Download Minireview: Cracking the Metabolic Code for Thyroid Hormone

M I N I R E V I E W
Minireview: Cracking the Metabolic Code for Thyroid
Hormone Signaling
Antonio C. Bianco
Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine,
Miami, Florida 33136
Cells are not passive bystanders in the process of hormonal signaling and instead can actively
customize hormonal action. Thyroid hormone gains access to the intracellular environment via
membrane transporters, and while diffusing from the plasma membrane to the nucleus, thyroid
hormone signaling is modified via the action of the deiodinases. Although the type 2 deiodinase
(D2) converts the prohormone T4 to the biologically active T3, the type 3 deiodinase (D3) converts
it to reverse T3, an inactive metabolite. D3 also inactivates T3 to T2, terminating thyroid hormone
action. Therefore, D2 confers cells with the capacity to produce extra amounts of T3 and thus
enhances thyroid hormone signaling. In contrast expression of D3 results in the opposite action.
The Dio2 and Dio3 genes undergo transcriptional regulation throughout embryonic development,
childhood, and adult life. In addition, the D2 protein is unique in that it can be switched off and
on via an ubiquitin regulated mechanism, triggered by catalysis of T4. Induction of D2 enhances
local thyroid hormone signaling and energy expenditure during activation of brown adipose tissue
by cold exposure or high-fat diet. On the other hand, induction of D3 in myocardium and brain
during ischemia and hypoxia decreases energy expenditure as part of a homeostatic mechanism to
slow down cell metabolism in the face of limited O2 supply. (Endocrinology 152: 3306 –3311, 2011)
ost eukaryotic cells are equipped with built-in genetic programs that control cell division, homeostatic functions, and basic phenotype. These cellular programs can be modified by environmental cues, such as
nutrient availability or biologically active molecules, the
nature and intensity over which most cells have very
little control. Hormones constitute an example of such
biologically active molecules, and cells are generally
classified as responsive or unresponsive, depending on
whether they have sufficient number of their cognate
receptors. However, it has become increasingly clear
that cells are not passive bystanders in this process and
instead can actively customize hormonal signals, such
as with sexual steroids and thyroid hormone. For example, cellular expression of 5␣-reductase or P450 aromatase, respectively, transforms the testosterone molecule into dihydrotestosterone or estradiol, locally
changing testosterone’s biological activity in opposite
M
directions. A similar scenario exists in the case of the
deiodinases, enzymes that can locally activate or inactivate thyroid hormone.
Cellular membranes are relatively impermeable to thyroid hormone and thus membrane transporters are necessary for access to the intracellular environment (1). Once
inside the cells, thyroid hormone diffuses toward the nucleus and eventually binds to its receptors, high affinity
ligand-dependent transcription factors that modify gene
expression (2). However, inside the cells, the prohormone
T4 can be transformed to the biologically active T3 molecule via the type 2 deiodinase (D2), or it can be inactivated to form reverse T3 via the type 3 deiodinase (D3).
Most importantly, T3 is also inactivated by D3, preventing
or terminating thyroid hormone action (3). Thus, although diffusing from the plasma membrane to the nucleus, thyroid hormone signaling is modified via the action
of the deiodinases.
ISSN Print 0013-7227 ISSN Online 1945-7170
Printed in U.S.A.
Copyright © 2011 by The Endocrine Society
doi: 10.1210/en.2011-1104 Received April 13, 2011. Accepted June 7, 2011.
First Published Online June 28, 2011
Abbreviations: ARC, Arcuate nucleus; BAT, brown adipose tissue; D2, type 2 deiodinase;
D3, type 3 deiodinase; D2KO, D2 knockout; E, embryonic day; ER, endoplasmic reticulum;
Fox, forkhead box; MBH, medial basal hypothalamus; ME, median eminence; Ub, ubiquitin;
UCP, uncoupling protein; USP, Ub-specific protease.
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Endocrinology, September 2011, 152(9):3306 –3311
Deiodinases are dimeric integral-membrane thyroredoxin fold-containing selenoproteins of about 60 kDa
(dimer) (4 –9). Each dimer counterpart consists of a selenocystein-containing globular domain that is anchored
to cellular membranes through a single amino-terminal
transmembrane segment. D2 is an endoplasmic reticulum
(ER)-resident protein that is retained in ER and generates
T3 in the proximity of the nuclear compartment (10). On
the other hand, most D3 goes through the Golgi complex
and reaches the plasma membrane, where it undergoes
endocytosis and recycles via the early endosomes (4).
