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Departments of Medicine (R.E.W., K.C., S.R.) and Pediatrics (S.R.) and the J. P. Kennedy, Jr. Mental Retardation Research Center (S.R.), The University of Chicago, Chicago, Illinois 60637; Division of Molecular and Cellular Adaptation (Y.M., Y.H., H.S.), Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
Address all correspondence and requests for reprints to: Roy E. Weiss, M.D., Ph.D., Thyroid Study Unit, MC 3090, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637-1470. E-mail: rweiss{at}medicine.bsd.uchicago.edu
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Abstract |
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and ß expressed
in most body tissues. However, their relative roles in the regulation
of specific gene expression remain unknown. The TRß knockout mouse,
which lacks both TRß1 and TRß2 isoforms, provides a model to
examine the role of these receptors in mediating TH action. TRß
deficient (TRß-/-) mice that show no compensatory increase in
TR, and wild-type (TRß+/+) mice of the same strain were deprived
of TH by feeding them a low iodine diet containing propylthiouracil,
and were then treated with supraphysiological doses of L-T3
(0.5, 5.5, and 25 µg/day/mouse). TH deprivation alone increased the serum cholesterol concentration by 25% in TRß+/+ mice and reduced it paradoxically by 23% in TRß-/- mice. TH deprivation reduced the serum alkaline phosphatase (AP) concentration by 31% in TRß+/+ mice but showed no change in the TRß-/- mice. Treatment with L-T3 (0.5 to 25 µg/mouse/day) caused a 57% decrease in serum cholesterol and a 231% increase in serum AP in the TRß+/+ mice. The TRß-/- mice were resistant to the L-T3 induced changes in serum cholesterol and showed increase in AP only with the highest L-T3 dose. Basal heart rate (HR) in TRß-/- mice was higher than that of TRß+/+ mice by 11%. HR and energy expenditure (EE) in both TRß+/+ and TRß-/- mice showed similar decreases (49 and 46%)and increases (49 and 41%) in response to TH deprivation and L-T3 treatment, respectively. The effect of TH on the accumulation of messenger RNA (mRNA) of TH regulated liver genes was also examined. TH deprivation down regulated spot 14 (S14) mRNA and showed no change in malic enzyme (ME) mRNA in both TRß+/+ and TRß-/- mice. In contrast treatment with L-T3 produced an increase in S14 and ME but no change in TRß-/- mice.
From these results, it can be concluded that regulation of HR and EE are independent of TRß. With the exception of serum cholesterol concentration and liver ME mRNA accumulation, all other markers of TH action examined during TH deprivation exhibited the expected responses in the absence of TRß. Thus, as previously shown for serum TSH, TRß is not absolutely necessary for some changes typical of hypothyroidism to occur. In contrast, except for HR and EE, the full manifestation of TH-mediated action required the presence of TRß.
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Introduction |
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and TRß are differentially expressed,
the two receptors often coexist in the same cell type (2, 3, 4). The
relative contribution of the two TR gene products in mediating a
particular TH response is poorly understood because of a paucity of
in vivo functional information. In vitro DNA
binding analyses and cell transfection functional assays have
generally indicated that the three TR isoforms that bind TH (TRß1,
TRß2, and TR1) exhibit similar ligand dependent transcriptional
activity (5). Some studies have generated conflicting results
concerning the specific effect of TR isoforms in gene regulation. For
example, while Lezoualc’h et al. (6) and Hollenberg
et al. (7) proposed that TH-mediated suppression of TRH
gene transcription is TRß1 specific, Feng et al. (8)
observed that the same effect was mediated by each of the three TR
isoforms. Interpretation of these apparently contradictory data are
complicated because they are derived from artificial systems using
overexpression of transfected chimeric gene constructs that may not be
faithful models of events occurring in the intact animal.
