MMI for 4 weeks, and euthyroid animals treated with L-T3 (50 µg/100 g BW, sc, daily) for 4 days before death to induce a hyperthyroid state.
A second series of experiments was conducted using a longer period of thyroid hormone treatment. Rats taking MMI for 2 weeks were continued on this agent for an additional 2 weeks, during which time they were administered once daily ip injections of L-T4, L-T3, or 10 mM sodium hydroxide vehicle. Rats treated with L-T4 received daily ip doses of 0.1 (n = 6), 0.2 (n = 6), 0.5 (n = 6), 1.5 (n = 10), 3 (n = 5), 4.5 (n = 5), or 10 µg/100 g BW (n = 4). Treatment with L-T3 involved administering doses of 0.25 (n = 10), 1 (n = 6), 1.7 (n = 4), 3 (n = 4), or 5 (n = 4) µg/100 g BW. Sixteen rats receiving MMI, treated only with vehicle, served as hypothyroid controls. Six euthyroid rats served as additional controls. The chosen doses of administered thyroid hormone were based on previous reports suggesting that L-T4 at 5–10 µg/100 g BW·day induces thyrotoxicosis (28, 29). Furthermore, T3 nuclear receptor saturation with an accompanying alteration in the transcriptional activity of specific liver genes is induced with L-T3 treatment in a dose of 15–50 µg/day (30) or with a single dose of 200 µg T3 (31). Serum T4, serum T3, T3 uptake, and cortical D2 mRNA concentrations were measured at the time of death in all chronically treated animals. Hepatic type I iodothyronine deiodinase (D1) mRNA and activity and cerebral cortex D2 activity were assayed in selected samples, including euthyroid rats and those receiving MMI receiving vehicle or low dose L-T3 or L-T4 treatment (dosage range, 0.1–3 µg/100 g BW).
The time course of thyroid hormone effects on D2 mRNA and activity was determined using rats rendered hypothyroid by the inclusion of MMI in their drinking water for 50 days. At the end of this period, animals were administered vehicle, 50 µg L-T4 (n = 5), or 200 µg L-T3 (n = 5) as a single ip dose 24 h before death. This experiment was repeated in MMI-treated rats who received vehicle or 200 µg L-T3 4, 12, or 24 h before death, and results were compared with those from a euthyroid control group (n = 4/group). Serum T4, serum T3, T3 uptake, and cortical D2 mRNA and activity were measured in all animals.
Rats were killed in the morning (24 h after the last dose of L-T3 or L-T4, or as otherwise noted) under Nembutal anesthesia by exsanguination through the carotid arteries. Brains were quickly removed, and the cortex was dissected out on ice for storage at -80 C until RNA extraction or homogenization for activity.
Isolation and analysis of RNA
In the initial experiment, RNA was isolated, and Northern
analysis was performed according to previously described procedures
(13) using 20 µg total RNA from the cerebral cortex of individual
rats. Final wash conditions used 0.1 x SSPE (sodium chloride,
sodium phosphate, EDTA)-0.1% SDS at 60 C for 1 h. Quantitation of
the hybridization signal was performed by phosphorimaging. The signal
was corrected for differences in loading and transfer by reprobing the
blot with a rat ß-actin probe and determining the ratio of the D2
band to the ß-actin band for each lane.
In other experiments, RNA extraction was performed by a modification of
the guanidine thiocyanate method (32) and was quantitated by reading
the optical density at 260 
. Using 20 µg total RNA/lane, agarose
gel electrophoresis was performed under denaturing conditions (33). The
RNA was transferred overnight via capillary action to a nylon membrane
and UV cross-linked (34). An XbaI fragment of the rat D2
(13) or a PvuII fragment of the rat D1 cDNA (35) was labeled
to high specific activity using the random primer technique and then
hybridized to the membrane at 43 C for 24–48 h (36, 37). Membranes
were washed at 63 C (for D2) or at 50 C (for D1) for a minimum of 40
min each in 2 x SSC (standard saline citrate)-0.1% SDS, 25
mM NaHPO4 (pH 7.2)-1 mM EDTA-0.1%
SDS, and 25 mM NaHPO4 (pH 7.2)-1 mM
EDTA-1% SDS. Quantitation of mRNA density was performed by
phosphorimaging the specific band with normalization to the 28S
ribosomal RNA band to correct for variations in loading. The 28S band
was visualized by ethidium bromide staining and photographed with type
665 positive-negative Polaroid film, and the density was quantitated by
densitometry of the negative (38, 39). The data are reported in
relative units corrected for the amount of 28S RNA present in each
lane. The relative level of D2 mRNA between gels and experiments was
standardized to either a rat brain or liver standard placed on all
gels.