Thus, D2 expression confers cells with the capacity to
produce additional amounts of T3 and thus enhances thyroid hormone signaling. In contrast, expression of D3 results in the opposite action. Furthermore, these events occur in the cell without relative changes to plasma thyroid
hormone levels (11, 12).
The Dio2 and Dio3 genes undergo transcriptional regulation throughout embryonic development, childhood,
and adult life (11). Dio2 is a highly sensitive cAMP-responsive gene (13) that is also positively regulated by nuclear factor ␬B (14) and forkhead box (Fox)O3 (15). At the
same time, Dio3 is up-regulated by retinoic acid, 12-Otetradecanoyl phorbol 13-acetate, basic fibroblast growth
factor (16), TGF␤ (17), the hedgehog-GLI family zinc finger 2 pathway (18), and hypoxia-inducible factor-1␣ (19).
The D2 protein is unique in that it can be switched off
and on via an ubiquitin (Ub)-regulated mechanism, triggered by catalysis of T4 (20 –22). It is assumed that T4
deiodination exposes Lys-residues in D2’s globular domain that are subsequently conjugated to Ub. Moreover,
this results in inactivating D2 by disruption of the dimer
formation (20). Ub-D2 is not immediately taken up by the
proteasome and instead can be deubiquitinated and reactivated to produce another molecule of T3, repeating the
cycle. Although two Ub conjugases are involved in the
process of D2 ubiquitination (23, 24), the limiting components of this pathway are two E3-ligase adaptors. These
include the hedgehog-inducible suppressor of cytokine
signaling-box containing WD repeat suppressor of cytokine signaling box-containing protein-1 (25) and TEB4
(26), a ligase involved in the ER-associated degradation
program. In contrast, two Ub-specific proteases (USP),
USP20 and USP33, mediate deubiquitination and reactivation of Ub-D2 (21).
Thus, it is clear that thyroid hormone levels in the
plasma do not faithfully reflect thyroid hormone signaling
in cells; this action takes place inside the cell. A complex
network of transcriptional and posttranscriptional mechanisms regulating deiodinase expression is at work in
health and disease, mediating rapid customization of thyroid hormone signaling on a cell-specific basis.
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Deiodinases and the Metabolic Effects of
Thyroid Hormone
Insulin typifies how metabolic pathways are controlled by
systemic hormones. In the minutes that follow a meal,
insulin is secreted into the bloodstream, exposing all tissues to elevated levels of insulin. As a result, glucose uptake and oxidation is increased, the synthesis of fatty acid
is accelerated, and protein anabolism is enhanced. A few
hours later, plasma insulin levels are back to premeal levels
and so are its metabolic effects. This is a very different
model to that which cells respond to thyroid hormone. On
the contrary, thyroid hormone levels in the plasma hardly
fluctuate in healthy individuals, as shown in a year-long
study of serum levels of T4 and T3 (27). Thus, thyroid
hormone-responsive metabolic processes are turned on
and off by thyroid hormone via deiodination pathways
that are taking place inside the target cells, seemingly invisible from the plasma viewpoint (11).
Even though we are just starting to understand these
pathways, some thyroid hormone effects on metabolism
are well recognized, including acceleration of substrate
cycles, ionic cycles, and mitochondrial respiration, all
leading to accelerated energy expenditure (28). Unfortunately, most of what we know about these effects is from
nonphysiological models in which subjects were systemically hypothyroid or thyrotoxic. To illustrate this point,
hypothyroidism and thyrotoxicosis are known to affect
sympathetic outflow to a number of metabolically active
tissues, such as white and brown adipose tissue (BAT),
liver, skeletal muscle, and heart (29, 30). These states mask
the true effects of thyroid hormone deficiency or its excess.
This is illustrated in the D2 knockout (D2KO) mice. At
room temperature, which is considered a significant thermal stress for mice, D2KO mice preferentially oxidize fat,
have a normal sensitivity to diet-induced obesity, and are
supertolerant to glucose load. However, when thermal
stress is eliminated and sympathetic activity minimized at
thermoneutrality (30 C), an opposite phenotype is encountered, one that includes obesity, glucose intolerance,
and exacerbated hepatic steatosis (31). Thus, the cell-specific metabolic effects of thyroid hormone are largely unknown, and cracking the code requires understanding the
deiodinase pathways.
A glimpse into this world is available through the studies in which D2 and D3 expression reciprocally affect energy expenditure in a number of cell and animal models.