The TRß knockout mouse, which does not express either TRß1 or
TRß2 (9), provides the means to explore the relative contribution of
the TR and TRß isoforms to the TH-mediated regulation of various
physiologic processes in different tissues. We have previously
demonstrated by the use of this mouse model that TRß is not required
for the up-regulation of TSH during TH deprivation, but enhances the
sensitivity of TSH down-regulation and may be essential for the
complete suppression of TSH (10). These mice display features of
resistance to thyroid hormone (RTH) similar to those observed in humans
with deletion of the TRß gene (11, 12, 13) including deafness, resistance
to TH-induced suppression of TSH, and goiter. Therefore, they provide a
model for the detailed investigation of TH regulation in different
tissues in the absence of one specific TR isoform, through hormonal
manipulations that could not be carried out in humans.
To this purpose, we examined the effects of TH deprivation and treatment with incremental doses of L-T3 on the liver, heart, and energy expenditure (EE) in homozygous, TRß deficient (TRß-/-) mice and compared them to those observed in wild-type (TRß+/+) mice. Our data show that TH deficiency can reduce and L-T3 increase HR and EE to the same extent in the TRß-/- and TRß+/+ mice. In contrast to the TRß+/+ mouse, the serum cholesterol of the TRß-/- mouse does not respond to L-T3, and the increase in serum alkaline phosphatase (AP) was severely blunted. The effect of L-T3 on the accumulation of liver mRNA derived from TH regulated genes [spot 14 (S14) and malic enzyme (ME)] was markedly reduced in the absence of the TRß. In contrast, TH deprivation had effects on S14 and ME in TRß-/- mice that were similar to those seen in TRß+/+ mice. These results indicate that, in the absence of TH, regulation of TH responsive genes can occur independently of the TRß, whereas TH-mediated effect of the same genes is augmented by the presence of TRß.
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Materials and Methods |
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Mice were weaned on the fourth week after birth and were fed Purina Rodent Chow (0.8 ppm Iodine) ad libitum and tap water. They were housed, 3 to 5 mice per cage, in a controlled environment of 19 C and 12 h alternating darkness and artificial light cycles.
All mice were 60–70 days old at the beginning of each experiment. Weights of TRß+/+ and TRß-/- mice overlapped and ranged from 16–21 g (female) and 17–24 g (male). TH deficiency was induced by feeding a low iodine (LoI) diet supplemented with 0.15% propylthiouracil (PTU) purchased from Harlan Teklad Co. (Madison, WI). Experiments were terminated by exsanguination through eye vein puncture under light methoxyflurane (Pitman Moore, Mundelein, IL) anesthesia. Serum was separated by centrifugation and stored at -20 C until analyzed in the same assay for each experiment.
TH deficiency was induced in TRß-/- and TRß+/+ mice by feeding the LoI/PTU diet for 14 days. On the eleventh day, groups of TRß-/- and TRß+/+ mice were treated for 4 days with 0 (the vehicle only), 0.5, 5.5, and 25 µg of L-T3/mouse daily. These L-T3 amounts correspond to 4, 40, and 200 times the daily replacement dose. Twelve to sixteen hours after the last injection, experiments were terminated by exsanguination. L-T3 was given by ip injections in a total volume of 0.2 ml of PBS and 0.002% human serum albumin as a vehicle. A stock solution of L-T3 (Sigma Chemical Co., St. Louis, MO) was prepared in water containing 4 mM NaOH and kept at 4 C, protected from light. The concentration of L-T3 was confirmed by RIA (Diagnostic Products, Los Angeles, CA).
Serum measurements
Serum TSH was measured in 50 µl of serum using a sensitive,
heterologous, disequilibrium double antibody precipitation RIA (10).
The sensitivity of this assay is 0.02–0.04 ng of TSH equivalent per
ml, depending on the rat–[125I]TSH batch, with
intraassay coefficients of variation of 12, 13, and 4% for TSH
concentrations of 0.03, 0.7, and 2.4 ng/ml, respectively.
T4 was measured by a double antibody precipitation RIA
(Diagnostic Products, Los Angeles, CA) modified to measure
T4 in 15 µl of serum with a sensitivity of 0.5 µg/dl
(6.4 nmol/liter). Cholesterol and AP were measured each on 10 µl of
serum using a clinical chemistry autoanalyzer that required an
additional 40 µl of serum to prime the pump. Isozyme fractionation of
AP was performed by Mayo Clinic Laboratories (Rochester, MN) on 2 ml of
serum pools from several animals of each group.
