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Minireview: Thyrotropin-Releasing Hormone and the
Thyroid Hormone Feedback Mechanism
Maria Izabel Chiamolera and Fredric E. Wondisford
Division of Metabolism, Departments of Pediatrics, Medicine, and Physiology, Johns Hopkins University Medical School,
Baltimore, Maryland 21287
Thyroid hormone (TH) plays a critical role in development, growth, and cellular metabolism. TH
production is controlled by a complex mechanism of positive and negative regulation. Hypothalamic TSH-releasing hormone (TRH) stimulates TSH secretion from the anterior pituitary. TSH then
initiates TH synthesis and release from the thyroid gland. The synthesis of TRH and TSH subunit
genes is inhibited at the transcriptional level by TH, which also inhibits posttranslational modification and release of TSH. Although opposing TRH and TH inputs regulate the hypothalamicpituitary-thyroid axis, TH negative feedback at the pituitary was thought to be the primary regulator of serum TSH levels. However, study of transgenic animals showed an unexpected, dominant
role for TRH in regulating the hypothalamic-pituitary-thyroid axis and an unanticipated involvement
of the thyroid hormone receptor ligand-dependent activation function (AF-2) domain in TH negative
regulation. These results are summarized in the review. (Endocrinology 150: 1091–1096, 2009)
S
erum concentrations of T4 and its biologically active form T3
are maintained in vivo in a narrow range by the ability of
thyroid hormone (TH) to limit its own production by negative
feedback at the hypothalamic TSH-releasing hormone (TRH)
neuron and pituitary thyrotroph. This feedback is critically dependent upon the presence of normal TH receptors (TRs),
which bind to the promoters of TRH and TSH subunit genes
and regulate their expression (1–5). In the presence of its ligand, T3, TRs mediate ligand-dependent repression of the
transcription of these genes, and in the absence of T3, the
transcription rate is not simply returned to baseline, but ligand-independent activation is observed (6 – 8). Although it is
still commonly stated that the major locus of TH regulation of
the hypothalamic-pituitary-thyroid (HPT) axis is the pituitary, new findings in mouse models suggest otherwise.
TH Action on the HPT Axis
Early studies using primary cell cultures of mouse thyrotropic
tumor cells demonstrated that TH treatment suppressed transcription of TSH subunit genes, and as a consequence, TSH synthesis was reduced (9). At about the same time, TH was shown to
ISSN Print 0013-7227 ISSN Online 1945-7170
Printed in U.S.A.
Copyright © 2009 by The Endocrine Society
doi: 10.1210/en.2008-1795 Received December 29, 2008. Accepted January 13, 2009.
First Published Online January 29, 2009
suppress prepro-TRH mRNA levels from certain neurons in the
hypothalamus (10). Finally, it was shown that TRH affected the
bioactivity of TSH by altering its glycosylation pattern (11). Thus,
TH could act at the pituitary, hypothalamic, or both levels to regulate TSH synthesis, which in turn would control TH production by
the thyroid.
Generation of mouse models where TRs were either deleted
or mutated helped to define better TH feedback action on the
HPT axis. These mouse lines were designed to model a human
disorder referred to as resistance to thyroid hormone (RTH)
where a dominantly inherited mutation in the ␤-isoforms of the
TR was found (12). The molecular basis of this disorder resides
in the dominant inhibition of endogenous TRs by a mutant receptor, which results in elevation of both serum TSH and TH
levels. To confirm that the pituitary was an important locus of
negative feedback by TH, a transgenic mouse expressing a pituitary-specific mutant TR (⌬337T) was generated (13). Transgenic mice developed profound pituitary RTH, as demonstrated
by markedly elevated baseline and non-T3-suppressible serum
TSH and pituitary TSH-␤ mRNA levels, and as expected, hypothalamic prepro-TRH mRNA levels were suppressed. Surprisingly, however, serum T4 levels were only marginally elevated in
Abbreviations: CoA, Coactivator; CoR, corepressor; CART, cocaine- and amphetamineregulated transcript; CREB, cAMP response element-binding protein; D2, type II deiodinase; DMN, dorsomedial nucleus; GR, glucocorticoid receptor; HPT, hypothalamic-pituitary-thyroid; KO, knockout; MCT, monocarboxylate transporter; NPY, neuropeptide Y;
OATP, organic anion transporting polypeptide; PVN, paraventricular nucleus; RTH, resistance to thyroid hormone; Src-1, steroid receptor CoA-1; TH, thyroid hormone; TR, TH
receptor; TRH, TSH-releasing hormone.
