Content uploaded by John Howard Duncan Bassett
Author content
All content in this area was uploaded by John Howard Duncan Bassett on Mar 12, 2014
Content may be subject to copyright.
REVIEW
Local control of thyroid hormone action: role of type 2 deiodinase
Graham R Williams and J H Duncan Bassett
Molecular Endocrinology Group, Department of Medicine and Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith
Hospital, Commonwealth Building 7th Floor, Du Cane Road, London W12 0NN, UK
(Correspondence should be addressed to G R Williams; Email: graham.williams@imperial.ac.uk)
Abstract
The thyroid gland predominantly secretes the pro-hormone
thyroxine (T
4
) that is converted to the active hormone
3,5,30-L-triiodothyronine (T
3
) in target cells. Conversion of
T
4
to T
3
is catalyzed by the type 2 iodothyronine deiodinase
enzyme (DIO2), and T
3
action in target tissues is determined
by DIO2-regulated local availability of T
3
to its nuclear
receptors, TRaand TRb. Studies of Dio2 knockout mice
have revealed new and important roles for the enzyme
during development and in adulthood in diverse tissues
including the cochlea, skeleton, brown fat, pituitary, and
hypothalamus. In this review, we discuss the molecular
mechanisms by which DIO2 controls intracellular T
3
availability and action.
Journal of Endocrinology (2011) 209, 1–12
Introduction
Thyroid hormones are important homeostatic regulators that
act via nuclear thyroid hormone receptors (TRs) in virtually all
tissues during development and throughout postnatal life. 3,5,30,
50-L-tetraiodothyronine (thyroxine, T
4
) is a pro-hormone that
circulates at a high concentration in peripheral blood relative to
the active hormone 3,5,30-L-triiodothyronine (T
3
). Concentra-
tions of T
4
and T
3
in target tissues are controlled by metabolism;
local conversion of T
4
to T
3
is catalyzed by the type 2 iodo-
thyronine deiodinase enzyme (DIO2), while the type 3 enzyme
(DIO3) prevents activation of T
4
and inactivates T
3
.Thispre-
receptor control of ligand availability to TRs in target cells is a
crucial mechanism that regulates the timing of cellular responses to
thyroid hormones in a tissue-specific manner. The physiological
importance of this coordinated process has been demonstrated in
several organ systems by a series ofe legant in vivo studies, and in this
study, we review recent developments with particular emphasis
on the importance of hormone activation mediated by DIO2.
Thyroid physiology
The hypothalamic–pituitary–thyroid axis
Circulating thyroid hormone concentrations are maintained
in the euthyroid range by a classical negative feedback loop
(Fig. 1). Thyrotropin-releasing hormone (TRH) is syn-
thesized in the hypothalamic para-ventricular nucleus (PVN)
and stimulates synthesis and release of TSH from thyrotroph
cells in the anterior pituitary gland. TSH in turn acts via the
TSH receptor (TSHR) in thyroid follicular cells to stimulate
cellular growth and the synthesis and release of T
4
and T
3
into
the circulation (Kopp 2001). Thyroid hormone action is
mediated in target tissues by TRs, but thyroid hormones also
inhibit TRH and TSH synthesis and secretion in the
hypothalamus and pituitary to complete a negative feedback
loop (Forrest et al. 1996b,Nikrodhanond et al. 2006). This
negative feedback loop maintains circulating thyroid hor-
mones and TSH in a physiological inverse relationship that
defines the hypothalamic–pituitary–thyroid (HPT) axis set-
point (Bassett & Williams 2008).
Circulating thyroid hormones and uptake into target cells
The thyroid gland predominantly secretes the inactive pro-
hormone T
4
, as well as small amounts of the physiologically
active thyroid hormone T
3
. Both T
4
and T
3
are lipophilic and
poorly soluble in water, and over 95% of thyroid hormones
are protein bound in the circulation. Thyroxine-binding
globulin (TBG), transthyretin, albumin, and several lipo-
proteins function as the transport proteins for T
4
and T
3
in plasma. Free thyroid hormone levels are thus dependent
upon the concentrations and saturations of these proteins.
The unbound free T
3
fraction represents 0.3% of the total T
3
concentration in plasma, but because of its higher binding
This paper is one of 3 papers that for m part of a thematic issue section on
thyroid. The Guest Editor for this section was Domenico Salvatore, Italy.
1
Journal of Endocrinology (2011) 209, 1–12 DOI: 10.1530/JOE-10-0448
0022–0795/11/0209–001 q2011 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org
affinity for TBG, the free T
4
fraction represents just 0.02%
of the total plasma T
4
concentration. Thus, despite the total
T
4
concentration being 50-fold greater than total T
3
, the
circulating free T
4
concentration is only fourfold higher. T
4
is exclusively synthesized and secreted by thyroid follicular
cells, whereas the majority of circulating T
3
is generated in
peripheral tissues by enzymatic removal of a 50-iodine from
T
4
. Due to their lipophilic nature, thyroid hormones had
been likely to enter target cells by a passive process of diffusion
(Friesema et al. 2005). In fact, the free hormones enter target
cells via an energy-dependent, ATP-requiring, stereospecific,
and saturable transport mechanism that is mediated by the
monocarboxylate transporter 8 (MCT8; Friesema et al. 2003,
2006,Dumitrescu et al. 2006), MCT10, and other transporter
proteins including OATP1c1, a member of the Na
C
-
independent organic anion transporter protein (OATP)
family ( Jansen et al. 2005,Heuer 2007,van der Deure et al.
2010;Fig. 2). Transport via MCT8, for example, increases
uptake of T
4
and T
3
by tenfold (Friesema et al. 2003).
Thyroid hormone metabolism
Deiodinase enzymes
The iodothyronine deiodinases are selenocysteine-containing
enzymes that metabolize thyroid hormones to active or
inactive products (Bianco et al. 2002). The type 1 deiodinase
enzyme (DIO1) is rather inefficient with an apparent
Michaelis constant (K
m
)of10
K6
–10
K7
M and catalyzes
removal of inner or outer ring iodine atoms in equimolar
proportions to generate T
3
, reverse T
3
(rT
3
), or 3,30-
diiodothyronine (T
2
) depending on the substrate. Most of
the circulating T
3
is derived from conversion of T
4
to T
3
by
the actions of DIO1, which is localized to the plasma
membrane and expressed in liver and kidney. Nevertheless,
activity of the DIO2 enzyme in skeletal muscle may also
contribute to circulating levels of T
3
, although its role is
controversial and may differ between species (Bianco et al.
2002,Maia et al. 2005,Bianco & Kim 2006,Heemstra et al.
2009b,Larsen 2009). The DIO2 enzyme is considerably more
efficient than DIO1, catalyzing only the removal of an outer
ring iodine atom from the pro-hormone T
4
with a K
m
of
10
K9
M to generate the physiologically active product T
3
.
The major role of DIO2 is to control the intracellular T
3
concentration, its availability to the nucleus, and the
saturation of the nuclear T
3
receptor in target tissues.
Moreover, DIO2 is likely to protect tissues from the
detrimental effects of hypothyroidism because its low K
m
continues to permit the efficient local conversion of T
4
to T
3
.
T
4
treatment of cells, in which MCT8 and DIO2 are
co-expressed, results in increased T
3
target gene expression
(Friesema et al. 2006), indicating that thyroid hormone
uptake and metabolism coordinately regulate T
3
action. By
contrast, the DIO3 enzyme irreversibly inactivates T
3
,or
prevents T
4
being activated, by catalyzing removal of an inner
ring iodine atom with a K
m
of 10
K9
M to generate T
2
or rT
3
respectively. Thus, inactivating DIO3 prevents thyroid
hormone access to specific tissues at cr itical times and reduces
TR saturation (Bianco et al. 2002,Bianco & Kim 2006).
Control of intracellular T
3
availability
The relative activities of DIO2 and DIO3, which have the
same K
m
values for substrate, consequently regulate intra-
cellular concentrations of T
3
and its availability to the nuclear
TR (Bianco et al. 2002,Bianco & Kim 2006,St Germain et al.
2009). In conjunction with serum-derived T
3
, DIO2 and
DIO3 are important local modulators of thyroid hormone
responsiveness in vivo. Expression of both enzymes is regulated
in a temporo-spatial and tissue-specific manner, resulting in
varying levels of T
3
action in individual tissues at distinct times
during development (Bates et al. 1999,St Germain et al. 2009).
Acting together, DIO2 and DIO3 thus control cellular T
3
availability by a mechanism that is largely independent of
serum thyroid hormone concentrations (Bianco & Kim 2006).
Thyroid hormone action
Thyroid hormone receptors
Thyroid hormone actions in target cells are ultimately
determined by the availability of T
3
to its nuclear receptor
(St Germain et al. 2009;Fig. 2). TRaand TRbare members
of the steroid/TR superfamily (Sap et al. 1986,Weinberger
et al. 1986). The TRs are ligand-inducible transcription factors
that regulate expression of hormone-responsive target genes.
In mammals, the THRA gene encodes three C-terminal
T4DIO2? T3TRβ2–PVN
T4
T4 + T3
DIO2 T3TRβ2–
+
+
Hypothalamus
Pituitary
TSH
TRH
Thyroid
Figure 1 Negative feedback regulation of the hypothalamic–
pituitary–thyroid axis. The role of DIO2 in negative feedback
control of the HPT axis occurs predominantly in thyrotrophs of the
anterior pituitary gland. PVN, para-ventricular nucleus; TRH,
thyrotropin-releasing hormone; DIO2, type 2 deiodinase enzyme;
TRb2, thyroid hormone receptor b2; T
4
, thyroxine; T
3
, 3,5,30-L-
triiodothyronine.
G R WILLIAMS and J H D BASSETT .Local control of T
3
action by Dio22
Journal of Endocrinology (2011) 209, 1–12 www.endocrinology-journals.org
variants of TRa.TRa1 is a functional receptor that binds
both DNA and T
3
, whereas TRa2 and TRa3 fail to bind T
3
and act as antagonists in vitro (Harvey & Williams 2002).