For example, cAMP-dependent induction of D2 expression during activation of brown adipocytes by cold exposure or high-fat diet enhances local thyroid hormone signaling and energy expenditure, the absence of which
prevents normal BAT function (31–34). On the other
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hand, hypoxia-inducible factor-1␣-dependent induction
of D3 in myocardium and brain during ischemia and hypoxia decreases energy expenditure, supposedly as part of
a homeostatic mechanism to slow down cell metabolism in
the face of limited O2 supply (19, 35). In fact, D3 reactivation in disease states can be so powerful that it compromises systemic thyroid economy, leading to euthyroid
sick syndrome (36). In rare instances, D3-mediated thyroid hormone inactivation is so dramatic that it exceeds
the thyroidal synthetic capacity to sustain thyroid economy, leading to consumptive hypothyroidism (37).
D2 expression is the target of a rapidly growing number
of molecules that accelerate energy expenditure and metabolic programs in cells and animal models. These include
bile acids (38), flavonols (39), and chemical chaperones
(40), which in-turn confer protection against diet-induced
obesity. Insulin and peroxisome proliferator-activated receptor ␥ agonists are also bona fide inducers of D2 in
skeletal muscle (41). On the other hand, signaling through
the D2 pathway is dampened by ER stress (42) and the
LXR-RXR pathway (43), the metabolic consequence of
which is currently under investigation.
Deiodinases and the Development of
Metabolically Relevant Tissues
During vertebrate embryogenesis, developmental signals
control the expression interplay between D2 and D3 in
metabolic relevant tissues, such as BAT (44), pancreatic
islets, and skeletal muscle (15), explaining how “systemic”
thyroid hormone can affect local control of tissue
embryogenesis.
In the 3-d developmental snapshot during which BAT
develops in mice [embryonic day (E)16.5–E18.5], D2 expression is up-regulated about 5-fold and D3 expression
drops by 75%. This results in increased local net T3 availability, whereas serum T3 remains unchanged. This rapid
enhancement in thyroid hormone signaling is critical for
the expression of genes defining BAT identity, i.e. uncoupling protein (UCP)1, peroxisome proliferator-activated
receptor gamma co-activator-1␣, and Dio2 (44). Notably,
these changes in gene expression are observed in utero,
without a thermogenic challenge, which highlights the relevance of D2 and its ability to amplify thyroid hormone
signaling in a developmental setting. The inactivation of
the Dio2 gene as in the D2KO mouse results in a permanent BAT thermogenic defect, compromising thermoregulation and the ability to dissipate excessive calories from
diet (31, 32).
The D2 pathway seems to also be critical for skeletal
muscle development and function (15). Besides regulating
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insulin sensitivity in myocytes (41), D2-mediated T3 production is also required for the T3-dependent expression of
myogenic factors, such as the myogenic regulatory factor
(MyoD), which drive myocyte development. As in BAT,
myocytes from D2KO mice have impaired development
and function supposedly due to lower intracellular T3 generation. The control of the D2 pathway in myocytes is
dependent on the transcription factor FoxO3, which directly binds to the Dio2 promoter, up-regulating D2 expression. The fact that FoxO3 KO myocytes also display
impaired cellular development, easily reversed by the addition of exogenous T3, underscores the physiological relevance of the FoxO3/D2 interplay.
The opposite scenario is observed during development
of the pancreatic ␤-cells, with D3 expression keeping thyroid hormone signaling to a minimum, from late embryonic development throughout adulthood (45). The late
emergence of D3 expression at E17.5 is restricted to insulin positive cells, indicating a focused role in ␤-cell but
not ␣-cell development. ␣-Cell development occurs at a
much earlier phase of embryogenesis (by E9.5). As a result
of untimely expression of thyroid hormone, D3KO animals exhibit a reduction in total islet area due to decreased
␤-cells area, insulin content and lower expression of key
islet genes involved in glucose sensing, insulin expression,
and exocytosis. This is physiologically significant given
that adult D3KO animals are glucose intolerant due to
impaired glucose-stimulated insulin secretion, without
changes in peripheral sensitivity to insulin.
Deiodinases in the Medial Basal
Hypothalamus (MBH)
In the central nervous system, D2 is expressed in astrocytes, whereas thyroid hormone receptor and D3 are
found in adjacent neurons (46, 47). Thus, glial cell D2
produces T3, which acts in a paracrine fashion to induce
thyroid hormone-responsive genes in the nearby neurons
(35), a process that is also modulated by D3 activity in the
neurons. This paracrine pathway of thyroid hormone action depends on the deiodinases and is thus regulated by
signals such as hypoxia, hedgehog signaling, and lipopolysaccharide-induced inflammation, as evidenced both in
vitro as well as in rat models of brain ischemia and mouse
models of inflammation (48). Therefore, as in other tissues, it is clear that deiodinases function as control points
for the regulation of thyroid signaling in the brain.
