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Endocrinology Vol. 148, No. 7 3077-3079
Copyright © 2007 by The Endocrine Society

An Inside Job

Antonio C. Bianco, Scott Ribich and Brian W. Kim

Thyroid Section Division of Endocrinology, Diabetes, and Hypertension Department of Medicine Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Dr. Antonio C. Bianco, Brigham and Women’s Hospital, Harvard Medical School Medicine/Endocrinology, Diabetes and Hypertension, 77 Avenue Louis Pasteur, Room 643, Boston, Massachusetts 02115. E-mail: abianco{at}partners.org.


   Introduction
Top
 Introduction
Personalized Thyroid Hormone...
 References
 
Thyroid hormone, a small polyiodinated tyrosine-based molecule, is essential not only for the development of all vertebrates, but also for the systemic and cellular control of energy homeostasis. It is released into the plasma by the thyroid gland as either the minimally active prohormone T4 or its biologically active counterpart T3. T3 acts through its nuclear receptors [thyroid hormone receptors (TRs)], transcription factors that positively or negatively regulate expression of a wide variety of genes (1). Its constant presence in health ensures a specific gene-expression profile, or footprint, that influences development and modulates the metabolic rate. It has been assumed by many that, under normal conditions, the thyroid signaling footprint arises directly as a result of T3 entering target cells from the plasma. However, a large body of work has indicated that additional complexity in thyroid hormone signaling exists, because T3 can be generated inside cells, and this T3 can change the footprint (2). In this issue of Endocrinology, Galton et al. (3) provide conclusive evidence, using a genetic approach, that T3 levels in the brain depend not only on plasma T3, but also on local production via the type 2 deiodinase (D2).

The dogma of plasma T3 being the only source of intracellular T3 was initially challenged by the discovery that cells containing D2 can produce T3 from the intracellular deiodination of T4. This D2-generated T3 did not rapidly exit the cell, but rather entered the cell nucleus and only after several hours equilibrated with serum T3 (2, 4, 5). It is likely that the location of D2 in the endoplasmic reticulum, a compartment that is highly connected with the nuclear envelope, facilitates the access of T3 to the nucleus (6). As would be expected in a system of this nature, there are other enzymes that modify thyroid hormone activity. D2 is a member of a group of three deiodinases that activate or inactivate thyroid hormone by removal of outer or inner ring iodine moieties, respectively (7, 8). Both D1 and D2 convert T4, the major circulating form, to T3. In contrast, D3 terminates the actions of both T3 and T4, converting them to inactive metabolites (Fig. 1Go).


Figure 1
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  		FIG. 1. Role of D2 and D3 in thyroid hormone signaling. Schematic includes T4 and T3 (represented by blue and green circles), active and inactive D2 (brown and red ovals), D3 (yellow ovals), and the nuclear T3 pool. In D2-expressing cells, the nuclear pool of T3 available to TRs originates from both plasma T3 and T3 generated by the D2 pathway. Antagonistically, D3 catalyzes the conversion of plasma and cellular T4 and T3 to the inactive metabolites reverse T3 (rT3) and T2, respectively. D2 can be inactivated by ubiquitination (Ub) via WSB-1 (whose gene expression is increased by the Hedgehog pathway), but can be rescued by VDU1/VDU2 (whose gene expression is stimulated by cAMP). Dio2 and Dio3 gene expression are also dynamic: Dio2 expression is highly stimulated by cAMP, produced either via the ß-adrenergic pathway or by bile acid-media stimulation of G-coupled protein receptor TGR5, and Dio3 expression is stimulated by TGF-ß and other growth factors. WSB1, WD repeat and SOCS box-containing protein 1; VDU1 and VDU2, VHL-interacting deubiquitinating enzyme 1 and 2.

 
Not surprisingly, the actions of D2 and D3 are integrated and thus promote T3 homeostasis. Fluctuations in serum T4 and T3 concentrations lead to homeostatic, reciprocal changes in the activity of D2 and D3 (7). As serum T3 concentration increases, expression of the D3 gene (Dio3) is up-regulated, increasing T3 clearance, whereas expression of the D2 gene (Dio2) and its activity are down-regulated, decreasing T3 production. Conversely, if serum T3 concentration was to fall, down-regulation of the D3 pathway would decrease the clearance of T3, and an up-regulation of the D2 pathway would compensate T3 production.

Two different but not mutually exclusive physiological roles of D2 and D3 thus emerged; the first, that these enzymes serve a homeostatic role to counteract changes in thyroid hormone supply to preserve thyroid hormone-dependent gene expression. The second is that primary changes in deiodinase activity can modulate TR saturation by increasing or decreasing cellular T3 concentrations, and thus, generating a specific and different downstream transcriptional response from cells not expressing deiodinases. This scenario of tissue- and time-specific modulation of T3 levels would be evolutionary advantageous in vertebrates that contain a wide variety of tissue types with varying developmental and metabolic demands (9, 10). A growing body of evidence supports the concept that D2 and D3 are tightly regulated in development and metamorphosis (11, 12, 13). Most recently, hedgehog signaling was demonstrated to regulate D2 inactivation via ubiquination in the chicken tibial growth plate, playing a direct role in PTHrP secretion and hence skeletogenesis (14).