A promoter within intron 7 of mouse Thra gives rise to two
truncated variants, TRDa1 and TRDa2, which act as potent
dominant-negative antagonists in vitro, although their phys-
iological role is unclear (Chassande et al. 1997). The THRB
gene encodes two N-terminal TRbvariants, TRb1 and
TRb, both of which act as functional receptors. Two further
transcripts, TRb3 and TRDb3, have also been described in
the rat, but their physiological role is also uncertain (Williams
2000,Harvey et al. 2007). TRa1 and TRb1 are expressed
widely, but their relative concentrations differ during
development and in adulthood due to tissue-specific and
temporo-spatial regulation (Forrest et al. 1990). The current
understanding is that most T
3
target tissues are either
predominantly TRa1orTRb1 responsive or lack TR
isoform specificity. Expression of TRb2, however, is
markedly restricted. In the hypothalamus and pituitary, it
controls the HPT axis feedback loop by mediating the
inhibitory actions of thyroid hormones on TRH and TSH
expression (Fig. 1;Abel et al. 1999,2001), while in the
cochlea and retina TRb2 is an important regulator of sensory
development (Ng et al. 2001,Jones et al. 2007).
Developmental control of T
3
action
Unliganded TRs compete with T
3
-bound TRs for DNA
response elements. They act as potent transcriptional
repressors and have been shown to have critical regulatory
roles in the development of a number of key tissues
(Hashimoto et al. 2001,Chassande 2003,Venero et al. 2005,
Wallis et al.2008). Unoccupied TRs interact with
co-repressor proteins, including nuclear receptor co-repressor
(NCoR) and the silencing mediator for retinoid and TR
(SMRT), which recruit histone deacetylases and maintain a
non-permissive closed chromatin structure to inhibit gene
transcription. Ligand-bound TRs, however, interact with
steroid receptor co-activator 1 (SRC1) and other related
co-activators in a hormone-dependent fashion. These
co-activator proteins function as histone acetyl transferases,
thereby promoting an open nucleosome structure leading to
target gene activation. The contrasting chromatin-modifying
effects of liganded and unliganded TRs, thus, greatly enhance
the magnitude of the transcriptional response to T
3
(Harvey
& Williams 2002,Chassande 2003). In addition to the
positive stimulatory effects on target gene expression, T
3
also
mediates transcriptional repression to inhibit the expression of
certain key target genes, including TSH. Although such
negative regulatory effects are physiologically critical, the
responsible underlying molecular mechanisms have not been
fully characterized (Cheng et al. 2010). Although expression
of both TRa1 and TRb1 is widespread, their relative levels of
expression differ between tissues during embryogenesis and in
postnatal life. Differential control of TRa1 and TRb1,
therefore, provides another mechanism to regulate tissue-
specific T
3
responses during development and growth
(O’Shea et al. 2006). Although the free T
4
concentration is
approximately fourfold greater than free T
3
, the TR-binding
affinity for T
3
is 15-fold higher than its affinity for T
4
MCT8
MCT10
OATP1C1
T4T4
T3
T3
T3
TRRXR
TRE
rT3
T2
T3
DIO3
DIO2
Figure 2 Regulation of intracellular supplies of T
3
to the nucleus of T
3
target cells. MCT8
and MCT10, monocarboxylate transporters 8 and 10; OATP1C1, organic acid transporter
protein-1C1; DIO2 and DIO3, type 2 and 3 deiodinase enzymes; TR, thyroid hormone
receptor, RXR, retinoid X receptor; T
4
, thyroxine; T
3
, 3,5,30-L-triiodothyronine; rT
3
,
3,30,50-triiodothyronine; T
2
, 3,30-diiodothyronine.
Local control of T
3
action by Dio2 .G R WILLIAMS and J H D BASSETT 3
www.endocrinology-journals.org Journal of Endocrinology (2011) 209, 1–12
(Lin et al. 1990). Thus, T
4
acts as a pro-hormone, which must
be metabolized to T
3
for the mediation of thyroid hormone
actions (Bianco & Kim 2006). Taken together, the temporo-
spatial and tissue-specific regulated expression of both the
DIO2 and the DIO3 enzymes (Bates et al. 1999) and the
TRa1 and TRb1 nuclear receptors (Forrest et al. 1990)
combine to provide a complex but co-ordinated system for
fine control of T
3
availability and action in individual cell
types during development. DIO3 is expressed in fetal tissues
and the utero-placental unit where it acts as a barrier that
prevents maternal thyroid hormone access to the developing
fetus (Wasco et al. 2003).
Unliganded TRs are key factors that prevent premature cell
differentiation and maintain cell proliferation in order to allow
organogenesis to proceed in the developing fetus (Plateroti
et al. 2001,Flamant et al. 2002,Chassande 2003). In mammals,
the reciprocally regulated decrease in DIO3 activity and
increase in DIO2 activity at birth results in a rapid rise in T
3
production (Bates et al. 1999). Similar changes have been
observed during metamorphosis and hatching in amphibians
and birds respectively (Huang et al. 2001). An increase in
DIO2 expression in target tissues together with a decrease in
DIO3 expression results in an increased intracellular T
3
concentration, binding of T
3
to its nuclear receptor, and
initiation of cell differentiation (Campos-Barros et al. 2000,
Sachs et al. 2000,Huang et al. 2001,Plateroti et al. 2001,
Flamant et al. 2002,Mai et al. 2004,Ng et al. 2004). Thus,
TRs function as developmental switches that are dependent
on the activities of the deiodinases and which regulate the
onset of T
3
target tissue differentiation during embryogenesis.
For example, in the developing embryo, DIO2 has been
shown to regulate the pace of endochondral ossification and
bone formation (Dentice et al. 2005), while activity of DIO2
in developing cartilage is regulated by the morphogen Indian
hedgehog and the ubiquitin ligase WSB-1 (Dentice et al.
2005). In addition, ubiquitin-mediated degradation of DIO2
has been shown to regulate thyroid hormone activation in
several other tissues (Bianco & Larsen 2005,Fekete et al. 2007,
Sagar et al. 2007). In this situation, ubiquitin-mediated
proteasomal degradation of DIO2 is increased following
exposure to substrate (T
4
), and this mechanism thus represents
a rapid and sensitive posttranslation mechanism to control and
limit the DIO2 activity and T
3
production (Gereben et al.
2000,Steinsapir et al. 2000,Zavacki et al. 2009).
These considerations are important physiologically and
in thyroid disease. In thyroid hormone deficiency, DIO2
expression and activity are increased, whereas its expression
and activity are reduced in thyrotoxicosis. By contrast, DIO3
expression is regulated in a reciprocal manner at extremes of
thyroid dysfunction. Thus, the ratio of DIO2 and DIO3
activity determines homeostatic control of T
3
availability to
the nuclear receptor even in thyroid disease. In the brain, the
DIO2 activity is increased in response to hypothyroidism
(Burmeister et al. 1997), whereas activity of DIO3 is markedly
reduced (Friedrichsen et al. 2003). This response is considered
to protect the developing brain from changes in circulating
thyroid hormones and to mitigate the severe and detrimental
effects of hypothyroidism (Calvo et al. 1990,Guadano-Ferraz
et al. 1999,Heuer 2007). Thus, maintenance of thyroid
hormone availability in specific brain regions is critically
regulated by reciprocal expression of DIO2 and DIO3 (Tu
et al. 1997,1999,Bianco et al. 2002,Kester et al. 2004).
Dio2 knockout mice
In order to investigate the function of DIO2 in vivo,
knockout mice deficient in the enzyme were generated and
found to have normal fertility (Schneider et al. 2001). Dio2
knockout (D2KO) mice exhibit isolated hypothyroidism in
critical tissues that depend on DIO2-catalyzed T
4
to T
3
conversion to regulate cellular thyroid status. Thus, D2KO
mice have an elevated circulating TSH concentration, are
unable to sustain a normal body temperature following cold
exposure despite a normal circulating T
3
concentration, are
deaf, and have brittle bones (de Jesus et al. 2001,Schneider
et al. 2001,Ng et al. 2004,Bassett et al. 2010), suggesting
important physiological roles for DIO2 in the pituitary
gland and brain, in brown adipose tissue, in the cochlea,
and in the skeleton.
Role of DIO2 in regulation of the HPT axis
Analysis of the HPT axis in D2KO mice demonstrated a two-
to threefold increase in the circulating TSH concentration, a
27–40% increase in the T
4
level accompanied by reduced
clearance of T
4
from plasma, but a normal T
3
(Schneider et al.
2001,Christoffolete et al. 2007,Galton et al. 2007). Serum
TSH was suppressed following treatment with T
3
but not in
response to T
4
, indicating that D2KO mice have pituitary
resistance to feedback regulation by T
4
(Schneider et al. 2001).
Surprisingly, TRH mRNA levels in the PVN were not
increased in D2KO mice despite their elevated TSH level,
suggesting that resistance to T
4
suppression results mainly from
Dio2 deficiency in the pituitary rather than the hypothalamus
(Rosene et al. 2010). Thus, DIO2 is essential for regulation of
the HPTaxis and enables the pituitary to respond to changes in
the circulating T
4
level (Fig. 1). In addition, it is important to
note that the inactivating DIO3 enzyme is also a key regulator
of the HPT axis. Analysis of DIO3-deficient (D3KO) mice
indicates that DIO3 plays a key role in the development of the
HPT axis set-point. Neonatal D3KO mutants have elevated
circulating thyroid hormone concentrations due to impaired
T
3
clearance, whereas central hypothyroidism is evident after
2 weeks of age and results from defective TRH and TSH
responsiveness in the pituitary and thyroid (Hernandez et al.
2006,2007). New-born D3KO mice display tissue thyrotoxi-
cosis in the brain despite low circulating T
4
levels. However,
they also have increased DIO2 activity as a result of
the low circulating T
4
levels, and this is reflected by an
increase in the cellular T
3
concentration (Hernandez et al.
2006). These observations demonstrate a vital role for DIO3 in
G R WILLIAMS and J H D BASSETT .Local control of T
3
action by Dio24
Journal of Endocrinology (2011) 209, 1–12 www.endocrinology-journals.org
the determination of thyroid status in peripheral target tissues
and indicate the close inverse relationship between DIO2
and DIO3 during maturation of the HPT axis.
