1 Departments of Medicine and Pediatrics, Committee on Genetics and the J. P. Kennedy Jr. Mental Retardation Research Center, The University of Chicago, Chicago, Illinois 60637-1470; Retinoid Research, Departments of 3 Biology and 4 Chemistry, Allergan, Irvine, California 92612; 5 Ecole Normale Superieure, 69364 Lyon, France; 2 Department of Molecular Sciences, Pfizer Global Research and Development-Ann Arbor Laboratories, Ann Arbor 48105; and 6 Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-0354
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ABSTRACT |
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High-affinity agonists for the retinoic
acid X receptors (RXR) have pleotropic effects when administered to
humans. These include induction of hypertriglyceridemia and
hypothyroidism. We determined the effect of a novel high-affinity RXR
agonist with potent antihyperglycemic effects on thyroid function of
female Zucker diabetic rats and nondiabetic littermates and in
db/db mice. In both nondiabetic and ZFF rats,
AGN194204 causes a 70-80% decrease in thyrotropin (TSH),
3,3',5-triiodothyronine, and thyroxine (T4) concentrations.
In the db/db mouse, AGN194204 causes a
time-dependent decrease in thyroid hormone levels with the fall in TSH
that was significant after 1 day of treatment preceding the fall in
T4 levels that was significant at 3 days of treatment.
Treatment with AGN194204 caused an initial increase in hepatic
5'-deiodinase mRNA levels which then fell to undetectable levels by 3 days of treatment and continued to be low at 7 days of treatment. After treatment for 5 days with AGN194204, both wild-type and thyroid hormone
receptor (TR
/
)-deficient mice demonstrated a
nearly 50% decrease in serum TSH and T4 concentrations.
The results suggest that a high-affinity RXR agonist with
antihyperglycemic activity can cause central hypothyroidism
independently of TR
, the main mediator of hormone-induced TSH suppression.
nuclear receptors; retinoic acid receptors; hypothyroidism; knockout mice
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INTRODUCTION |
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THE LEVEL OF
circulating thyroid hormones (TH), 3,3',5-triiodothyronine
(T3) and thyroxine (T4), is tightly regulated
by thyrotropin (TSH) in serum through a negative feedback mainly at the
level of the pituitary thyrotrophs. It involves the binding of
T3 to specific nuclear TH receptors (TR) that interact with
upstream specific DNA sequences located in the - and
-subunits of
TSH (29). The two TRs,
and
, are members of the
nuclear receptor superfamily, which includes the vitamin D receptor,
glucocorticoid and sex hormone receptors, retinoic acid (RAR) and
retinoid X receptors (RXR), and the peroxisome proliferator-activated
receptor (PPAR) isoforms (7, 19, 21).
TRs act as ligand-dependent nuclear transcription factors that mediate the action of TH by positive and negative regulation of TH-responsive genes through binding to hormone response element (HRE) which consist of specific DNA sequences usually located in their promoter region (21). On the other hand, the cognate ligands of RAR and RXR, retinoic acid (RA) and 9-cis-retinoic acid (9-cis-RA), respectively, can transactivate through the same synthetic palindromic HRE and several natural HREs that are normally involved in TR-mediated gene regulation (32, 37). Specificity of gene transcription via RXR is thought to be mediated by the heterodimeric partner. Thus the RAR/RXR heterodimer binds to sequences oriented as direct repeats (DRs) that are separated by two or five nucleotides (DR-2 and DR-5). In contrast, PPAR/RXR heterodimers are thought to act via DR-1 elements, and TR/RXR can form complexes with DR-4 or DR-5 (6, 18, 20).
The RXR agonist Targretin has been used in clinical trials for
cutaneous T-cell lymphomas (28). All patients treated for T-cell lymphoma with this RXR agonist developed reversible central hypothyroidism (28). Because TR-mediated transactivation
induced by T3 is facilitated by the formation of TR/RXR
heterodimers (1, 24), the above finding suggested the
possibility that 9-cis-RA agonists may suppress TSH
gene expression through binding to TR/RXR heterodimers. In contrast, in
vitro studies suggest that the downregulation of TSH by
9-cis-RA is mediated through an RXR-dependent mechanism involving a region in the TSH promoter distinct from the one that mediates the T3-dependent TSH suppression
(14). However, this system provides for some degree of
functional overspill. The latter has been observed in vitro but also in
vivo. In the rat, vitamin A deficiency produces an increase in serum
TSH that results in an increase in plasma THs, T4 and
T3 (22), whereas excess vitamin A or RA has
the opposite effect (5, 27). More recently, Brown et al.
(3) showed that mice deficient in the RXR exhibited a
mild resistance to TH. These effects appear to be mediated through the
regulation of TSH gene expression (2).
High-affinity RXR agonists are under development as agents to treat
insulin-resistant diabetes (31). One proposed mechanism of
action is transactivation through a PPAR/RXR heterodimer. In this
model, similar to TR, PPAR
directs the heterodimeric complexes to
distinct HRE sites, a DR-1, and the binding of ligand to RXR attracts
cofactors to the complex that activates or suppresses PPAR
responsive genes in a manner similar to PPAR
ligands
(23).