Heart rate and energy expenditure
Heart rate was determined electrocardiographically under chloral
hydrate anesthesia (4 mg per 10 g body weight, ip) using a Hewlett
Packer Monitor/Terminal Model 78534AA with a chart speed of 25 mm per
second. Energy expenditure (EE) was determined by measurement of change
in body weight and food consumption over 4 days as previously described
(15) EE was calculated using the formula:
EE(Kcal/day) = [food consumption (g/day) x 4.0581 x 0.8**] ±
[weight change (g/day) x 7***]
Where, 1 is the caloric value of the food (in Kcal/g); ** is adjustment for 20% food wasted in litter as determined by bomb calorimetry; *** is caloric value of 1 g body weight change. Loss of weight is added and weight gain subtracted.
Liver tissue analyzes
A, T3-binding activity of TR: Approximately 1 g
of liver from mice given LoI/PTU diet, was mechanically homogenized (10
strokes) in a Dounce homogenizer (Iwaki Glass Ltd., Tokyo, Japan) using
pestle B with a buffer [SMTD-phenylmethylsulfonyl fluoride (PMSF)]
containing 0.32 M sucrose, 1 mM
MgCl2, 20 mM Tris-HCl (pH 7.5), 1
mM dithiothreitol, 1 mM PMSF. Nuclei were
pelleted by centrifugation at 1,000 x g for 10 min.
The pellets were homogenized again and washed once with SMTD-PMSF.
Triton X-100 was added to a final concentration of 1% and 0.5% for
the first and second homogenizations, respectively. The pellets were
washed 3 times with SMTD-PMSF without Triton X-100 and resuspended in
SMTD-PMSF for the performance of T3 binding assay. All
procedures were performed at 4 C.
The T3-binding assay was performed in the isolated liver nuclei as previously described (16). In brief, nuclei were incubated for 2 h at 22 C with increasing amount of [125I] T3 (0.32–2.0 x 10-9 M) with or without unlabeled T3 (3 x 10-7 M) to determine nonspecific T3 binding. Nuclei were then collected by centrifugation at 1,000 x g for 10 min. Because approximately 10–30% of nuclear T3 receptor is released from the nuclei during centrifugation, the radioactivity in the supernatant was also counted after adsorption of free T3 onto Dowex resin (Dowex 1–8 CL-200–400 mesh anion exchange resin, Bio-Rad Laboratories, Inc., Richmond, CA) as previously described (16). Receptor bound T3 was the sum of the radioactivity in the precipitate and excluded from the resin. Affinity constant (Ka) and maximal T3 binding capacity (MBC) of nuclei were determined by Scatchard analysis (17). DNA was measured by Burton’s method (18). Sucrose, dithiothreitol, and Triton X-100 were purchased from Wako Pure Chemicals, Ltd. (Osaka, Japan), PMSF was from Sigma Chemical Co. (St. Louis, MO), [125I] T3 (specific activity, 81.45 tetraBq/mmol) was obtained from DuPont NEN (Boston, MA).
B, Determination of S14 and ME mRNA: Total RNA was extracted by the
acid-guanidinium thiocyanate-phenol-chloroform method (19) from liver
that was frozen 1 to 2 min after death and kept at -85 C. Aliquots of
15 µg of total RNA were denatured and fractionated by electrophoresis
on 0.8% agarose gel then transferred onto GeneScreen Plus
(DuPont NEN) using VacuGene (Pharmacia) and hybridized as
previously described (20). Hybridization probes were prepared by
labeling S14 (21), and ME (22) complementary DNAs (cDNAs) with
[32P] 
deoxycytidine triphosphate (specific activity,
111 tetraBq/mmol (DuPont NEN) using the Random Primed DNA
Labeling Kit (Boehringer Mannheim, Germany). The quantity of mRNA on
radiographs was measured either by Molecular Imager (Bio-Rad Laboratories, Inc.) or by Fujix Bioimage Analyser (BAS 2000,
Fuji Photo Film Co., Ltd., Tokyo, Japan). The hybridized
membranes were reprobed with glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) cDNA to assure uniformity of RNA transfer. Data from the
quantitation of GAPDH was used to correct the results of S14 and ME
analyzes.