Role of DIO2 in the brain
In the brain, DIO2 is expressed in glial cells, third ventricle
tanycytes, astrocytes, and some sensory neurons including
nuclei within the trigeminal and auditory pathways (Guadano-
Ferraz et al. 1997,1999,Tu et al. 1997). As discussed earlier,
studies in D2KO mice indicated that DIO2 is required
for local T
3
generation in the pituitary and essential for
normal control of the HPT axis (Schneider et al. 2001).
In addition, neonatal D2KO mice have a 25–50% reduction
in tissue T
3
concentrations throughout the brain, which is
similar to that seen in hypothyroid wild-type littermate mice.
The reduced tissue T
3
concentration in neonatal D2KO mice
does not result from increased T
3
degradation, as activity of
the inactivating DIO3 enzyme is not altered in any brain
regions (Galton et al. 2007). Thus, deficiency of DIO2 results
in reduced local T
3
generation throughout the developing
brain. Nevertheless, expressions of the T
3
-responsive genes
Hairless,TrkB,Rc3, and Srg1 are less susceptible to change in
D2KO mice compared with the altered expression observed
in thyroid-deficient mice (Galton et al. 2007). Thus, despite
the markedly increased expression of DIO2 in the newborn
brain (Bates et al. 1999), D2KO mice have a mild neurological
phenotype in comparison with the severe consequences of
systemic hypothyroidism. Although T
3
availability in neurons
is dependent on the DIO2 activity in adjacent glial cells, these
surprising data reveal that compensatory mechanisms can
mitigate the neurological damage resulting from DIO2
deficiency and also show that alternative sources of T
3
can
access the brain during development (Galton et al. 2007).
These compensatory sources are not likely to involve
increased transport mediated by MCT8 because the levels
of MCT8 expression in the brain are similar in euthyroid,
hypothyroid, and D2KO mice (Galton et al. 2007). Although
D2 expression peaks at important times during development
of the brain and is required to generate adequate intracellular
concentrations of T
3
throughout the brain, it seems that the
consequences of DIO2 deficiency during central nervous
system development are mitigated by other sources of T
3
such
as the cerebrospinal fluid (CSF) or serum (Galton et al. 2007).
The physiological efficiency of these compensatory sources
of T
3
was demonstrated following assessment of neurobeha-
vioral function, which revealed only minimal differences
between D2KO and wild-type mice following testing of
reflexes, locomotion and agility, learning and memory,
olfaction, anxiety, and exploration (Galton et al. 2007).
Interestingly, a recent study was performed in which T
3
target
gene expression in cerebral cortex was compared between
hypothyroid wild-type D2KO and MCT8KO mice (Morte
et al. 2010). The aim was to investigate whether the source of
tissue T
3
in brain via local T
3
generation (disrupted in D2KO
mice) or via transport across the blood–brain barrier
(disrupted in MCT8KO mice) elicited differing target gene
responses. Little effect on T
3
target gene response was seen in
MCT8KO mice because a compensatory increase in DIO2
expression was identified which was proposed to mitigate local
T
3
deficiency. By contrast, in D2KO mice, therewas increased
expression of T
3
target genes normally inhibited by T
3
, but no
effect was seen on genes that are normally positively regulated
by T
3
. In hypothyroid wild-type mice, however, expression of
both negatively and positively regulated T
3
target genes was
affected (Morte et al. 2010). Taken together, these intriguing
observations suggest that the source of T
3
in the brain (locally
generated T
3
versus T
3
transported from serum and CSF)
may influence the T
3
response elicited.
Role of DIO2 in brown adipose tissue and adaptive
thermogenesis
D2KO mice exposed to cold are unable to maintain their body
temperature despite the presence of a normal circulating
T
3
concentration. The mild hypothermia following cold
exposure results from impaired energy expenditure in brown
adipose tissue that is mitigated by a compensatory shivering
response associated with acute weight loss (de Jesus et al. 2001).
Isolated brown adipocytes from D2KO mice fail to respond
normally to adenylyl cyclase activators or noradrenaline
resulting in impaired cAMP, oxygen consumption, and
mitochondrial uncoupling protein 1 mRNA responses to
adrenergic stimulation. These defects are similar to obser-
vations in hypothyroidism but are not seen in brown
adipocytes obtained from D2KO mice treated with T
3
(de Jesus et al. 2001). The findings indicate that the cAMP-
dependent DIO2 enzyme is required for adrenergic respon-
siveness and adaptive thermogenesis in brown adipocytes.
Further studies, however, revealed a large compensatory
increase in brown fat sympathetic stimulation that bypasses the
reduced adrenergic responsiveness of D2KO brown adipo-
cytes. The increased sympathetic tone in brown fat induced a
marked lipolytic response, which depletes fatty acid stores and
results in the defective adaptive thermogenesis and hypother-
mia observed in D2KO mice (Christoffolete et al. 2004).
Subsequent studies also showed that bile acids activate DIO2
in brown fat via a cAMP-dependent mechanism involving the
G-protein-coupled receptor TGR5, thus identifying a new
role for DIO2 in diet-induced thermogenesis as bile acids were
also shown to protect mice from diet-induced obesity
(Watanabe et al. 2006). Accordingly, D2KO mice have greater
susceptibility to diet-induced obesity that may result in part
from impaired brown adipose tissue development during
embryogenesis (Hall et al. 2010) as well as impaired diet-
induced thermogenesis.
Role of DIO2 in muscle
Muscle is an important T
3
target tissue, and euthyroidism is
required for its efficient function and regeneration. Recent
studies in mice have demonstrated that Dio2 mRNA and
Local control of T
3
action by Dio2 .G R WILLIAMS and J H D BASSETT 5
www.endocrinology-journals.org Journal of Endocrinology (2011) 209, 1–12
activity are expressed in skeletal muscle. Type I slow-twitch
fibers displayed fivefold greater Dio2 activity than type II fast-
twitch fibers, and hypothyroidism resulted in a threefold
induction of activity without changes in mRNA levels
(Marsili et al. 2010). MyoD is a master regulator of myogenic
differentiation and muscle regeneration, and new studies have
established that Dio2-mediated generation of T
3
is essential
for efficient transcription of MyoD (Dentice et al. 2010).
Furthermore, the Dio2 activity is present in muscle stem cells
and increases during myogenic differentiation. Accordingly,
in D2KO mice, myocytes exhibit a hypothyroid phenotype
despite normal circulating T
3
levels, the expression of T
3
-
responsive genes including MyoD is markedly reduced, and
muscle regeneration is delayed following injury. In primary
myoblasts, a forkhead box transcription factor, FoxO3, has
been shown to induce Dio2 expression and mediate the surge
in Dio2 activity necessary to increase the local intracellular T
3
concentration and thereby ensures normal muscle formation
and regeneration (Dentice et al. 2010). Thus, Dio2 is essential
for skeletal muscle development, function, and repair.
Role of DIO2 in the cochlea
In the cochlea, DIO2 is expressed in periosteal connective
tissue surrounding the internal sensory tissues, with enzyme
activity peaking at postnatal day P7, a few days prior to the
onset of hearing around P14. TR expression, however, is
localized to the cochlea sensory epithelium, suggesting that
periosteal DIO2 provides a temporo-spatially regulated
paracrine supply of T
3
to the sensory epithelium that is
necessary for correct timing of cochlea development and
maturation (Campos-Barros et al. 2000). This hypothesis
was supported by findings in D2KO mice, which exhibit
delayed differentiation of the auditory sensory epithelium
and delayed cochlea development with abnormal formation
of the tectorial membrane. The resulting deafness in D2KO
mice is similar to that seen in systemic hypothyroidism or
in TRbknockout mice (Forrest et al. 1996a,Rusch et al.
1998,2001) but occurs despite circulating levels of thyroid
hormones that are normally permissive for development of
hearing. Treatment of D2KO mice with T
3
ameliorated the
phenotype, indicating that DIO2-dependent local gener-
ation of T
3
in the surrounding bony labyrinth is essential
for development of the cochlea and subsequent auditory
function (Ng et al. 2004). In this case, the activating DIO2
enzyme functions as a local paracrine amplifier of T
3
action
to regulate sensory development. More recently, DIO3 was
also found to be expressed in the cochlea, and D3KO mice
were shown to be deaf and have advanced cochlear
maturation (Ng et al. 2009), indicating that DIO3 normally
protects the cochlea from premature T
3
-induced differen-
tiation. Thus, development of the cochlea and the onset
of normal auditory function require tightly controlled and
correctly timed availability of T
3
that is achieved by
co-ordinated reciprocal alterations in the expression and
activities of DIO2 and DIO3.
Role of DIO2 in the skeleton
It is well known that hypothyroidism causes delayed bone
formation and linear growth retardation. Possible roles for
DIO1 and DIO2 in the skeleton were first studied in the
context of growth. A minor and transient impairment of
weight gain was initially reported in male D2KO mice,
although linear growth was not determined (Schneider et al.
2001). Weight gain and growth, however, were normal in
D1KO- and in DIO1-deficient C3H/HeJ mice and in
combined C3H/HeJ D2KO mutants with DIO1 and DIO2
deficiency (Berry et al. 1993,Schoenmakers et al. 1993,
Schneider et al. 2006,Christoffolete et al. 2007). We and
others showed that DIO1 is not expressed in bone and
cartilage (LeBron et al. 1989,Dreher et al. 1998,Gouveia et al.
2005,Williams et al. 2008), indicating that DIO1 does not
directly influence T
3
action in bone.
Nevertheless, important roles for DIO2 during skeletogen-
esis and in adult bone are emerging. The DIO2 activity was
demonstrated in the perichondrium surrounding the
embryonic chick growth plate where its activity is regulated
by the skeletal morphogen SHH (Dentice et al. 2005). SHH is
secreted by perichondrial cells and acts in growth plate
chondrocytes to stimulate ubiquitin-mediated degradation of
DIO2. The resulting modulation of thyroid hormone
signaling in the growth plate is accompanied by increased
PTHrP signaling, which is also seen in hypothyroidism
(Stevens et al. 2000) and which regulates the pace of
chondrocyte differentiation during early skeletogenesis
(Dentice et al. 2005). Analysis of developing bone from
mice at embryonic days E14.5–E18.5 revealed the presence of
DIO2 activity (Capelo et al. 2008), suggesting that a similar
regulatory role for DIO2 in cartilage during early skeletogen-
esis may occur in the mouse as well as the developing chick
(Dentice et al. 2005).