In the present study we examined the effect of novel RXR-ligand
agonists on thyroid function in diabetic rodents and in a mouse
deficient in TR. While of high affinity and selectivity for RXR,
this agonist binds all three RXR isoforms. Our data indicate that the
high-affinity RXR agonist can cause secondary hypothyroidism. To gain
insight into the mechanism involved in the RXR ligand-mediated regulation of TSH in vivo, we made use of a knockout mouse
(TR
/
) that does not express TR
, the principal
isoform that mediates TH-induced TSH suppression (8, 34).
These mice have resistance to TH, and their responses to T4
and T3 have been characterized over a wide range of TH
deprivation and replacement doses (34). The findings in
TR
-null mice demonstrate that the presence of TR
is not required
for downregulation of TSH by RXR ligands.
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MATERIALS AND METHODS |
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Animal Procedures
All animal studies were approved by the Institutional Animal Care and Use Committee of Pfizer Global Research and Development-Ann Arbor Laboratories and the Institutional Animal Care and Use Committee at the University of Chicago.Rat studies. Female Wistar and female Zucker diabetic fatty rats (ZDF/Gmi-fa/fa; ZDF rats) were purchased from Genetic Models (Indianapolis, IN) at 5-6 wk of age and were fed a semipurified high-fat diet (48% fat, 16% protein, diet no. 13004) prepared by Research Diets (New Brunswick, NJ). After the animals became hyperglycemic (fed blood glucose >250; ~3 wk on the diet), they were treated orally with vehicle (carboxymethyl cellulose) or AGN194204 (0.3 or 10 mg/kg) (14, 33) at 10:00 AM for 7 days. On the morning of the 8th day, the animals were anesthetized, and blood was collected by cardiac puncture.
Mouse studies. Male diabetic db/db (10-wk-old) mice were maintained on standard laboratory food treated by oral gavage with vehicle or AGN194204 at 4 mg/kg at 10:00 AM for 1, 3, or 7 days. They were killed after a 4-h fast when serum was obtained for TH measurements.
The method for the generation of TRMeasurements in Serum Samples
Rat TSH was measured in 50 µl of serum using the rat TSH radioimmunoassay system form Amersham Pharmacia Biotech (Piscataway, NJ), according to the manufacturer's instruction with minor modifications. Mouse TSH was measured in 50 µl of serum using a sensitive, heterologous, disequilibrium, double-antibody precipitation radioimmunoassay as described (26). Results were expressed in terms of bioassayable TSH units, calibrated with bovine TSH (Sigma Chemical, St. Louis, MO).Serum total T4 and total T3 concentrations were measured by radioimmunoassays using antibody-coated tubes (Diagnostic Products, Los Angeles, CA) in 25 and 50 µl of serum, respectively. The sensitivity of the assays was 0.2 µg T4/dl (2.6 nM) and 20 ng T3/dl (0.5 nM). The serum-free T4 concentration was estimated from the free T4 index, calculated as the product of the serum T4 concentration and the T4-resin uptake value. Whole blood glucose was measured using an HemoCue (Angelholm, Sweden). Triglyceride levels were determined with a commercial kit (Triglycerides/GB; Boeringer Mannheim, Indianapolis, IN).
Northern Blotting
Total RNA was extracted from liver of db/db mice at the time of death using TRIzol reagent. RNA was subjected to Northern analysis, hybridized overnight at 42°C with cDNA encoding mouse 5'-deiodinase (15), and labeled with D-[32P]CTP by the random primer method. The blots were washed and subjected to autoradiography and quantitated by phosphoimaging.Data Presentation and Statistical Analyses
Values are reported as means ± SE. P values were calculated by Student's t-test or ANOVA, as appropriate. Values corresponding to the respective limits of the assay sensitivities were assigned to samples that measured below the detectable range. In the mouse TSH assay, one outlier in each of the treatment groups of TR ![]() |
RESULTS |
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The high-affinity ligand for the RXR/RXR homodimer AGN194204
(33) was administered by gavage to Wistar rats (10 mg · kg1 · day
1) or ZDF
rats (0.3 or 10 mg · kg
1 · day
1) for 7 days. The diabetic rats showed a reduction in blood glucose to normal
levels and an increase in serum triglyceride levels at both doses of
the RXR activator, whereas the WT animals remained normoglycemic. There
were no significant changes in weight in the RXR ligand-treated group
(Table 1).
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Evaluation of thyroid function tests in these animals showed that there
was a significant decrease of serum total T4
(TT4) in both control and diabetic rats (Fig.