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these mice. After TRH administration, T4 concentrations increased in both transgenic and wild-type animals, but transgenic animals had a sustained increase over 72 h. Hypothyroid
transgenic mice also exhibited a TSH response that was only
30% of the response observed in wild-type animals. These
findings indicate that pituitary expression of this mutant TR
impairs both T3-independent activation and T3-dependent
suppression of TSH subunit gene expression in vivo. The discordance between basal TSH and T4 levels and the reversal of
these findings with TRH administration demonstrates that
resistance at the level of both the thyrotroph and the hypothalamic TRH neuron are required to elevate TH levels in
patients with RTH (13).
Although hypothalamic TRH is the major stimulator of TSH
synthesis and release from the anterior pituitary (14, 15), TH
negative feedback at the pituitary was believed to be the most
important physiological regulator of serum TSH levels (9). Recently, the central role for TRH in normal TH feedback of the
HPT axis was demonstrated. Mice that lack either TRH [TRH
knockout (KO)], the ␤-isoforms of TH receptors (TR␤ KO), or
both (double KO) were studied. As previously reported, TR␤
KO mice have significantly higher TH and TSH levels compared with wild-type mice. In contrast, double KO mice had
reduced TH and TSH levels compared with control animals.
Unexpectedly, hypothyroid double KO mice also failed to
mount a significant rise in serum TSH levels, and pituitary
TSH immunostaining was markedly reduced compared with
all other hypothyroid mouse genotypes. This impaired TSH
response, however, was not due to a reduced number of pituitary thyrotrophs because thyrotroph cell number, as assessed by TSH-immunopositive cell number, was restored after chronic TRH treatment. Thus, the TRH neuron is
absolutely required for both TSH and TH synthesis and appears to be the locus of the set-point in the HPT axis (16).
FIG. 1.
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TRH and the Hypophysiotropic TRH Neuron
TRH is a tripeptide amide (pyro-Glu-His-Pro-NH2) derived
from a large precursor protein, prepro-TRH (ppTRH), by posttranslational processing (prohormone convertase enzymes PC1,
-2, and -3) (17). The rat prepro-TRH is a 29-kDa polypeptide
composed of 255 amino acids. The rat precursor contains an
N-terminal 25-amino-acid leader sequence, five copies of the
TRH progenitor sequence Gln-His-Pro-Gly flanked by paired
basic amino acids (Lys-Arg or Arg-Arg), four non-TRH peptides
lying between the TRH progenitors, an N-terminal flanking peptide, and a C-terminal flanking peptide (18, 19). Rats and mice
have five Gln-His-Pro-Gly TRH progenitor sequences, whereas
humans have six TRH sequences (19). Serum TH levels can affect
the processing of pro-TRH by altering the prohormone convertases; low TH levels stimulate TRH and prohormone convertase
expression in the paraventricular nucleus (PVN) (20, 21).
The hypothalamic PVN, a triangular shaped nucleus located
at the dorsal limits of the third ventricle (22–24), consists of a
periventricular parvocellular part containing neurosecretory
neurons (hypophysiotropic neurons) that release their hormones
into the hypophyseal portal circulation in the median eminence,
and a magnocellular part that contains neurosecretory cells projecting to the posterior pituitary, which release oxytocin and
vasopressin (25). Studies in rats showed an inverse relationship
between serum TH levels and the expression of prepro-TRH
mRNA in the PVN during experimentally induced hypo- and
hyperthyroidism confirming an essential role for these neurons in
this classical endocrine negative feedback loop (10). This regulation was confined to a small population of TRH neurons located within the PVN.
Three main neuronal groups mediate the effects of other physiological stimuli on hypophysiotropic TRH neurons (17) (Fig. 1).
First, adrenergic input from the medulla is believed to mediate
the stimulatory effects of cold exposure on
the TRH neuron (26, 27). Catecholamines
are believed to increase the set-point for inhibition of TRH gene expression by T3,
thereby permitting high circulating levels of
TH to contribute to increased thermogenesis. Catecholamines act on TRH neurons
primarily through ␣1 adrenergic receptors
(26) that can induce the phosphorylation of
the cAMP response element-binding protein
(CREB) (28). CREB activates the TRH promoter by binding to a CREB response element in the promoter, which overlaps with a
TR binding site (29). It is hypothesized that
cold exposure increases phosphorylated
CREB, which then competes with TR for
binding to the promoter region of TRH (17).