There have been conflicting reports regarding the
expression and activity of DIO2 in whole bone tissue extracts
and in skeletal cells (LeBron et al. 1989,Bohme et al. 1992,
Ballock & Reddi 1994,Dreher et al. 1998,Wakita et al. 1998,
Gouveia et al. 2005,Morimura et al. 2005,Capelo et al. 2008).
Using a sensitive and highly specific HPLC-based assay, we
demonstrated that specific DIO2 activity is restricted to
differentiated osteoblasts but is undetectable in chondrocytes
and osteoclasts (Williams et al. 2008). The significance of this
finding was investigated in D2KO mice (Bassett et al. 2010).
There were no differences in linear growth and bone
formation between D2KO and wild-type mice, although
adult D2KO mice had brittle bones with impaired resistance to
fracture. The phenotype was due to reduced osteoblastic bone
formation without impairment of osteoclastic bone resorp-
tion, which caused a reduced rate of mineral apposition and
prolongation of the formation phase of the bone remodeling
cycle, thus facilitating an increase in secondary mineralization
that resulted in a generalized increase in bone mineralization
density (Bassett et al. 2010). The T
3
target gene analysis
demonstrated cellular T
3
deficiency restricted to osteoblasts,
G R WILLIAMS and J H D BASSETT .Local control of T
3
action by Dio26
Journal of Endocrinology (2011) 209, 1–12 www.endocrinology-journals.org
indicating that maintenance of adult bone mineralization
and optimal bone strength requires local DIO2-mediated
production of T
3
in osteoblasts (Bassett et al. 2010).
These findings suggest that the restricted expression of
DIO2 in adult bone is necessary to maintain a higher
intracellular T
3
concentration in osteoblasts relative to other
skeletal cells. As in other tissues, the DIO2 activity in
osteoblasts is increased in hypothyroidism and inhibited
in hyperthyroidism (Gouveia et al. 2005). Thus, DIO2 acts
to buffer the effects of altered serum thyroid hormone levels
on the skeleton; the adverse effects of T
3
deficiency on bone
mineralization may be mitigated by increased DIO2 activity
in osteoblasts, while inhibition of DIO2 activity in
hyperthyroidism limits the detrimental effects of thyroid
hormone excess (Bassett et al. 2010). This hypothesis suggests
that optimal bone mineralization and strength are maintained
over the physiological range of systemic thyroid hormone
concentrations by the regulated activity of DIO2 in
osteoblasts. Escape from this local feedback mechanism in
osteoblasts may account in part for the increased susceptibility
to fracture observed in hypothyroidism and thyrotoxicosis
(Vestergaard & Mosekilde 2002,Vestergaard et al. 2005),
suggesting the possibility of DIO2 as a therapeutic target for
the treatment of osteoporosis.
A recent human population study has also suggested
that DIO2 may influence susceptibility to osteoarthritis.
A genome-wide linkage analysis identified an association
between the DIO2 polymorphism rs225014 and the
generalized symptomatic osteoarthritis (Meulenbelt et al.
2008), although the association was not replicated in a
subsequent association study and meta-analysis (Kerkhof et al.
2010). Nevertheless, a recent meta-analysis has also identified
a possible role for DIO3 in osteoarthritis susceptibility
(Meulenbelt et al. 2010). Taken together, these new and
preliminary findings suggest that deiodinase-regulated T
3
availability in chondrocytes may play an important role in the
regulation of cartilage renewal and repair.
Conserved and pivotal role of DIO2 in the control
of seasonal reproduction
A series of recent elegant studies, initially in the Japanese
quail (Coturnix japonica;Yoshimura et al. 2003) but also in
mammals, have identified a major role for DIO2 in the
seasonal control of reproduction. Seasonal time measurement
is achieved by sensing of the changing photoperiod in
temperate zones. Regulatory sensing of the changing
photoperiod and the subsequent gonadal response are
localized to the medio-basal hypothalamus (MBH). In
subtraction hybridization studies in the Japanese quail,
DIO2 expression was found to be induced by light and the
MBH tissue T
3
concentration was increased tenfold
following long-day exposure compared with short-day
exposure (Yoshimura et al. 2003). Furthermore, i.c.v. infusion
of T
3
, like exposure to long-day conditions, stimulated
gonadal growth while infusion of long-day-exposed quails
with iopanoic acid (a DIO2 inhibitor) prevented testicular
growth. These findings demonstrated that DIO2-mediated
local conversion of T
4
to T
3
in the MBH in response to light
is a key pathway mediating the photoperiodic seasonal
reproduction response (Yoshimura et al. 2003). Further
studies revealed that the photoperiod response is triggered
by light-induced expression of TSH in the pars tuberalis,
which subsequently stimulates DIO2 expression in ependy-
mal cells of the MBH via a TSHR-mediated pathway
coupled to cAMP that results in light-induced LH secretion
(Nakao et al. 2008). Additional studies have also revealed
that reciprocal changes in DIO2 and DIO3 expression are
inducedintheMBHinresponsetochangesinthe
photoperiod (Yasuo et al. 2005), and thus coordinated
regulation of DIO2 and DIO3 expression has the capacity
to mediate sensitive and rapid responses to changes in the
photoperiod, thereby highlighting the importance of local
control of tissue T
3
availability in the MBH for seasonal
reproduction. Nevertheless, the precise downstream mole-
cular consequences of increased T
3
production in the MBH
still remain to be elucidated. A melatonin-responsive
photoperiod response system in various mammals has also
been shown to involve TSH and DIO2 (Watanabe et al.2004,
Revel et al. 2006,Yasuo et al. 2006,2007,Hanon et al. 2008,
Nakao et al. 2008,Ono et al. 2008), suggesting that seasonal
reproduction in mammals and birds is regulated by similar
conserved pathways that lie downstream of the initial light or
melatonin photoperiod stimulus (Yoshimura 2010).
Conclusions
In recent years, the importance of controlled intracellular
availability of T
3
in target tissues has been appreciated. The
vital roles played by DIO2 in development, during the
establishment of the HPT axis and in specific tissues including
the pituitary gland, brain, brown adipose tissue, cochlea, and
bone, have been documented in considerable detail. Yet,
much remains and exciting and important discoveries are
inevitable. For example, recent studies are identifying new
roles for DIO2 in the heart (Wang et al. 2010), in skeletal
muscle (Grozovsky et al.2009), during inflammation
(Kwakkel et al. 2009), and in the pituitary in response to
specific drug challenges (Rosene et al. 2010). Given the
breadth of expression of DIO2 and its response to cellular
stress (Gereben et al. 2008), it is likely that the functional
repertoire for DIO2 will expand. The immediate challenges
will be to identify these new roles and to determine whether
functions ascribed to DIO2 from animal studies and genetic
manipulation have physiological or pathological importance
in man. Of importance in this context, a common Thr92Ala
polymorphism has been identified in DIO2 (Peeters et al.
2003). Although in vitro biochemical studies indicated no
difference in the enzymatic properties of the DIO2 Thr and
Ala variants (Peeters et al. 2003,Canani et al. 2005), thyroid
Local control of T
3
action by Dio2 .G R WILLIAMS and J H D BASSETT 7
www.endocrinology-journals.org Journal of Endocrinology (2011) 209, 1–12
and skeletal muscle tissue extracts from Ala/Ala individuals
displayed reduced DIO2 activities (Canani et al. 2005). The
mechanism responsible for reduced tissue activity is not
known but may result from linkage disequilibrium between
the Thr92Ala polymorphism and a second functional variant
elsewhere (Canani et al. 2005). Nevertheless, in addition to
osteoarthritis (Meulenbelt et al. 2008,Kerkhof et al. 2010),
the Thr92Ala polymorphism has also been associated with
variation in the HPT axis (Peeters et al. 2005,Butler et al.
2010), altered bone turnover (Heemstra et al. 2010), variable
and contradictory effects on cognitive parameters, and the
response to thyroid hormone replacement (Appelhof et al.
2005,Torlontano et al. 2008,Heemstra et al. 2009a,Panicker
et al. 2009), as well as having an inconsistent relationship to
hypertension, insulin resistance, and the metabolic syndrome
(Mentuccia et al. 2002,2005,Canani et al. 2005,2007,
Grarup et al. 2007,Gumieniak & Williams 2007,Gumieniak
et al. 2007,Peeters et al. 2007,van der Deure et al. 2009,Dora
et al. 2010,Estivalet et al. 2010).
Ultimately, an important challenge will be to exploit DIO2
as a drug target to manipulate tissue thyroid status, perhaps in
the treatment of metabolic disorders including obesity or
skeletal disorders such as osteoporosis and osteoarthritis.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived
as prejudicing the impartiality of the research reported.
Funding
This work was supported by the Medical Research Council (grant numbers
G0501486, G0800261) and Biotechnology and Biological Sciences Research
Council (BBlF021704).
References
Abel ED, Boers ME, Pazos-Moura C, Moura E, Kaulbach H, Zakaria M,
Lowell B, Radovick S, Liberman MC & Wondisford F 1999 Divergent roles
for thyroid hormone receptor beta isoforms in the endocrine axis and
auditory system. Journal of Clinical Investigation 104 291–300. (doi:10.1172/
JCI6397)
Abel ED, Ahima RS, Boers ME, Elmquist JK & Wondisford FE 2001 Critical
role for thyroid hormone receptor beta2 in the regulation of paraventricular
thyrotropin-releasing hormone neurons. Journal of Clinical Investigation 107
1017–1023. (doi:10.1172/JCI10858)
Appelhof BC, Peeters RP, Wiersinga WM, Visser TJ, Wekking EM, Huyser J,
Schene AH, Tijssen JG, Hoogendijk WJ & Fliers E 2005 Polymorphisms
in type 2 deiodinase are not associated with well-being, neurocognitive
functioning, and preference for combined thyroxine/3,5,30-triiodothyr-
onine therapy. Journal of Clinical Endocrinology and Metabolism 90 6296–6299.