In their study, Galton et al. (3) examine the role of D2 as a determinant of T3 concentration in neonatal and adult mouse brain. Neonate mice with targeted disruption of Dio2 (D2KO) have half as much cerebral T3 as wild-type mice, elegantly confirming the prediction derived from older kinetic studies that D2 produces a large percentage of the T3 present in the brain (2). The strength of the study is its genetic approach; as in the other animal models of genetically modified deiodinase expression (15), isolated Dio2 inactivation addresses many of the technical limitations and assumptions of studies using radioactive tracers. The residual levels of T3 present in the D2KO mouse brain can only be derived from plasma (and cerebral spinal fluid), and no mechanism exists to restore T3 concentration in the absence of D2. These findings unequivocally demonstrate that the T3 present in D2-expressing tissues arises from a combination of both D2-generated T3 and plasma-derived T3.


   Personalized Thyroid Hormone Signaling
Top
 Introduction
 Personalized Thyroid Hormone...
References
 
A recent evolutionary step in our understanding of the physiological role of the deiodinases came with the recognition that primary, or initial, changes in deiodinase activity can trigger thyroid hormone-dependent metabolic or developmental events in multiple systems. The initial evidence that primary changes in deiodinase activity could elicit downstream metabolic events came from studies of brown adipose tissue (16). D2 activation in this tissue by sympathetic signaling leads to cell-specific TR saturation with T3 that is generated within the adipocyte, amplifying the thyroid hormone signaling for as long as the brown adipose is stimulated (17). This mechanism is so efficient that the TRs will be saturated even if serum T4 concentrations are reduced by more than 50% (18). This in turn leads to the induction of T3-responsive thermogenic genes such as uncoupling protein 1 (19), with neither an antecedent nor a concurrent change in plasma T3 levels. This model was further validated using the same D2KO mouse used by Galton et al. in the present study, which has normal plasma T3 levels but must activate shivering thermogenesis to survive in the cold (20, 21). Thus, D2-mediated tissue-specific thyrotoxicosis can be a potent mechanism for promoting metabolic changes.

The metabolic role of D2 is not limited to adipocyte tissue. A specific role for D2 in the brain was recently discovered in the hypothalamic arcuate nucleus (ARC), which is critical for the regulation of appetite (22). In that study, fasting mice increase D2 activity in astrocytes surrounding the arcuate nucleus, causing increased T3 production, and hence increasing thyroid hormone signaling in these cells. This caused a subsequent increase in the amount of uncoupling protein uncoupling protein 2, and higher excitability of the neuropeptide Y/agouti-related protein neurons that regulate food intake. These molecular mechanisms resulted in a clear behavioral phenotype, with the increased D2 activity causing higher levels of rebound feeding after forced fasting. These findings follow the observation that, in the medial basal hypothalamus of the Japanese quail, D2 expression is induced by light and results in increase gonadal growth, whereas a D2 inhibitor prevents it (23).

Despite the 50% decrease in brain T3 levels, the authors found that the central nervous system phenotype of the D2KO mice appears to be mild compared with hypothyroid animals with respect to gene expression and behavior. This may seem surprising because there is high expression of D2 in the neonate brain, and central hypothyroidism causes severe neurological developmental problems.

The authors examined locomotion and agility, learning and memory, reflexes, and anxiety and exploratory levels in both wild-type and D2KO mice with a varied set of behavioral tests. Although the behavioral phenotype of the mice was not as severe as that seen with hypothyroid mice, there were clear defects in certain agility tasks. These findings may indicate that the residual brain T3, originating from plasma, was sufficient to preserve functions examined in the study. Furthermore, compensation via unknown mechanisms could be operant, as pointed out by the authors. At the neonatal time where the animals were studied, no clear compensation from the other deiodinases could be identified. However, as the authors also note, only a single neonatal age was examined, and it is possible that levels of D1 and D3 might fluctuate at earlier ages and thus limiting the differences in gene expression in the D2KO mouse brain. It is also likely that D2 gene expression might be crucial for subsets of brain cells, and that differences in gene expression would be difficult to observe without profiling specific subsets of neurons or a larger set of genes. Finally, studies of the D2KO animals under iodine deficiency or other situations where T4 is limited may reveal a more dramatic phenotype.

The fact that the D2KO animals have substantially less T3 in their brain tissue provides clear support for the current paradigm that thyroid hormone signaling is not equal among cells, varying based on the expression of the deiodinases (Fig. 1Go). Whereas we understand some of the signals that modulate deiodinase expression and thus cell-specific thyroid hormone signaling, e.g. adrenergic signaling, bile acids/G-coupled protein receptor TGR5 pathway, Hedgehog pathway, and other morphogens (14, 24, 25, 26), we are left with the fascinating job of identifying the diverse signals that regulate these enzymes during development and adulthood.


   Footnotes
 
This work was supported by National Institutes of Health Grants DK58538, DK65655, DK77148, and K08 DK064643.

Disclosure Summary: All authors have nothing to disclose.

Abbreviations: D2 or D3, Type 2 or 3 deiodinase; TR, thyroid hormone receptor.

Received March 19, 2007.

Accepted for publication March 20, 2007.


   References
Top
 Introduction
 Personalized Thyroid Hormone...
 References
 

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B. Gereben, A. M. Zavacki, S. Ribich, B. W. Kim, S. A. Huang, W. S. Simonides, A. Zeold, and A. C. Bianco
Cellular and Molecular Basis of Deiodinase-Regulated Thyroid Hormone Signaling
Endocr. Rev., December 1, 2008; 29(7): 898 - 938.
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