Measurement of 5'-deiodinase activity
A portion of the cerebral cortex from individual animals was
homogenized (1:5, wt/vol) in 0.25 M sucrose and 0.02
M Tris-HCl, pH 7.4, and assayed for D2 activity using 1
nM radiolabeled rT3 as substrate and
in the presence of 20 mM dithiothreitol, 1 mM
EDTA, and 0.1 mM 6n-propyl-2-thiouracil, as
previously described (13). D2 activity is expressed as
femtomoles/h·mg protein. Livers were homogenized at 1:10 in the same
buffer, diluted 1:100, and assayed for D1 activity as described above,
except that no 6n-propyl-2-thiouracil was included in the
assay mixture. For a given experiment, all determinations were made in
a single assay, with duplicate determinations for each sample. D1
activity is expressed as picomoles/h·mg protein. Protein
concentrations were determined by the method of Bradford (40).
Hormone measurements
Serum total T4, total
T3, and T3 uptake were
measured by RIA (Coat-A-Count, Diagnostic Products Corp., Los Angeles,
CA). A rat thyroid hormone binding ratio was obtained by normalizing
the T3 uptake determination to a rat euthyroid
standard. Free T4 index and free
T3 index were calculated by multiplying the serum
total T4 or total T3,
respectively, by the thyroid hormone binding ratio. The
T4 and T3 concentrations
obtained in the study are expressed as micrograms per dl and nanogram
per ml, respectively. The free T4 index and free
T3 index are without units.
Statistical analysis
Statistical analysis was performed in some cases using
log-transformed data. Where appropriate, linear regression was
performed or comparisons between groups were assessed by ANOVA, with
appropriate post-hoc mean comparisons by the method of Tukey
(41) (Systat Program, Evanston, IL) or Dunnett’s test for multiple
comparisons with a control group. P < 0.05 is
considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). This is the same size RNA species
identified previously on Northern blots of BAT, anterior pituitary, and
cerebral cortex using polyadenylated RNA (13). Quantitation of this
7-kilobase band by phosphorimager analysis permitted a comparison of
the effects of hormone treatments on D2 mRNA levels. Representative
blots of cerebral cortical RNA samples from hypothyroid rats and
animals treated with L-T3 and
L-T4 are shown in Fig. 1, b and
c.
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, hypothyroidism was associated with a
70% increase in cortical D2 mRNA levels compared with those in
euthyroid control animals (P = 0.03). In contrast,
T3 administration for 4 days resulted in an 80%
decrease in mRNA levels compared with levels in this control group
(P < 0.001). Likewise, as shown in Table 1, administration of
T3 (5 µg/100 g BW·day) or
T4 (10 µg/100 g BW·day) for 14 days to
MMI-treated rats resulted in 59% and 71% decreases, respectively, in
the cortical D2 mRNA level compared with that in the 28-day MMI-treated
hypothyroid group.
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). This was associated with
a dose-dependent decrease in cerebral cortex D2 mRNA (P
= 0.006; Fig. 3b). However, L-T3
administration did not statistically alter the high levels of D2
activity observed in the hypothyroid state (P = 0.31;
Fig. 3c). For comparison, hepatic D1 mRNA and activity were determined
in the same animals (Fig. 3, d and e). As expected from prior studies
(35, 42, 43), D1 mRNA and activity progressively increased with
increasing doses of T3 (P <
0.001). Of note, significant increases in these parameters were noted
at the lowest dose of T3 administered (0.25
µg/100 g BW·day), whereas higher doses (3 µg/100 g BW·day) were
required to effect inhibition of D2 mRNA in the cerebral cortex.
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, the
free T3 index was increased markedly by 4 h
after L-T3 administration and
remained elevated for 24 h (P < 0.001).
Associated with this, the D2 mRNA level was significantly decreased at
4 h (P < 0.01; Fig. 4b) and declined further at
12–24 h (P < 0.001). This was associated with a
progressive decrease in D2 activity (P = 0.02; Fig. 4c)
that appeared to be somewhat delayed and of lesser magnitude than the
changes in the D2 mRNA level.