1B) after AGN194204 treatment. The serum total T3 (TT3) concentration was
significantly decreased only in rats given 10 mg · kg1 · day
1 of the RXR
agonist, although there was a trend to lower levels in the ZDF rats
given the 0.3-mg/kg dose (Fig. 1C). The decline in TH levels
was due to a central effect, either on the pituitary or hypothalamus,
since there was a significant concomitant decrease in serum TSH levels
(Fig. 1A). A dose-dependent decline in the free
T4 index, in parallel with that of TT4, was
also documented. Similar effects were observed in ZDF rats treated with
a second high-affinity RXR-ligand, AGN195203 (data not shown).
The decline in thyroid function was not strain specific,
since Fisher rats, receiving continuous infusion of AGN194204 for
2 wk, similarly showed a decline in TT4 and TT3
and TSH levels (data not shown).
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To ascertain the time course of changes in thyroid function by RXR
agonists, db/db mice were treated for 1, 3, or 7 days with 4 mg/kg AGN194204, after which serum TH levels were measured. There was a significant decrease in serum TSH levels after 24 h of
treatment, and these remained suppressed in animals treated for 3 and 7 days (Fig. 2A). The mean serum
TT4 levels fell significantly only on the third and seventh
day of treatment (Fig. 2B), suggesting it was secondary to
the fall in TSH. The decrease of thyroid hormone action in a peripheral
tissue (liver) was demonstrated by the decline in the levels of mRNA
encoding 5'-deiodinase (Fig. 2C). The reason for the small
rise after 24 h of treatment is not readily apparent but may be
due to a direct effect of the RXR agonist.
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Effect of the RXR Ligand Agonists in WT Mice and in Mice
Deficient in TR
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DISCUSSION |
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The mechanism by which nuclear receptors control transcription of
negatively regulated genes is not well understood. Although HREs have
been identified in the proximal promoter region of genes negatively
regulated by TH, their nature and structural requirement for
ligand-dependent repression have not been defined (4, 17). Recent investigations have suggested two mechanisms for the
transcriptional control of genes that are negatively regulated by the
liganded TR. One proposes the partitioning of histone deacetylases and histone acetyltransferases between TR and other transcription factors
that bind to the TSH subunits in promoters (30). Another suggests that TR2, through its unique AF-1 domain, specifically mediates a ligand-independent recruitment of coactivator to the transcription complex (25). The demonstration of
ligand-specific RXR repression of TSH gene expression could help
identify additional mechanisms for transcriptional control.
Although Brown et al. (3) showed that T3 and
9-cis-RA acted independently on distinct sites on the TSH
promoter to suppress gene expression, it was still unclear whether the
9-cis-RA required TR. To address this we tested the effect
of a new RXR ligand agonist, AGN194204, in diabetic animals and showed
that this compound induces a potent and rapid reduction in TH levels.
The time course demonstrates that this is likely due to a rapid
suppression of TSH levels (Fig. 2), similar to that seen in patients
treated with Targretin for lymphoma (28). When we
determined the effect of AGN194204 on the regulation of thyroid
function in mice lacking the two products encoded by the TR
gene
(TR
1 and TR
2), the experiment yielded two findings. First,
treatment with the RXR agonist reduced the serum TSH levels in the
absence of the TR
gene, indicating that in vivo the response to
ligand-activated RXR is TR
independent, very likely mediated by RXR
without the recruitment of TR. Although we cannot exclude the
involvement of TR
, this TR isoform plays a lesser role in the
downregulation of TSH (34). The second relevant finding is
that the 9-cis-RA analog is equally potent in the
suppression of TSH in WT and TR
knockout mice, whereas TH has a
lesser effect in these mice (34). The data thus suggest that this RXR agonist can override the resistance of thyrotrophs to TH.
Our results are in agreement with the in vitro studies suggesting a
pathway for the 9-cis-RA-mediated suppression of TSH, independent of that of TR. Although the recent demonstration of TH
resistance in RXR-deficient mice (3) does not exclude the role of TR through the formation of RXR/TR heterodimers, our results with TR-deficient animals indicate that TSH can be suppressed through RXR independently of TR
in vivo. Although both
T3 and 9-cis-RA could independently suppress
TSH
promoter activity, the combination of both ligands may produce a
stronger suppressive effect than either alone (2),
suggesting that these two hormones can cooperate in the TSH
suppression. Thus RXR agonists may be useful in the suppression of
TSH required for the control of thyroid cancer growth, especially in
older individuals in whom administration of supraphysiological doses of
TH are likely to produce cardiac complications. In addition, they
could be useful in the treatment of patients with congenital resistance
to TH, a condition in which the suppression of TSH cannot be
accomplished readily with exogenous TH (36).
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ACKNOWLEDGEMENTS |
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We thank Kristina Blanchard for excellent technical assistance.
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FOOTNOTES |
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This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-15070 (to S. Refetoff).
Address for reprint requests and other correspondence: C. F. Burant, Dept. of Internal Medicine, Univ. of Michigan, 5570D MSRB II, Box 0678, 1150 Medical Center Dr., Ann Arbor, MI 48109-0354 (E-mail: burantc{at}med.umich.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpendo.00313.2001
Received 18 July 2001; accepted in final form 2 October 2001.
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