(doi:10.1210/jc.2005-0451)
Ballock RT & Reddi AH 1994 Thyroxine is the serum factor that regulates
morphogenesis of columnar cartilage from isolated chondrocytes in
chemically defined medium. Journal of Cell Biology 126 1311–1318.
(doi:10.1083/jcb.126.5.1311)
Bassett JH & Williams GR 2008 Critical role of the hypothalamic–pituitary–
thyroid axis in bone. Bone 43 418–426. (doi:10.1016/j.bone.2008.05.007)
Bassett JH, Boyde A, Howell PG, Bassett RH, Galliford TM, Archanco M,
Evans H, Lawson MA, Croucher P, St Germain DL et al. 2010 Optimal bone
strength and mineralization requires the type 2 iodothyronine deiodinase
in osteoblasts. PNAS 107 7604–7609. (doi:10.1073/pnas.0911346107)
Bates JM, St Germain DL & Galton VA 1999 Expression profiles of the
three iodothyronine deiodinases, D1, D2, and D3, in the developing rat.
Endocrinology 140 844–851. (doi:10.1210/en.140.2.844)
Berry MJ, Grieco D, Taylor BA, Maia AL, Kieffer JD, Beamer W, Glover E,
Poland A & Larsen PR 1993 Physiological and genetic analyses of inbred
mouse strains with a type I iodothyronine 50deiodinase deficiency.
Journal of Clinical Investigation 92 1517–1528. (doi:10.1172/JCI116730)
Bianco AC & Kim BW 2006 Deiodinases: implications of the local control of
thyroid hormone action. Journal of Clinical Investigation 116 2571–2579.
(doi:10.1172/JCI29812)
Bianco AC & Larsen PR 2005 Cellular and structural biology of the
deiodinases. Thyroid 15 777–786. (doi:10.1089/thy.2005.15.777)
Bianco AC, Salvatore D, Gereben B, Berry MJ & Larsen PR 2002
Biochemistry, cellular and molecular biology, and physiological roles of the
iodothyronine selenodeiodinases. Endocrine Reviews 23 38–89. (doi:10.
1210/er.23.1.38)
Bohme K, Conscience-Egli M, Tschan T, Winterhalter KH & Bruckner P
1992 Induction of proliferation or hypertrophy of chondrocytes in serum-
free culture: the role of insulin-like growth factor-I, insulin, or thyroxine.
Journal of Cell Biology 116 1035–1042. (doi:10.1083/jcb.116.4.1035)
Burmeister LA, Pachucki J & St Germain DL 1997 Thyroid hormones inhibit
type 2 iodothyronine deiodinase in the rat cerebral cortex by both pre- and
posttranslational mechanisms. Endocrinology 138 5231–5237. (doi:10.1210/
en.138.12.5231)
Butler PW, Smith SM, Linder man JD, Brychta RJ, Alberobello AT,
Dubaz OM, Luzon JA, Skarulis MC, Cochran CS, Wesley RA et al. 2010
The Thr92Ala 50type 2 deiodinase gene polymor phism is associated
with a delayed triiodothyronine secretion in response to the thyrotropin-
releasing hormone-stimulation test: a phar macogenomic study. Thyroid 20
1407–1412. (doi:10.1089/thy.2010.0244)
Calvo R, Obregon MJ, Ruiz de Ona C, Escobar del Rey F & Morreale de
Escobar G 1990 Congenital hypothyroidism, as studied in rats. Crucial role
of maternal thyroxine but not of 3,5,30-triiodothyronine in the protection
of the fetal brain. Journal of Clinical Investigation 86 889–899. (doi:10.1172/
JCI114790)
Campos-Barros A, Amma LL, Faris JS, Shailam R, Kelley MW & Forrest D
2000 Type 2 iodothyronine deiodinase expression in the cochlea before the
onset of hearing. PNAS 97 1287–1292. (doi:10.1073/pnas.97.3.1287)
Canani LH, Capp C, Dora JM, Meyer EL, Wagner MS, Harney JW, Larsen
PR, Gross JL, Bianco AC & Maia AL 2005 The type 2 deiodinase A/G
(Thr92Ala) polymorphism is associated with decreased enzyme velocity
and increased insulin resistance in patients with type 2 diabetes mellitus.
Journal of Clinical Endocrinology and Metabolism 90 3472–3478. (doi:10.1210/
jc.2004-1977)
Canani LH, Leie MA, Machado WE, Capp C & Maia AL 2007 Type 2
deiodinase Thr92Ala polymorphism is not associated with arterial
hypertension in type 2 diabetes mellitus patients. Hypertension 49 e47.
(doi:10.1161/HYPERTENSIONAHA.107.088278)
Capelo LP, Beber EH, Huang SA, Zorn TM, Bianco AC & Gouveia CH 2008
Deiodinase-mediated thyroid hormone inactivation minimizes thyroid
hormone signaling in the early development of fetal skeleton. Bone 43
921–930. (doi:10.1016/j.bone.2008.06.020)
Chassande O 2003 Do unliganded thyroid hormone receptors have
physiological functions? Journal of Molecular Endocrinology 31 9–20.
(doi:10.1677/jme.0.0310009)
Chassande O, Fraichard A, Gauthier K, Flamant F, Legrand C, Savatier P,
Laudet V & Samarut J 1997 Identification of transcr ipts initiated from an
internal promoter in the c-erbA alpha locus that encode inhibitors of
retinoic acid receptor-alpha and triiodothyronine receptor activities.
Molecular Endocrinology 11 1278–1290. (doi:10.1210/me.11.9.1278)
Cheng SY, Leonard JL & Davis PJ 2010 Molecular aspects of thyroid hormone
actions. Endocrine Reviews 31 139–170. (doi:10.1210/er.2009-0007)
Christoffolete MA, Linardi CC, de Jesus L, Ebina KN, Carvalho SD, Ribeiro
MO, Rabelo R, Curcio C, Martins L, Kimura ET et al. 2004 Mice with
G R WILLIAMS and J H D BASSETT .Local control of T
3
action by Dio28
Journal of Endocrinology (2011) 209, 1–12 www.endocrinology-journals.org
targeted disruption of the Dio2 gene have cold-induced overexpression
of the uncoupling protein 1 gene but fail to increase brown adipose
tissue lipogenesis and adaptive thermogenesis. Diabetes 53 577–584.
(doi:10.2337/diabetes.53.3.577)
Christoffolete MA, Arrojo e Drigo R, Gazoni F, Tente SM, Goncalves V,
Amorim BS, Larsen PR, Bianco AC & Zavacki AM 2007 Mice with
impaired extrathyroidal thyroxine to 3,5,30-triiodothyronine conversion
maintain normal serum 3,5,3 0-triiodothyronine concentrations.
Endocrinology 148 954–960. (doi:10.1210/en.2006-1042)
Dentice M, Bandyopadhyay A, Gereben B, Callebaut I, Christoffolete MA,
Kim BW, Nissim S, Mornon JP, Zavacki AM, Zeold A et al. 2005 The
Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid
hormone activation and PTHrP secretion in the developing growth plate.
Nature Cell Biology 7698–705. (doi:10.1038/ncb1272)
Dentice M, Marsili A, Ambrosio R, Guardiola O, Sibilio A, Paik JH,
Minchiotti G, DePinho RA, Fenzi G, Larsen PR et al. 2010 The
FoxO3/type 2 deiodinase pathway is required for normal mouse
myogenesis and muscle regeneration. Journal of Clinical Investigation 120
4021–4030. (doi:10.1172/JCI43670)
van der Deure WM, Peeters RP, Uitterlinden AG, Hofman A, Breteler MM,
Witteman J & Visser TJ 2009 Impact of thyroid function and poly-
morphisms in the type 2 deiodinase on blood pressure: the Rotterdam
Study and the Rotterdam Scan Study. Clinical Endocrinology 71 137–144.
(doi:10.1111/j.1365-2265.2008.03447.x)
van der Deure WM, Peeters RP & Visser TJ 2010 Molecular aspects of thyroid
hormone transporters, including MCT8, MCT10, and OATPs, and the
effects of genetic variation in these transporters. Journal of Molecular
Endocrinology 44 1–11. (doi:10.1677/JME-09-0042)
Dora JM, Machado WE, Rheinheimer J, Crispim D & Maia AL 2010
Association of the type 2 deiodinase Thr92Ala polymorphism with type 2
diabetes: case–control study and meta-analysis. European Journal of
Endocrinology 163 427–434. (doi:10.1530/EJE-10-0419)
Dreher I, Schutze N, Baur A, Hesse K, Schneider D, Kohrle J & Jakob F 1998
Selenoproteins are expressed in fetal human osteoblast-like cells. Biochemical
and Biophysical Research Communications 245 101–107. (doi:10.1006/bbrc.
1998.8393)
Dumitrescu AM, Liao XH, Weiss RE, Millen K & Refetoff S 2006 Tissue-
specific thyroid hormone deprivation and excess in monocarboxylate
transporter (mct) 8-deficient mice. Endocrinology 147 4036–4043. (doi:10.
1210/en.2006-0390)
Estivalet AA, Leiria LB, Dora JM, Rheinheimer J, Boucas AP, Maia AL &
Crispim D 2010 D2 Thr92Ala and PPARgamma2 Pro12Ala polymorph-
isms interact in the modulation of insulin resistance in type 2 diabetic
patients. Obesity.(doi:10.1038/oby.2010.231)
Fekete C, Freitas BC, Zeold A, Wittmann G, Kadar A, Liposits Z,
Christoffolete MA, Singru P, Lechan RM, Bianco AC et al. 2007
Expression patterns of WSB-1 and USP-33 underlie cell-specific
posttranslational control of type 2 deiodinase in the rat brain. Endocrinology
148 4865–4874. (doi:10.1210/en.2007-0448)
Flamant F, Poguet AL, Plateroti M, Chassande O, Gauthier K, Streichenberger
N, Mansouri A & Samarut J 2002 Congenital hypothyroid Pax8(K/K)
mutant mice can be rescued by inactivating the TRalpha gene. Molecular
Endocrinology 16 24–32. (doi:10.1210/me.16.1.24)
Forrest D, Sjoberg M & Vennstrom B 1990 Contrasting developmental and
tissue-specific expression of alpha and beta thyroid hormone receptor
genes. EMBO Journal 91519–1528.