Adrenergic fibers in contact with TRH neurons also contain at least two neuropeptides:
cocaine- and amphetamine-regulated transcript (CART) and neuropeptide Y (NPY)
(30, 31). CART exerts a stimulatory effect on
Physiological pathways for regulation of hypophysiotropic TRH neurons.
the synthesis and release of TRH (22) and may
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potentiate the action of epinephrine on the TRH neurons during
cold exposure. In contrast, NPY exerts a potent inhibitory effect on
the transcription of the TRH gene (32) through inhibition of the
cAMP-CREB second messenger pathway (33). NPY may play a role
in antagonizing the increased release of epinephrine in the PVN in
several physiological or pathological situations (34).
A second input to TRH neurons arises from peptidergic neurons in the arcuate nucleus; these neurons are believed to mediate
leptin changes in the HPT axis during fasting (35). Fasting reduces leptin secretion, which results in an increased appetite,
energy conservation, and alterations in neuroendocrine axes (36,
37). The HPT axis is affected by fasting resulting in reduced
prepro-TRH mRNA synthesis in the PVN, and as a consequence,
lower TSH and TH serum levels (38). Two separate leptin-responsive neuronal groups in the arcuate nucleus, with opposing
function, send projections to TRH neurons. These neurons signal
through either the anorectic peptides CART and ␣-MSH or the
orexigenic peptides NPY and agouti-related protein (AGRP)
(35). The balance between the effects of both neuronal groups
may also be important in establishing the TRH neuronal setpoint for TH feedback inhibition.
Finally, the hypothalamic dorsomedial nucleus (DMN)
works as a metabolic sensor for hypophysiotropic TRH neurons.
The arcuate nucleus sends axon terminals containing ␣-MSH to
the DMN and then the DMN send projections to TRH neurons
(39). Direct arcuate-PVN and indirect arcuate-DMN-PVN signaling to the TRH neuron may represent alternative pathways by
which leptin acts to regulate this neuron (18). In summary, TRH
can be synthesized and secreted in many regions of the brain (40,
41), but the hormone synthesized in the hypophysiotropic TRH
neurons is the only one regulated by TH (10). In addition to TH,
stress, cold, and nutrition can affect TRH expression.
TRs
TR isoforms are members of the nuclear receptor superfamily of
ligand-modulated transcriptional factors (42). Alternative splicing and transcription initiation of two genes produce all known
ligand-binding TR isoforms: TR␣1, TR␤1, TR␤2, and TR␤3.
The expression and regulation of the TRs vary with isoform and
tissue type (5, 43, 44). The immunocytochemical localization of
TR isoforms in the adult rat brain was reported in several areas
including the hypothalamus (45). More intense TR expression
was found in the PVN, the arcuate nucleus, and median eminence
of the adult rat (46), and TR␤2 was found in high abundance
in the PVN (5). Indeed, the restricted expression of TR␤2
(thyrotroph, TRH neurons of PVN, developing ear, and developing retina) contrasts with the more ubiquitous expression of TR␣1 and TR␤1 isoforms (42). A study using siRNA
delivery to the mouse hypothalamus showed that the siRNA
directed against TR␤1 blocks both T3-independent activation
and T3-dependent modulation of TRH transcription. In contrast, siRNA directed against TR␤2 abrogated only T3 repression of transcription (47).
In addition to these findings, the study of TR␤2-null mice
(animals lacking the TR␤2 isoform) demonstrated that basal
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prepro-TRH expression was increased in TR␤2-null mice to levels seen in hypothyroid wild-type mice, but expression did not
change significantly in response to either hypothyroidism or T3
treatment. In contrast, the suppression of prepro-TRH mRNA
expression in response to fasting was preserved in TR␤2-null
mice. Thus, TR␤2 is the key TR isoform responsible for T3mediated negative-feedback regulation by hypophysiotropic
TRH neurons (48).