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, a and b). Although cerebral
cortical D2 activity significantly decreased (P <
0.001), cortical D2 mRNA remained relatively stable, with the exception
of an apparent increase in mRNA associated with the 0.1 µg/100 g
BW·day L-T4 dose that proved not to
be statistically significant (P = 0.13 vs.
hypothyroid rats). Again, as expected, hepatic D1 mRNA and activity
could be readily induced by L-T4
treatment (P < 0.001, Fig. 5, a and c).
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. These data represent the values
for the individual animals from the experiments depicted in Figs. 3
and 5 as well as other confirmatory experiments not shown. Here, it can be
seen that the transition from the euthyroid to the hypothyroid state is
associated with a relatively larger increase in D2 activity than in
mRNA concentration. When comparing the effects of
T4 vs. T3
treatment on these parameters, it is apparent that
T4 treatment is associated with large changes in
D2 activity relative to alterations in mRNA levels, whereas the
opposite occurs with T3 treatment, in that mRNA
levels are primarily affected.
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. A highly significant inverse linear
relationship is observed between log D2 mRNA and the log serum free
T3 index (Fig. 7a; r = 0.520 and
P < 0.001; r = 0.61 if we exclude the outlier),
with overlap in the values regardless of whether the animals were
treated with L-T4 or
L-T3. No such relationship was found
between log D2 mRNA and log serum free T4 index
(r = 0.115; P = 0.213). In contrast to Fig. 7a, a
marked difference was noted in T4- and
T3-injected animals in the relationship between
the log D2 activity and the log free T3 index
(Fig. 7b; T4-treatment: r = 0.74;
P < 0.001; T3 treatment: r
= 0.65; P < 0.001). Thus, for any given level of free
T3 index, D2 activity was significantly lower in
the T4-treated animals than in those given
T3. Of importance, the euthyroid control group
(indicated by the box in Fig. 7b) falls along the line for
the T4-injected animals, suggesting that
T4 exerts the dominant controlling effect on D2
activity in the euthyroid animal.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In confirmation of previous studies (16, 44), treatment of hypothyroid rats with L-T4 resulted in a greater degree of inhibition of D2 activity than did administration of similar doses of L-T3. In addition, L-T4 administration resulted in greater proportional changes in D2 activity relative to alterations in mRNA levels. For example, chronic L-T4 administered to hypothyroid animals at a dose of 0.2 µg/100 g BW·day resulted in a significant inhibition of D2 activity, yet no change in D2 mRNA levels occurred. Indeed, treatment with L-T4 at doses as high as 1.5 µg/100 g BW·day did not significantly decrease cortical D2 mRNA, whereas it had a profound effect on inhibiting D2 activity. Such observations are compatible with a predominantly posttranslational mechanism of D2 inhibition by L-T4. In contrast, treatment with L-T3 resulted in larger changes in D2 mRNA levels than in activity. Thus, L-T3 treatment at 3 µg/100 g BW·day did not significantly decrease cortical activity, but it was associated with a significant decrease in cortical D2 mRNA, suggesting a primary effect of this thyroid hormone on pretranslational D2 regulation. However, at high doses of administered hormone [chronic L-T3 (5 µg/100 g BW·day), L-T4 (10 µg/100 g BW·day), or L-T3 (200 µg), or L-T4 (50 µg) as a single ip dose 24 h before death], the level of cerebral cortex D2 mRNA suppression was the same with either L-T4 or L-T3 (data not shown).
The predominant effect of thyroidal status on regulating D2 activity occurs in the transition from the euthyroid to the hypothyroid state, whereas D2 mRNA levels appear to vary across the entire range of thyroid hormone levels. Thus, the relative importance of the pretranslational and posttranslational mechanisms in regulating D2 expression probably depends on the intracellular concentrations of both L-T3 and L-T4. These dual mechanisms of regulating D2 expression may work in concert to ensure that D2 activity, and thus T4 to T3 conversion, is appropriate to maintain the cortex in a euthyroid state. Of note, the posttranslational effects of L-T4 on D2 activity have been demonstrated to occur rapidly (in <2 h) (12, 15), whereas the effects of L-T3 in inhibiting D2 mRNA appear to take somewhat longer. Thus, the pretranslational mechanism of D2 regulation may assume greater importance over a more chronic time frame. It is also interesting to speculate that a decrease in D2 mRNA in the hyperthyroid state may, by decreasing translation of the D2 protein, allow for the conservation of selenocysteine so that it can be directed into the synthesis of other essential selenoproteins, such as D3, whose activity is increased in this condition.