Statistics
Values are reported as mean ± SD P
values were calculated by an ANOVA unpaired t test using the
Statview 4.5 software (Abacus, Berkely, CA). P values
0.05 were considered not significant. Note that slight differences
in number of animals in each group are due to loss of an animal, tissue
or insufficient sample.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
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).
Serum cholesterol and alkaline phosphatase
Cholesterol levels (Fig. 1, upper panel) were slightly but significantly higher in the
untreated TRß-/- mice compared with the TRß+/+ mice (110 ±
17 vs. 98 ± 20 mg/dl, P < 0.03)
despite the elevated serum T4 level in the TRß-/- mice.
While TH deprivation resulted in a significant increase in serum
cholesterol in TRß+/+ mice (137 ± 48 mg/dl, P
< 0.02), a paradoxical decrease in cholesterol (85 ± 8 mg/dl,
P < 0.0005) was observed in TRß-/- mice. Treatment
with T3 (0.5, 5.5, or 25 µg/mouse) resulted in a
significant reduction in serum cholesterol in TRß+/+ but not in the
TRß-/- mice.
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, lower panel). TH
deprivation resulted in a decrease in serum AP concentration in
TRß+/+ mice from 154 ± 36 to 106 ± 24 IU/liter
(P < 0.03). This was not observed in TRß-/- mice.
In TRß+/+ mice, treatment with L-T3 (0.5, 5.5 and 25
µg) produced a dose-dependent increase in the serum AP concentration
(171 ± 28, 271 ± 72, and 351 ± 146 IU/liter,
respectively). In TRß-/- mice there was no significant change in
the serum AP except with the highest L-T3 dose of 25
µg/day (Fig. 1, lower panel)
The decrease in serum AP concentration in TRß+/+ mice during TH
deprivation was predominantly due to a decline in the liver isozyme,
from 47% to 17% of the total AP (Table 2). In contrast, in the TRß-/- mice,
the liver isozyme remained unchanged and was 50 and 63% of the total
AP prior and during TH deprivation, respectively. In both TRß+/+ and
TRß-/- mice there was appearance of intestinal AP isozymes during
TH deprivation accounting for 9% of the total.
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, upper panel). This increase
in HR is consistent with the slightly higher serum T4
observed in the TRß-/- mice. TH deprivation resulted in a decreased
HR in both TRß+/+ and TRß-/- mice (270 ± 65 and 349 ±
88, respectively) with obliteration of the significant difference
between the two types of mice. L-T3 treatment produced an
increase in HR of equal magnitude in both TRß+/+ and TRß-/- mice
(Fig. 2, upper panel).
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, lower panel).
T3 binding to liver nuclei
Results of T3 binding activity of TR are shown in Fig. 3. The MBC in liver of TRß+/+ was 72
fmol/100 µg DNA with a Ka of 7.1 x 109
M-1. These values were almost identical to those reported
in rat liver (23). In TRß-/- mice the MBC was markedly reduced to
24% the TRß+/+ mice and the Ka was slightly lower at 3.9 x
109 M-1. Based on previous observations that
TR contributes 13% of the total TR activity in rat liver (2), the
present data suggest that there is no compensatory increase in TR in
the liver of TRß-/- mice.
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and 5).
At baseline, before treatment, there was no difference between TRß+/+
and TRß-/- mice in the quantity of cytoplasmic S14 or ME mRNAs
despite the elevated serum T4 level in the TRß-/-
mice.
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, upper
panel, and Fig. 5, upper row).
TH deprivation was without effect on the abundance of ME mRNA in either
the TRß+/+ mice or TRß-/- mice, the decline in the former group
not being statistically significant. Similar to the response of S14 to
L-T3 treatment, ME mRNA increased significantly in the
TRß+/+ mice but not in the TRß-/- mice (Fig. 4, lower
panel, and Fig. 5, lower row).