Deiodinase and MCT8
The intracellular concentration of T3 is an essential determinant of TRH regulation. The intracellular concentration of T3 is
determined by cellular uptake as well as T3 production and degradation in the central nervous system. The two most important
transporter families that are involved in the TH transport in the
brain are the organic anion transporting polypeptide (OATP)
and the monocarboxylate transporter (MCT). Among these,
MCT8 shows particularly high activity toward T3 (49). One
member of the OAT family, OATP 14, is expressed in the PVN,
but this is not the higher-affinity TH transporter. On the other
hand, MCT8 is expressed in many tissues, including the brain,
where it is predominantly localized in neurons. MCT8 plays an
important role in the transport of T3 in neurons and mutations
in MCT8 interfere with the action and metabolism of T3 in these
cells (49). Mice lacking MCT8 have normal TSH levels despite
having high T3 levels. Furthermore, mice lacking the MCT8 have
low cerebral T3 levels consistent with an inability to transport T3
into neurons (50). In humans, mutations in the MCT8 gene,
located on the X chromosome, result in males with neurological
abnormalities, including global developmental delay, central hypotonia, spastic quadriplegia, dystonic movements, rotary nystagmus, and impaired gaze and hearing. The endocrine findings
include elevated T3 and decreased T4 levels in the presence of a
normal TSH secretion (51).
T3 production and degradation occurs through T4 deiodination by two separate enzymes, type II (D2) and type III (D3)
deiodinase (52). D2 activates thyroid hormone by converting T4
to T3, whereas D3 inactivates thyroid hormone by converting T3
into T2 and T4 into reverse T3. In some studies, hypothyroidism
induced only a moderate increase in D2 mRNA in the hypothalamus and no increase in D2 activity (53). In the same way, when
hypothalamic cells were analyzed in association with iodine deficiency, there was no increase in D2 activity in the hypothalamus
contrary to what was observed in other regions in the brain (54).
Taken together, these studies suggest that maintenance of a constant T3 tissue level may not be the main function of D2 in the
hypothalamus.
In contrast, T3 produced by tanycytes, a unique glial cell type
that lines the third ventricle, may be the primary source of T3 for
feedback regulation of TRH neurons. Tanycytes express high
concentration of D2 mRNA and produce T3 from peripheral
circulating T4 (55). T3 can then diffuse into the substance of the
brain to reach the hypothalamic PVN (55) or may be released
into the median eminence and transported by axon terminals to
the hypophysiotropic TRH neurons (24, 56 –59). The D2 activity in the tanycytes under different circulating TH levels seems to
contribute to the negative feedback regulation of the HPT axis
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perhaps because it allows the hypophysiotropic TRH neurons to
sense any changes in T4 output by the thyroid gland. D2-KO mice
demonstrated the critical importance of local T3 production to
control of the HPT axis. These animals have low brain T3 levels
associated with elevated serum T4 and TSH levels, indicating the
presence of central resistance to TH due to inadequate central
production of T3 (60).
The Thyroid Feedback Mechanism
TH regulates TRH gene expression and production through a
negative feedback mechanism; TRH expression is high when TH
levels are low, and TRH expression is suppressed when TH levels
are increased. As outlined earlier, TRH expression is regulated by
TH in the PVN (10, 61). This cell-specific action of TH suggests that
the TRH neurons in the PVN have all the elements necessary to
sense and respond to circulating peripheral TH levels.
As noted above, circulating T4 is converted to T3 by D2 in
tanycytes. The balance of evidence suggests that T3 then gains
access to the TRH neuron via the MCT8 transporter. After T3
enters TRH neurons in the PVN, regulation occurs at two levels:
expression of the prepro-TRH transcript and processing of proTRH into the mature TRH peptide. The regulation of TRH gene
expression by T3 occurs mostly through TR␤2, presumably via
a direct mechanism. It is also possible that T3 acts in the signaling
pathway of TRH gene expression via other hypothalamic nuclei
because TR␤2 is also expressed in the arcuate and ventromedial
nuclei, and both nuclei can alter the set-point of TRH expression
to fasting.
Clearly, the basal level of TRH gene expression is important
in determining the set-point for regulation by TH through either
a direct or indirect mechanism. What determines the basal level
of TRH gene transcription is a matter of much debate. In in vitro
studies, the unliganded TR-␤2 has been shown to activate the
TRH gene via its unique amino-terminal domain (62). This finding is consistent with the critical in vivo role of TR-␤2 in regulating the HPT axis (48). Moreover, it does not appear to be
possible to dissociate T3-independent properties of the TR,
which activate genes like TRH, from its T3-dependent activities
that result in TH inhibition of gene expression.