Differences were noted in these studies in the apparent sensitivity of cortical D2 and hepatic D1 to regulation by thyroid hormones. For example, low doses of L-T3 that did not affect cortical D2 activity or mRNA levels did induce significant increases in hepatic D1 mRNA and activity. This finding may reflect the observations of others that tissue concentrations of T3 are higher in the liver than in the cerebral cortex over a range of thyroid states (45, 46). Alternatively, these differences may indicate an inherently greater sensitivity of hepatic D1, compared with cortical D2, to pretranslational regulation by L-T3. In contrast, the exquisite sensitivity of D2 in the brain to posttranslational regulation by L-T4 is evident by the marked inhibition of D2 activity by administered doses of this hormone that have little or no effect on hepatic D1 levels.
In conclusion, we have demonstrated that D2 in the rat cerebral cortex is regulated by thyroid hormones at a pretranslational as well as a posttranslational level. This provides an additional mechanism of autoregulatory control over the activity of this important enzyme.
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Acknowledgments |
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Footnotes |
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Received July 2, 1997.
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References |
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J. Steinsapir, A. C. Bianco, C. Buettner, J. Harney, and P. R. Larsen Substrate-Induced Down-Regulation of Human Type 2 Deiodinase (hD2) Is Mediated through Proteasomal Degradation and Requires Interaction with the Enzyme's Active Center Endocrinology, March 1, 2000; 141(3): 1127 - 1135. [Abstract] [Full Text] [PDF]
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J. Pachucki, L. A. Burmeister, and P. R. Larsen Thyroid Hormone Regulates Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel (HCN2) mRNA in the Rat Heart Circ. Res., September 17, 1999; 85(6): 498 - 503. [Abstract] [Full Text] [PDF]
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Y. Hosoi, M. Murakami, H. Mizuma, T. Ogiwara, M. Imamura, and M. Mori Expression and Regulation of Type II Iodothyronine Deiodinase in Cultured Human Skeletal Muscle Cells J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3293 - 3300. [Abstract] [Full Text]
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S. Pallud, M. Ramaugé, J.-M. Gavaret, A.-M. Lennon, N. Munsch, D. L. St. Germain, M. Pierre, and F. Courtin Regulation of Type 3 Iodothyronine Deiodinase Expression in Cultured Rat Astrocytes: Role of the Erk Cascade Endocrinology, June 1, 1999; 140(6): 2917 - 2923. [Abstract] [Full Text]
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B. Gereben, T. Bartha, H. M. Tu, J. W. Harney, P. Rudas, and P. R. Larsen Cloning and Expression of the Chicken Type 2 Iodothyronine 5'-Deiodinase J. Biol. Chem., May 14, 1999; 274(20): 13768 - 13776. [Abstract] [Full Text] [PDF]
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 A. Guadano-Ferraz, M. J. Escamez, E. Rausell, and J. Bernal Expression of Type 2 Iodothyronine Deiodinase in Hypothyroid Rat Brain Indicates an Important Role of Thyroid Hormone in the Development of Specific Primary Sensory Systems J. Neurosci., May 1, 1999; 19(9): 3430 - 3439. [Abstract] [Full Text] [PDF]
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S.-W. Kim, J. W. Harney, and P. R. Larsen Studies of the Hormonal Regulation of Type 2 5'-Iodothyronine Deiodinase Messenger Ribonucleic Acid in Pituitary Tumor Cells Using Semiquantitative Reverse Transcription-Polymerase Chain Reaction Endocrinology, December 1, 1998; 139(12): 4895 - 4905. [Abstract] [Full Text] [PDF]
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S. Diano, F. Naftolin, F. Goglia, and T. L. Horvath Fasting-Induced Increase in Type II Iodothyronine Deiodinase Activity and Messenger Ribonucleic Acid Levels Is Not Reversed by Thyroxine in the Rat Hypothalamus Endocrinology, June 1, 1998; 139(6): 2879 - 2884. [Abstract] [Full Text] [PDF]
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,
P < 0.05 (relative to zero dose hypothyroid
vehicle in post-hoc analysis). Values are the mean
± SEM (n = 6/group).
,
L-T3-treated hypothyroid rats (n = 27;
dose range, 0.25–80 µg/100 g BW·day); 
, vehicle-treated
hypothyroid rats (n = 20). 
, Mean of a group of euthyroid rats
(n = 10). Linear regression was performed on the
L-T3 plus vehicle group (r = 0.64;
P < 0.001) or on the L-T4
plus vehicle group (r = 0.56; P < 0.001).