Forrest D, Erway LC, Ng L, Altschuler R & Curran T 1996aThyroid
hormone receptor beta is essential for development of auditory function.
Nature Genetics 13 354–357. (doi:10.1038/ng0796-354)
Forrest D, Hanebuth E, Smeyne RJ, Everds N, Stewart CL, Wehner JM &
Curran T 1996bRecessive resistance to thyroid hormone in mice lacking
thyroid hormone receptor beta: evidence for tissue-specific modulation
of receptor function. EMBO Journal 15 3006–3015.
Friedrichsen S, Christ S, Heuer H, Schafer MK, Mansouri A, Bauer K &
Visser TJ 2003 Regulation of iodothyronine deiodinases in the Pax8K/K
mouse model of congenital hypothyroidism. Endocrinology 144 777–784.
(doi:10.1210/en.2002-220715)
Friesema EC, Ganguly S, Abdalla A, Manning Fox JE, Halestrap AP &
Visser TJ 2003 Identification of monocarboxylate transporter 8 as a
specific thyroid hormone transporter. Journal of Biological Chemistry 278
40128–40135. (doi:10.1074/jbc.M300909200)
Friesema EC, Jansen J, Milici C & Visser TJ 2005 Thyroid hormone
transporters. Vitamins and Hormones 70 137–167. (doi:10.1016/S0083-
6729(05)70005-4)
Friesema EC, Kuiper GG, Jansen J, Visser TJ & Kester MH 2006 Thyroid
hormone transport by the human monocarboxylate transporter 8 and its
rate-limiting role in intracellular metabolism. Molecular Endocrinology 20
2761–2772. (doi:10.1210/me.2005-0256)
Galton VA, Wood ET, St Germain EA, Withrow CA, Aldrich G, St Germain
GM, Clark AS & St Germain DL 2007 Thyroid hormone homeostasis and
action in the type 2 deiodinase-deficient rodent brain during development.
Endocrinology 148 3080–3088. (doi:10.1210/en.2006-1727)
Gereben B, Goncalves C, Harney JW, Larsen PR & Bianco AC 2000 Selective
proteolysis of human type 2 deiodinase: a novel ubiquitin-proteasomal
mediated mechanism for regulation of hormone activation. Molecular
Endocrinology 14 1697–1708. (doi:10.1210/me.14.11.1697)
Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS,
Zeold A & Bianco AC 2008 Cellular and molecular basis of deiodinase-
regulated thyroid hormone signaling. Endocrine Reviews 29 898–938.
(doi:10.1210/er.2008-0019)
Gouveia CH, Christoffolete MA, Zaitune CR, Dora JM, Har ney JW,
Maia AL & Bianco AC 2005 Type 2 iodothyronine selenodeiodinase is
expressed throughout the mouse skeleton and in the MC3T3-E1 mouse
osteoblastic cell line during differentiation. Endocrinology 146 195–200.
(doi:10.1210/en.2004-1043)
Grarup N, Andersen MK, Andreasen CH, Albrechtsen A, Borch-Johnsen K,
Jorgensen T, Auwerx J, Schmitz O, Hansen T & Pedersen O 2007 Studies of
the common DIO2 Thr92Ala polymorphism and metabolic phenotypes in
7342 Danish white subjects. Journal of Clinical Endocrinology and Metabolism
92 363–366. (doi:10.1210/jc.2006-1958)
Grozovsky R, Ribich S, Rosene ML, Mulcahey MA, Huang SA, Patti ME,
Bianco AC & Kim BW 2009 Type 2 deiodinase expression is induced by
peroxisomal proliferator-activated receptor-gamma agonists in skeletal
myocytes. Endocrinology 150 1976–1983. (doi:10.1210/en.2008-0938)
Guadano-Ferraz A, Obregon MJ, St Germain DL & Bernal J 1997 The type 2
iodothyronine deiodinase is expressed primarily in glial cells in the neonatal
rat brain. PNAS 94 10391–10396. (doi:10.1073/pnas.94.19.10391)
Guadano-Ferraz A, Escamez MJ, Rausell E & Bernal J 1999 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. Journal of Neuroscience 19 3430–3439.
Gumieniak O & Williams GH 2007 Response to type 2 deiodinase Thr92Ala
polymorphism is not associated with arter ial hypertension in type 2 diabetes
mellitus patients. Hypertension 49 e48. (doi:10.1161/HYPERTENSIO-
NAHA.107.088559)
Gumieniak O, Perlstein TS, Williams JS, Hopkins PN, Brown NJ, Raby BA &
Williams GH 2007 Ala92 type 2 deiodinase allele increases r isk for the
development of hypertension. Hypertension 49 461–466. (doi:10.1161/01.
HYP.0000256295.72185.fd)
Hall JA, Ribich S, Christoffolete MA, Simovic G, Correa-Medina M, Patti
ME & Bianco AC 2010 Absence of thyroid hormone activation during
development underlies a permanent defect in adaptive thermogenesis.
Endocrinology 151 4573–4582. (doi:10.1210/en.2010-0511)
Hanon EA, Lincoln GA, Fustin JM, Dardente H, Masson-Pevet M, Morgan
PJ & Hazlerigg DG 2008 Ancestral TSH mechanism signals summer in a
photoperiodic mammal. Current Biology 18 1147–1152. (doi:10.1016/j.cub.
2008.06.076)
Harvey CB & Williams GR 2002 Mechanism of thyroid hormone action.
Thyroid 12 441–446. (doi:10.1089/105072502760143791)
Harvey CB, Bassett JH, Maruvada P, Yen PM & Williams GR 2007 The rat
thyroid hormone receptor (TR) Deltabeta3 displays cell-, TR isoform-,
and thyroid hormone response element-specific actions. Endocrinology 148
1764–1773. (doi:10.1210/en.2006-1248)
Local control of T
3
action by Dio2 .G R WILLIAMS and J H D BASSETT 9
www.endocrinology-journals.org Journal of Endocrinology (2011) 209, 1–12
Hashimoto K, Curty FH, Borges PP, Lee CE, Abel ED, Elmquist JK, Cohen
RN & Wondisford FE 2001 An unliganded thyroid hormone receptor
causes severe neurological dysfunction. PNAS 98 3998–4003. (doi:10.
1073/pnas.051454698)
Heemstra KA, Hoftijzer HC, van der Deure WM, Peeters RP, Fliers E,
Appelhof BC, Wiersinga WM, Corssmit EP, Visser TJ & Smit JW 2009a
Thr92Ala polymorphism in the type 2 deiodinase is not associated with T
4
dose in athyroid patients or patients with Hashimoto thyroiditis. Clinical
Endocrinology 71 279–283. (doi:10.1111/j.1365-2265.2008.03474.x)
Heemstra KA, Soeters MR, Fliers E, Serlie MJ, Burggraaf J, van Doorn MB,
van der Klaauw AA, Romijn JA, Smit JW, Corssmit EP et al. 2009bType 2
iodothyronine deiodinase in skeletal muscle: effects of hypothyroidism and
fasting. Journal of Clinical Endocrinology and Metabolism 94 2144–2150.
(doi:10.1210/jc.2008-2520)
Heemstra KA, Hoftijzer H, van der Deure WM, Peeters RP, Hamdy NA,
Pereira A, Corssmit EP, Romijn JA, Visser TJ & Smit JW 2010 The type 2
deiodinase Thr92Ala polymorphism is associated with increased bone
turnover and decreased femoral neck bone mineral density. Journal of
Bone and Mineral Research 25 1385–1391. (doi:10.1002/jbmr.27)
Hernandez A, Martinez ME, Fiering S, Galton VA & St Germain D 2006
Type 3 deiodinase is cr itical for the maturation and function of the thyroid
axis. Journal of Clinical Investigation 116 476–484. (doi:10.1172/JCI26240)
Hernandez A, Martinez ME, Liao XH, Van Sande J, Refetoff S, Galton VA &
St Germain DL 2007 Type 3 deiodinase deficiency results in functional
abnormalities at multiple levels of the thyroid axis. Endocrinology 148
5680–5687. (doi:10.1210/en.2007-0652)
Heuer H 2007 The importance of thyroid hormone transporters for brain
development and function. Best Practice and Research. Clinical Endocrinology
and Metabolism 21 265–276. (doi:10.1016/j.beem.2007.03.003)
Huang H, Cai L, Remo BF & Brown DD 2001 Timing of metamorphosis and
the onset of the negative feedback loop between the thyroid gland and the
pituitary is controlled by type II iodothyronine deiodinase in Xenopus laevis.
PNAS 98 7348–7353. (doi:10.1073/pnas.131198998)
Jansen J, Friesema EC, Milici C & Visser TJ 2005 Thyroid hormone
transporters in health and disease. Thyroid 15 757–768. (doi:10.1089/thy.
2005.15.757)
de Jesus LA, Carvalho SD, Ribeiro MO, Schneider M, Kim SW, Harney JW,
Larsen PR & Bianco AC 2001 The type 2 iodothyronine deiodinase is
essential for adaptive thermogenesis in brown adipose tissue. Journal of
Clinical Investigation 108 1379–1385.
Jones I, Ng L, Liu H & Forrest D 2007 An intron control region differentially
regulates expression of thyroid hormone receptor beta2 in the cochlea,
pituitary, and cone photoreceptors. Molecular Endocrinology 21 1108–1119.
(doi:10.1210/me.2007-0037)
Kerkhof HJ, Lories RJ, Meulenbelt I, Jonsdottir I, Valdes AM, Ar p P,
Ingvarsson T, Jhamai M, Jonsson H, Stolk L et al. 2010 A genome-wide
association study identifies an osteoarthritis susceptibility locus on
chromosome 7q22. Arthritis and Rheumatism 62 499–510. (doi:10.1002/
art.27184)
Kester MH, Martinez de Mena R, Obregon MJ, Marinkovic D, Howatson A,
Visser TJ, Hume R & Morreale de Escobar G 2004 Iodothyronine levels
in the human developing brain: major regulatory roles of iodothyronine
deiodinases in different areas. Journal of Clinical Endocr inology and Metabolism
89 3117–3128. (doi:10.1210/jc.2003-031832)
Kopp P 2001 The TSH receptor and its role in thyroid disease. Cellular
and Molecular Life Sciences 58 1301–1322. (doi:10.1007/PL00000941)
Kwakkel J, van Beeren HC, Ackermans MT, Platvoet-Ter Schiphorst MC,
Fliers E, Wiersinga WM & Boelen A 2009 Skeletal muscle deiodinase type
2 regulation during illness in mice. Journal of Endocr inology 203 263–270.