One of the first steps toward understanding TRH regulation
by TH was to map TH response elements in the promoter. Deletional analysis of the TRH gene identified a region in the proximal promoter, named site 4, that contained two structurally
different negative TH response elements. This region is highly
conserved both in murine and human species (2, 63). The core
sequence of site 4 (TGACCTCA) is similar to a CREB response
element, suggesting a mechanism for cAMP and TH cross talk at
the promoter (64). Although this site is important for cAMP and
T3 regulation of the TRH gene in vitro, the physiological importance of this region in vivo has yet to be proven.
Using transgenic knock-in mouse models, the mechanism of
TH negative regulation has begun to be explored in vivo. In one
model, two amino acids within the P box of the DNA binding
domain of TR-␤ were mutated to those residues found in the
glucocorticoid receptor (GR). This mutation (GS125) in vitro
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completely abolished TR␤ DNA binding while preserving T3
binding and cofactor interactions with TR. In functional assays, the mutant displayed defective trans-activation on both
positively and negatively regulated promoters (TRH, TSH␣,
and TSH␤). However, the mutant GS125 TR␤ bound to a
composite TR/GR-response element and was fully functional
on this hybrid TR/GR-response element. Mice carrying this
mutation in the germline of both alleles displayed abnormal
T3 regulation of the HPT axis identical to phenotypic abnormalities previously observed in TR␤ KO mice. TR-␤ DNA
binding, therefore, is essential for negative feedback regulation
of the HPT axis by TH (65, 66).
A second transgenic knock-in mouse model was constructed
to determine whether TR cofactor interactions were essential for
TH negative regulation. In vitro studies have demonstrated that
TR activity is regulated by binding to both corepressor (CoR)
and coactivator (CoA) proteins on TH positively regulated
genes. TH stimulation is thought to involve dissociation of CoRs,
such as nuclear receptor corepressor (NCoR) and silencing mediator for retinoic acid and TR (SMRT) (67), from the transcriptional complex and recruitment of CoAs, such as steroid receptor
CoA-1 (Src-1), to the liganded TR. The physiological role of
CoAs bound to TRs, however, had yet to be defined in vivo. A TR
knock-in mouse was generated using the E457A TR␤ mutation;
this mutation completely abolished CoA recruitment in vitro
while preserving normal T3 binding and CoR interactions. As
expected, mice bearing this allelic mutation displayed abnormal
TH-stimulated gene expression. Interestingly, however, these
animals also displayed abnormal regulation of the HPT axis.
Serum TH, TSH level, and pituitary TSH subunit mRNA levels
were inappropriately elevated compared with those of wild-type
animals, and T3 treatment failed to suppress serum TSH and
pituitary TSH subunit mRNA levels. These data illustrate the
importance of an intact CoA-binding surface for both positive
and negative regulation by TH in vivo (68).
CoAs are proteins that can remodel chromatin via enzymatic
acetylation of histone tails or via regulation of transcriptional
complex assembly at the promoter by interactions with RNA
polymerase and general transcription factors (69). One of the
best studied CoA proteins is Src-1, a member of the p160 class of
transcriptional factors, first identified as steroid receptor coactivator (70) and then characterized as a coactivator of other
nuclear receptors, including the TR (71, 72). Src-1 KO mice
showed mild resistance to TH (73), suggesting that this CoA may
be critical in TH regulation of the HPT axis in the E457A mouse.
How recruitment of a CoA to the liganded TR results in inhibition of gene expression in the HPT axis remains a puzzle. Perhaps
binding of this cofactor to the TR AF-2 domain recruits other
corepressor proteins to the transcriptional complex, which then
repress gene expression.
In conclusion, the mechanism of TH negative feedback control of the HPT axis has been clarified by recent studies. Experimental models demonstrated the critical role of hypothalamic
TRH in the control of HPT axis and in establishing the set-point
of the axis. The realization that the TR-␤2 isoform primarily
regulates the HPT axis defined a mechanistic difference between
TH inhibition and stimulation. Further studies are directed at
Endocrinology, March 2009, 150(3):1091–1096
understanding other unique features of TH inhibition at the transcriptional level. Finally, TRH gene expression is also regulated
by temperature, food intake, and stress. Thus the TRH neuron is
well positioned to integrate information about the environment
as well as circulating TH levels and ultimately affect metabolism
in response to these physiological changes.
Acknowledgments
Address all correspondence and requests for reprints to: Fredric E.
Wondisford, Division of Metabolism, Departments of Pediatrics, Medicine, and Physiology, Johns Hopkins University Medical School, Baltimore,
Maryland 21287. E-mail: [email protected].
Disclosure Statement: The authors have nothing to disclose.
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