In summary, the absence of TRß does not produce compensatory increase
in the amount of TR in liver nuclei. TRß appears not to be
necessary for the down-regulation of S14 mRNA during TH deprivation. On
the other hand, the T3 mediated up-regulation of S14 and ME
mRNA requires the presence of TRß.
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Discussion |
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1, TRß1, and TRß2 (5).
These ligand-dependent nuclear transcription factors regulate target
genes by binding to specific thyroid hormone response elements, either
as homodimers or as heterodimers in association with retinoid X
receptors (25, 26). Recent studies indicate that TRs mediate both
TH-independent and TH-dependent transcriptional control, possibly
through association with corepressors and coactivators (27, 28, 29, 30, 31). Ample experimental evidence from in vitro studies indicates that unliganded TRs exert a silencing effect on genes regulated positively by TH (32, 33, 34, 35) and it has been suggested that unliganded TRs have constitutively stimulating effect on genes regulated negatively by TH (6, 7, 36). That the former effect has physiological relevance and is dependent on the concentration of TR has been recently shown in vivo by the over expression of TRß in mouse liver (37).
Because both TR and TRß genes are expressed in most tissues,
either one or both can be implicated in the mediation of TH-dependent
suppression (TSH and cholesterol) or stimulation (AP, EE, heart rate,
S14, and ME) in vivo. Experiments were designed to determine
the role of TRß, the quantitative effect of total unliganded TR, and
the ability of TH to regulate the above mentioned markers of TH action
using TRß-/- and TRß+/+ mice. The targeted mutation in the mouse
TRß gene inactivates its function, but leaves the 5' end of the
coding reigon intact (9). In these TRß-/- mice, some expression of
the amino terminal fragment of the TRß1, and possibly of the TRß2
could be demonstrated by immunohistochemical analyzes of brain tissue
(38). Although the physiological implication of this truncated peptide
is unknown it does not bind to DNA or TH, and lacks the domains
necessary for dimerization and interaction with corepressors and
coactivators.
TH action on HR may be indirectly mediated by its effect on ß (39) or
(40) adrenergic receptors, extranuclear effects on glucose
metabolism and sodium transport, and nuclear effects by regulating
transcription of TH responsive genes. Furthermore TH effect on HR may
be mediated via the nervous tissue at the level of the cardiac
pacemaker. Although TR and TRß are both expressed in heart (41),
the relative contribution of each of these receptors to TH action in
the heart is unknown. Observations of the influence of TH on the heart
and EE in subjects from the single family with RTH due to TRß gene
deletion are not definitive but, as in other patients with RTH, there
is a trend for increase in HR at baseline and variable effect on the
basal metabolic rate (11, 42). Thus, the TRß deficient mouse provided
the opportunity to examine the role of TRß on the regulation of HR
and EE under conditions of TH deprivation and excess. The chronotropic
effect of TH on the heart appears independent of the TRß. Explanation
of the observations noted here is consistent with TH action on the
heart or nervous tissue controlling the pacing of the heart mediated by
TR. Recent demonstration that the mice lacking TR1, have on the
average HR lower than that of control animals, both before and after
L-T3 treatment, supports this hypothesis (43). The effect
of TH on energy expenditure is no doubt multigenic. However, it appears
that TRß is not required to reduce the EE during TH deprivation and
to produce an increase in EE in response to L-T3 treatment.
This is based on the observation that TH dependent changes in EE were
not significantly different in TRß +/+ and TRß-/- mice and the
finding of higher EE in TRß-/- mice before treatment when their
serum T4 concentration was elevated.
We have previously reported that fibroblasts from subjects lacking the
TRß gene show no compensatory increase in TR1 mRNA (44).
Similarly, it has been shown that in TRß-/- mice there is no
obvious compensatory alteration in the levels of TR1 or TR2 mRNA
in a variety of tissues including the liver (9). This was now confirmed
at the protein level by the finding of 76% reduction in total nuclear
T3-binding capacity in liver of TRß-/- mice that
corresponds to the proportion of the TRß isoform in liver nuclei of
intact rats determined by isoform specific immunoprecipitation in the
intact animal (2, 23). Thus, TR mediated effect in the liver of
TRß-/- mouse reflects the contribution of this isoform in the
normal TRß+/+ mouse. However, we cannot fully exclude the possibility
that blunting in ligand dependent and independent responses of some of
the TH regulated markers may not be due to the overall reduction in the
quantity of TR brought about by absence of TRß.