(doi:10.1677/JOE-09-0118)
Larsen PR 2009 Type 2 iodothyronine deiodinase in human skeletal muscle:
new insights into its physiological role and regulation. Journal of Clinical
Endocrinology and Metabolism 94 1893–1895. (doi:10.1210/jc.2009-0791)
LeBron BA, Pekary AE, Mirell C, Hahn TJ & Hershman JM 1989 Thyroid
hormone 50-deiodinase activity, nuclear binding, and effects on mitogenesis
in UMR-106 osteoblastic osteosarcoma cells. Journal of Bone and Mineral
Research 4173–178. (doi:10.1002/jbmr.5650040207)
Lin KH, Fukuda T & Cheng SY 1990 Hormone and DNA binding activity of
a purified human thyroid hor mone nuclear receptor expressed in Escherichia
coli.Journal of Biological Chemistry 265 5161–5165.
Mai W, Janier MF, Allioli N, Quignodon L, Chuzel T, Flamant F & Samarut J
2004 Thyroid hormone receptor alpha is a molecular switch of cardiac
function between fetal and postnatal life. PNAS 101 10332–10337.
(doi:10.1073/pnas.0401843101)
Maia AL, Kim BW, Huang SA, Har ney JW & Larsen PR 2005 Type 2
iodothyronine deiodinase is the major source of plasma T
3
in euthyroid
humans. Journal of Clinical Investigation 115 2524–2533. (doi:10.1172/
JCI25083)
Marsili A, Ramadan W, Harney JW, Mulcahey M, Castroneves LA, Goemann
IM, Wajner SM, Huang SA, Zavacki AM, Maia AL et al. 2010 Type 2
iodothyronine deiodinase levels are higher in slow-twitch than fast-twitch
mouse skeletal muscle and are increased in hypothyroidism. Endocrinology
151 5952–5960. (doi:10.1210/en.2010-0631)
Mentuccia D, Proietti-Pannunzi L, Tanner K, Bacci V, Pollin TI, Poehlman
ET, Shuldiner AR & Celi FS 2002 Association between a novel variant
of the human type 2 deiodinase gene Thr92Ala and insulin resistance:
evidence of interaction with the Trp64Arg variant of the beta-3-adrenergic
receptor. Diabetes 51 880–883. (doi:10.2337/diabetes.51.3.880)
Mentuccia D, Thomas MJ, Coppotelli G, Reinhart LJ, Mitchell BD,
Shuldiner AR & Celi FS 2005 The Thr92Ala deiodinase type 2 (DIO2)
variant is not associated with type 2 diabetes or indices of insulin
resistance in the old order of Amish. Thyroid 15 1223–1227. (doi:10.
1089/thy.2005.15.1223)
Meulenbelt I, Min JL, Bos S, Riyazi N, Houwing-Duistermaat JJ, van der
Wijk HJ, Kroon HM, Nakajima M, Ikegawa S, Uitterlinden AG et al. 2008
Identification of DIO2 as a new susceptibility locus for symptomatic
osteoarthritis. Human Molecular Genetics 17 1867–1875. (doi:10.1093/hmg /
ddn082)
Meulenbelt I, Bos SD,Chapman K, van der Breggen R, Houwing-Duistermaat
JJ, Kremer D, Kloppenburg M, Carr A, Tsezou A, Gonzalez A et al. 2010
Meta-analyses of genes modulating intracellular T
3
bio-availability reveal a
possible role for the DIO3 gene in osteoarthritis susceptibility. Annals of
Rheumatic Disease 70 164–167. (doi:10.1136/ard.2010.133660)
Morimura T, Tsunekawa K, Kasahara T, Seki K, Ogiwara T, Mori M &
Murakami M 2005 Expression of type 2 iodothyronine deiodinase
in human osteoblast is stimulated by thyrotropin. Endocrinology 146
2077–2084. (doi:10.1210/en.2004-1432)
Morte B, Ceballos A, Diez D, Grijota-Martinez C, Dumitrescu AM, Di
Cosmo C, Galton VA, Refetoff S & Bernal J 2010 Thyroid hormone-
regulated mouse cerebral cortex genes are differentially dependent on the
source of the hormone: a study in monocarboxylate transporter-8- and
deiodinase-2-deficient mice. Endocrinology 151 2381–2387. (doi:10.1210/
en.2009-0944)
Nakao N, Ono H, Yamamura T, Anraku T, Takagi T, Higashi K, Yasuo S,
Katou Y, Kageyama S, Uno Y et al. 2008 Thyrotrophin in the pars tuberalis
triggers photoperiodic response. Nature 452 317–322. (doi:10.1038/
nature06738)
Ng L, Hurley JB, Dierks B, Srinivas M, Salto C, Vennstrom B, Reh TA &
Forrest D 2001 A thyroid hormone receptor that is required for the
development of green cone photoreceptors. Nature Genetics 27 94–98.
(doi:10.1038/83829)
Ng L, Goodyear RJ, Woods CA, Schneider MJ, Diamond E, Richardson GP,
Kelley MW, Germain DL, Galton VA & Forrest D 2004 Hearing loss and
retarded cochlear development in mice lacking type 2 iodothyronine
deiodinase. PNAS 101 3474–3479. (doi:10.1073/pnas.0307402101)
Ng L, Hernandez A, He W, Ren T, Srinivas M, Ma M, Galton VA, St Germain
DL & Forrest D 2009 A protective role for type 3 deiodinase, a thyroid
hormone-inactivating enzyme, in cochlear development and auditory
function. Endocrinology 150 1952–1960. (doi:10.1210/en.2008-1419)
Nikrodhanond AA, Ortiga-Carvalho TM, Shibusawa N, Hashimoto K, Liao
XH, Refetoff S, Yamada M, Mori M & Wondisford FE 2006 Dominant
role of thyrotropin-releasing hormone in the hypothalamic–pituitary–
thyroid axis. Journal of Biological Chemistry 281 5000–5007. (doi:10.1074/
jbc.M511530200)
G R WILLIAMS and J H D BASSETT .Local control of T
3
action by Dio210
Journal of Endocrinology (2011) 209, 1–12 www.endocrinology-journals.org
Ono H, Hoshino Y, Yasuo S, Watanabe M, Nakane Y, Murai A, Ebihara S,
Korf HW & Yoshimura T 2008 Involvement of thyrotropin in
photoperiodic signal transduction in mice. PNAS 105 18238–18242.
(doi:10.1073/pnas.0808952105)
O’Shea PJ, Bassett JH, Cheng SY & Williams GR 2006 Character ization of
skeletal phenotypes of TRalpha1 and TRbeta mutant mice: implications for
tissue thyroid status and T
3
target gene expression. Nuclear Receptor Signaling
4e011.
Panicker V, Saravanan P, Vaidya B, Evans J, Hattersley AT, Frayling TM &
Dayan CM 2009 Common variation in the DIO2 gene predicts
baseline psychological well-being and response to combination thyroxine
plus triiodothyronine therapy in hypothyroid patients. Journal of
Clinical Endocrinology and Metabolism 94 1623–1629. (doi:10.1210/
jc.2008-1301)
Peeters RP, van Toor H, Klootwijk W, de Rijke YB, Kuiper GG, Uitterlinden
AG & Visser TJ 2003 Polymorphisms in thyroid hormone pathway genes
are associated with plasma TSH and iodothyronine levels in healthy
subjects. Journal of Clinical Endocrinology and Metabolism 88 2880–2888.
(doi:10.1210/jc.2002-021592)
Peeters RP, van den Beld AW, Attalki H, Toor H, de Rijke YB, Kuiper GG,
Lamberts SW, Janssen JA, Uitterlinden AG & Visser TJ 2005 A new
polymorphism in the type II deiodinase gene is associated with circulating
thyroid hormone parameters. American Journal of Physiology. Endocrinology
and Metabolism 289 E75–E81. (doi:10.1152/ajpendo.00571.2004)
Peeters RP, van der Deure WM, van den Beld AW, van Toor H, Lamberts SW,
Janssen JA, Uitterlinden AG & Visser TJ 2007 The Asp727Glu
polymorphism in the TSH receptor is associated with insulin resistance
in healthy elderly men. Clinical Endocrinology 66 808–815. (doi:10.1111/
j.1365-2265.2007.02817.x)
Plateroti M, Gauthier K, Domon-Dell C, Freund JN, Samarut J & Chassande
O 2001 Functional interference between thyroid hormone receptor alpha
(TRalpha) and natural truncated TRDeltaalpha isoforms in the control of
intestine development. Molecular and Cellular Biology 21 4761–4772.
(doi:10.1128/MCB.21.14.4761-4772.2001)
Revel FG, Saboureau M, Pevet P, Mikkelsen JD & Simonneaux V 2006
Melatonin regulates type 2 deiodinase gene expression in the Syrian
hamster. Endocrinology 147 4680–4687. (doi:10.1210/en.2006-0606)
Rosene ML, Wittmann G, Arrojo EDR, Singru PS, Lechan RM & Bianco
AC 2010 Inhibition of the type 2 iodothyronine deiodinase underlies the
elevated plasma TSH associated with amiodarone treatment. Endocrinology
151 5961–5970. (doi:10.1210/en.2010-0553)
Rusch A, Erway LC, Oliver D, Vennstrom B & Forrest D 1998 Thyroid
hormone receptor beta-dependent expression of a potassium conductance
in inner hair cells at the onset of hear ing. PNAS 95 15758–15762. (doi:10.