The neurons in MBH are a target of thyroid hormone,
and thus, local D2 and D3 expression can affect thyroid
economy and a number of other homeostatic functions
(46, 47, 49, 50). Within the MBH, D2 expression is largely
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restricted to the tanycytes, which are ependymal cells lining the floor and infralateral walls of the third ventricle
extending from the rostral tip of the median eminence
(ME) to the infundibular recess, surrounding blood vessels
in the arcuate nucleus (ARC), and in the ME adjacent to
the portal vessels and overlying the tuberoinfundibular
sulci (49, 50). Thus, the tanycytes seem to be a major
source of T3 to the ARC-ME region of the hypothalamus,
likely with important metabolic consequences.
For example, hypothalamic D2 activity in rodents
exhibits a circadian rhythmicity with an activity peak at
night, which coincides with their peak of metabolic activity (51). At the same time, fasting induces a state of
central hypothyroidism that has been linked to an approximately 2-fold up-regulation of D2 expression in
the hypothalamus (52) and suppression in TRH/TSH
secretion. It has also been suggested that D2 expression
in the ARC is localized in glial cells that are in direct
opposition to neurons coexpressing neuropeptide Y,
Agouti-related peptide, and UCP2 (53). Notably, the fasting-induced increase in D2 activity and local thyroid hormone activation in the ARC is paralleled by an increase in
UCP2-dependent mitochondrial uncoupling in neuropeptide Y/Agouti-related peptide expressing neurons. These
events were shown to be linked to the increased excitability of these orexigenic neurons and consequent rebound
feeding after food deprivation (54).
Deiodinases and the Skeleton
There are strong links emerging between metabolic control and bone and the role of the deiodinases in the skeleton (55). The skeleton is a target of thyroid hormone,
which responds by accelerating bone turnover to the extent that there is a net loss of bone mass during systemic
thyrotoxicosis (56). In mice, thyroid hormone signaling is
kept to a minimum during early bone development due to
the high D3 expression (57). Later, during E14.5–E18.5,
there is a decrease in D3 and an increase in D2 expression,
thus increasing thyroid hormone signaling toward the end
of gestation (57). Studies in the developing chicken skeleton indicate that hedgehog signaling mediates the reciprocal control of D2 and D3 expression, transcriptionally
increasing Dio3 gene expression and inactivating D2 via
induction of WSB-1, the E3 ligase Ub adaptor that ubiquitinates D2 (18, 25). In adult mice, D2 is present in wholebone extracts, as well as in skeletal cells and differentiated
osteoblasts (58), but it is undetectable in chondrocytes and
osteoclasts (59). Its absence, as in the D2KO mouse, results in brittle bones due to reduced bone formation, without changes in bone resorption (60). T3 target gene anal-
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ysis indicates osteoblastic T3 deficiency (60), suggesting
that D2-mediated T3 production in osteoblasts is important for maintenance of adult bone mineralization and
optimal bone strength.
Conclusion
Thyroid hormone signaling is a local event, with target
cells playing a major role through controlled expression
of the activating or inactivating deiodinases. Although
it is conceivable that plasma T3 plays a metabolic role
in some tissues, its relative constancy throughout adult
life precludes it from controlling major metabolic pathways. The local role played by the deiodinases in customizing thyroid hormone signaling is the predominant
modus operandi through which thyroid hormone exerts
its metabolic effects, including in the BAT, ␤-cell, MBH,
bone, and skeletal muscle. Much of this new paradigm
of thyroid hormone action was validated through the
study of mice with targeted disruption of the deiodinase
genes (61). Much remains to be learned while we decipher
this code, particularly through the use of a new generation
of tissue-specific deiodinase KO animals (62). The consequence of this new way of looking at thyroid hormone
action has very significant clinical implications, because
serum hormone levels may not be predictive of events that
are driving clinical symptoms. This is well illustrated by
the series of reports correlating polymorphisms in the
three deiodinase genes with a growing number of diseases
and clinical conditions in individuals with normal thyroid
function tests (63).
Acknowledgments
I thank Dr. Valerie Galton, Dr. Donald St. Germain, and Dr.
Arturo Hernandez for graciously sharing different deiodinase
KO mouse models and Rafael Arroyo e Drigo, Dr. Tatiana Fonseca, and Dr. Barry Hudson for reviewing the manuscript.
Address all correspondence and requests for reprints to: Antonio C. Bianco, Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, 1400
North West 10th Avenue, Suite 816, Miami, Florida 33136.
E-mail: [email protected].
This work was supported in part by National Institute of
Diabetes and Digestive and Kidney Diseases Grants DK58538,
DK65055, DK77148, and DK7856.
Disclosure Summary: The author has nothing to disclose.
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