Serum levels of cholesterol seem to be mainly regulated by TH action on
the liver (37). Serum cholesterol changes in response to TH are similar
to those of TSH in the TRß+/+ mouse. Indeed, hypothyroidism increases
serum cholesterol and treatment with excess L-T3 results in
a decrease. We have previously shown that up-regulation of TSH is
independent of TRß in this TRß deficient mouse model (10), however
this is not true for cholesterol. In fact, in the absence of TRß
there is a paradoxical decrease in serum cholesterol concentration.
Since it has been demonstrated that TH stimulates the transcription of
low-density lipoprotein receptor and cholesterol 7- hydroxylase
genes, thereby enhancing the removal of LDL and cholesterol (45, 46),
differential action of TRß and TR on the expression of these genes
should be determined in the future. TH is known to regulate serum AP
concentration. In this study the observed changes in serum AP also
appear to be mainly regulated by the effect of TH on liver (Table 2).
In TRß-/- mice, TH deprivation did not reduce the serum AP level
and TH produced a minimal increase. While this suggests a TRß
mediated regulation of liver AP, it is interesting to note that
modulation of the expression of the AP gene by TR was demonstrated
in TR- null ES cells (47).
Transcription of S14 and ME genes is regulated by TH (21, 22, 24). This
report demonstrates the differential roles of TRß and TR in the
regulation of their expression. The suppression of S14 in the absence
of ligand is not reduced by the absence of TRß. In contrast, TH
mediated accumulation of S14 and ME mRNA beyond baseline appears to be
dependent only on TRß.
This report demonstrates that S14 is an example of a TH responsive gene in the liver that maintains ligand independent suppression in the absence of TRß. This is the first in vivo demonstration of such effect. TH-mediated accumulation of S14 and ME mRNA in the presence of ligand excess appears to totally depend on the presence of TRß. TH-mediated increase of serum AP was minimally dependent on TRß.
TH action in tissues is therefore dependent to a variable degree on the
presence of the TRß. Whether the responses to TH observed in the
absence of TRß are due to interaction of TH with TR or another yet
unidentified TR, is unknown. Furthermore, because the total number of
TRs is substantially decreased in the liver of TRß-/- mice due to
the lack of compensatory increase in TR1, it is unclear to what
extent the total amount of TR modulates the response of specific TH
regulated genes. Nevertheless, based on data presented herein, TH
regulated genes could be fully dependent, partially dependent or
independent of TRß. Serum cholesterol and liver ME mRNA fall under
the first category because both up and down regulation was not observed
in the absence of TRß. The response of S14 mRNA was partially
dependent on TRß since down regulation during TH deprivation was not
affected while up-regulation was blunted. The preservation of normal HR
and EE responses to TH deprivation and excess indicated independence of
TRß.
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Acknowledgments |
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Footnotes |
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Received April 13, 1998.
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1. EMBO J 17:455–461[CrossRef][Medline]
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G. J. Grover, D. M. Egan, P. G. Sleph, B. C. Beehler, G. Chiellini, N.-H. Nguyen, J. D. Baxter, and T. S. Scanlan Effects of the Thyroid Hormone Receptor Agonist GC-1 on Metabolic Rate and Cholesterol in Rats and Primates: Selective Actions Relative to 3,5,3'-Triiodo-L-Thyronine Endocrinology, April 1, 2004; 145(4): 1656 - 1661. [Abstract] [Full Text] [PDF]
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R. A. DosSantos, A. Alfadda, K. Eto, T. Kadowaki, and J. E. Silva Evidence for a Compensated Thermogenic Defect in Transgenic Mice Lacking the Mitochondrial Glycerol-3-Phosphate Dehydrogenase Gene Endocrinology, December 1, 2003; 144(12): 5469 - 5479. [Abstract] [Full Text] [PDF]
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) indicates statistical
differences between TRß+/+ and TRß-/- mice at baseline, before
treatment, and with each treatment dose.