1073/pnas.95.26.15758)
Rusch A, Ng L, Goodyear R, Oliver D, Lisoukov I, Vennstrom B, Richardson
G, Kelley MW & Forrest D 2001 Retardation of cochlear maturation and
impaired hair cell function caused by deletion of all known thyroid
hormone receptors. Journal of Neuroscience 21 9792–9800.
Sachs LM, Damjanovski S, Jones PL, Li Q, Amano T, Ueda S, Shi YB &
Ishizuya-Oka A 2000 Dual functions of thyroid hormone receptors during
Xenopus development. Comparative Biochemistry and Physiology. Part B,
Biochemistry & Molecular Biology 126 199–211. (doi:10.1016/S0305-
0491(00)00198-X)
Sagar GD, Gereben B, Callebaut I, Mornon JP, Zeold A, da Silva WS, Luongo
C, Dentice M, Tente SM, Freitas BC et al. 2007 Ubiquitination-induced
conformational change within the deiodinase dimer is a switch regulating
enzyme activity. Molecular and Cellular Biology 27 4774–4783. (doi:10.1128/
MCB.00283-07)
Sap J, Munoz A, Damm K, Goldberg Y, Ghysdael J, Leutz A, Beug H &
Vennstrom B 1986 The c-erb-A protein is a high-affinity receptor for
thyroid hormone. Nature 324 635–640. (doi:10.1038/324635a0)
Schneider MJ, Fiering SN, Pallud SE, Parlow AF, St Germain DL & Galton
VA 2001 Targeted disruption of the type 2 selenodeiodinase gene (DIO2)
results in a phenotype of pituitary resistance to T
4
.Molecular Endocrinology
15 2137–2148. (doi:10.1210/me.15.12.2137)
Schneider MJ, Fiering SN, Thai B, Wu SY, St Ger main E, Parlow AF,
St Germain DL & Galton VA 2006 Targeted disr uption of the type 1
selenodeiodinase gene (Dio1) results in marked changes in thyroid hormone
economy in mice. Endocrinology 147 580–589. (doi:10.1210/en.2005-0739)
Schoenmakers CH, Pigmans IG, Poland A & Visser TJ 1993 Impairment of
the selenoenzyme type I iodothyronine deiodinase in C3H/He mice.
Endocrinology 132 357–361. (doi:10.1210/en.132.1.357)
Steinsapir J, Bianco AC, Buettner C, Harney J & Larsen PR 2000 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 141 1127–1135. (doi:10.1210/en.141.3.1127)
Stevens DA, Hasserjian RP, Robson H, Siebler T, Shalet SM & Williams GR
2000 Thyroid hormones regulate hypertrophic chondrocyte differentiation
and expression of parathyroid hormone-related peptide and its receptor
during endochondral bone formation. Journal of Bone and Mineral Research
15 2431–2442. (doi:10.1359/jbmr.2000.15.12.2431)
St Germain DL, Galton VA & Hernandez A 2009 Minireview: defining the
roles of the iodothyronine deiodinases: current concepts and challenges.
Endocrinology 150 1097–1107. (doi:10.1210/en.2008-1588)
Torlontano M, Durante C, Torrente I, Crocetti U, Augello G, Ronga G,
Montesano T, Travascio L, Verrienti A, Bruno R et al. 2008 Type 2
deiodinase polymorphism (threonine 92 alanine) predicts L-thyroxine dose
to achieve target thyrotropin levels in thyroidectomized patients. Journal of
Clinical Endocrinology and Metabolism 93 910–913. (doi:10.1210/jc.2007-
1067)
Tu HM, Kim SW, Salvatore D, Bartha T, Legradi G, Larsen PR & Lechan RM
1997 Regional distribution of type 2 thyroxine deiodinase messenger
ribonucleic acid in rat hypothalamus and pituitary and its regulation by
thyroid hormone. Endocrinology 138 3359–3368. (doi:10.1210/en.138.8.
3359)
Tu HM, Legradi G, Bartha T, Salvatore D, Lechan RM & Larsen PR 1999
Regional expression of the type 3 iodothyronine deiodinase messenger
ribonucleic acid in the rat central nervous system and its regulation by
thyroid hormone. Endocrinology 140 784–790. (doi:10.1210/en.140.2.784)
Venero C, Guadano-Ferraz A, Herrero AI, Nordstrom K, Manzano J, de
Escobar GM, Bernal J & Vennstrom B 2005 Anxiety, memory impairment,
and locomotor dysfunction caused by a mutant thyroid hormone receptor
alpha1 can be ameliorated by T
3
treatment. Genes and Development 19
2152–2163. (doi:10.1101/gad.346105)
Vestergaard P & Mosekilde L 2002 Fractures in patients with hyperthyroidism
and hypothyroidism: a nationwide follow-up study in 16,249 patients.
Thyroid 12 411–419. (doi:10.1089/105072502760043503)
Vestergaard P, Rejnmark L & Mosekilde L 2005 Influence of hyper- and
hypothyroidism, and the effects of treatment with antithyroid drugs and
levothyroxine on fracture risk. Calcified Tissue International 77 139–144.
(doi:10.1007/s00223-005-0068-x)
Wakita R, Izumi T & Itoman M 1998 Thyroid hormone-induced
chondrocyte terminal differentiation in rat femur organ culture. Cell Tissue
Research 293 357–364. (doi:10.1007/s004410051127)
Wallis K, Sjogren M, van Hogerlinden M, Silberberg G, Fisahn A, Nordstrom
K, Larsson L, Westerblad H, Morreale de Escobar G, Shupliakov O et al.
2008 Locomotor deficiencies and aberrant development of subtype-specific
GABAergic interneurons caused by an unliganded thyroid hormone
receptor alpha1. Journal of Neuroscience 28 1904–1915. (doi:10.1523/
JNEUROSCI.5163-07.2008)
Wang YY, Morimoto S, Du CK, Lu QW, Zhan DY, Tsutsumi T, Ide T,
Miwa Y, Takahashi-Yanaga F & Sasagur i T 2010 Up-regulation of type 2
iodothyronine deiodinase in dilated cardiomyopathy. Cardiovascular Research
87 636–646. (doi:10.1093/cvr/cvq133)
Wasco EC, Martinez E, Grant KS, St Germain EA, St Germain DL & Galton
VA 2003 Deter minants of iodothyronine deiodinase activities in rodent
uterus. Endocrinology 144 4253–4261. (doi:10.1210/en.2003-0490)
Watanabe M, Yasuo S, Watanabe T, Yamamura T, Nakao N, Ebihara S &
Yoshimura T 2004 Photoper iodic regulation of type 2 deiodinase gene in
Djungarian hamster: possible homologies between avian and mammalian
photoperiodic regulation of reproduction. Endocrinology 145 1546–1549.
(doi:10.1210/en.2003-1593)
Local control of T
3
action by Dio2 .G R WILLIAMS and J H D BASSETT 11
www.endocrinology-journals.org Journal of Endocrinology (2011) 209, 1–12
Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H,
Messaddeq N, Harney JW, Ezaki O, Kodama Tet al. 2006 Bile acids induce
energy expenditure by promoting intracellular thyroid hormone activation.
Nature 439 484–489. (doi:10.1038/nature04330)
Weinberger C, Thompson CC, Ong ES, Lebo R, Gruol DJ & Evans RM
1986 The c-erb-A gene encodes a thyroid hormone receptor. Nature 324
641–646. (doi:10.1038/324641a0)
Williams GR 2000 Cloning and characterization of two novel thyroid hormone
receptor beta isoforms. Molecular and Cellular Biology 20 8329–8342.
(doi:10.1128/MCB.20.22.8329-8342.2000)
Williams AJ, Robson H, Kester MH, van Leeuwen JP, Shalet SM, Visser TJ &
Williams GR 2008 Iodothyronine deiodinase enzyme activities in bone.
Bone 43 126–134. (doi:10.1016/j.bone.2008.03.019)
Yasuo S, Watanabe M, Nakao N, Takagi T, Follett BK, Ebihara S &
Yoshimura T 2005 The reciprocal switching of two thyroid hormone-
activating and -inactivating enzyme genes is involved in the photoperiodic
gonadal response of Japanese quail. Endocrinology 146 2551–2554.
(doi:10.1210/en.2005-0057)
Yasuo S, Nakao N, Ohkura S, Iigo M, Hagiwara S, Goto A, Ando H,
Yamamura T, Watanabe M, Watanabe T et al. 2006 Long-day
suppressed expression of type 2 deiodinase gene in the mediobasal
hypothalamus of the Saanen goat, a short-day breeder: implication for
seasonal window of thyroid hormone action on reproductive
neuroendocrine axis. Endocrinology 147 432–440. (doi:10.1210/
en.2005-0507)
Yasuo S, Watanabe M, Iigo M, Nakamura TJ, Watanabe T, Takagi T,
Ono H, Ebihara S & Yoshimura T 2007 Differential response of
type 2 deiodinase gene expression to photoperiod between photoperiodic
Fischer 344 and nonphotoperiodic Wistar rats. American Journal of Physiology.
Regulatory, Integrative and Comparative Physiology 292 R1315–R1319. (doi:10.
1152/ajpregu.00396.2006)
Yoshimura T 2010 Neuroendocrine mechanism of seasonal reproduction in
birds and mammals. Animal Science Journal 81 403–410. (doi:10.1111/j.
1740-0929.2010.00777.x)
Yoshimura T, Yasuo S, Watanabe M, Iigo M, Yamamura T, Hirunagi K &
Ebihara S 2003 Light-induced hormone conversion of T
4
to T
3
regulates
photoperiodic response of gonads in birds. Nature 426 178–181. (doi:10.
1038/nature02117)
Zavacki AM, Arrojo EDR, Freitas BC, Chung M, Harney JW, Egr i P,
Wittmann G, Fekete C, Gereben B & Bianco AC 2009 The E3
ubiquitin ligase TEB4 mediates degradation of type 2 iodothyronine
deiodinase. Molecular and Cellular Biology 29 5339–5347. (doi:10.1128/
MCB.01498-08)
Received in final form 20 January 2011
Accepted 3 February 2011
Made available online as an Accepted Preprint
3 February 2011
G R WILLIAMS and J H D BASSETT .Local control of T
3
action by Dio212
Journal of Endocrinology (2011) 209, 1–12 www.endocrinology-journals.org
