Faculty Opinions recommendation of Thyroid hormone receptor phosphorylation regulates acute fasting-induced suppression of the hypothalamic-pituitary-thyroid axis.

ABSTRACT Mutations of the thyroid hormone receptor β (TRβ) gene cause resistance to thyroid hormone (RTH). RTH is characterized by increased serum thyroid hormone associated with nonsuppressible thyroid-stimulating hormone (TSH) and impaired growth. It is unclear how the actions of TRβ mutants are modulated in vivo to affect the manifestation of RTH. Using a mouse model of RTH that harbors a knockin mutation of the TRβ gene (TRβPV mouse), we investigated the effect of the steroid hormone receptor coactivator 3 (SRC-3) on RTH. In TRβPV mice deficient in SRC-3, dysfunction of the pituitary-thyroid axis and hypercholesterolemia was lessened, but growth impairment of RTH was worsened. The lessened dysfunction of the pituitary-thyroid axis was attributed to a significant decrease in growth of the thyroid and pituitary. Serum insulin-like growth factor 1 (IGF-1) was further reduced in TRβPV mice deficient in SRC-3. This effect led to reduced signaling of the IGF-1/phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway that is known to mediate cell growth and proliferation. Thus, SRC-3 modulates RTH by at least two mechanisms, one via its role as a receptor coregulator and the other via its growth regulatory role through the IGF-1/PI3K/AKT/mTOR signaling.

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Thyrotropin-Releasing Hormone and the Thyroid Hormone Feedback Mechanism

Endocrinology ◽

10.1210/en.2008-1795 ◽

2009 ◽

Vol 150 (3) ◽

pp. 1091-1096 ◽

Cited By ~ 183

Author(s):

Maria Izabel Chiamolera ◽

Fredric E. Wondisford

Keyword(s):

Thyroid Hormone ◽

Thyroid Hormone Receptor ◽

Dominant Role ◽

Critical Role ◽

Negative Regulation ◽

Thyrotropin Releasing Hormone ◽

Transcriptional Level ◽

Releasing Hormone ◽

Pituitary Thyroid Axis ◽

Thyroid Axis

Thyroid hormone (TH) plays a critical role in development, growth, and cellular metabolism. TH production is controlled by a complex mechanism of positive and negative regulation. Hypothalamic TSH-releasing hormone (TRH) stimulates TSH secretion from the anterior pituitary. TSH then initiates TH synthesis and release from the thyroid gland. The synthesis of TRH and TSH subunit genes is inhibited at the transcriptional level by TH, which also inhibits posttranslational modification and release of TSH. Although opposing TRH and TH inputs regulate the hypothalamic-pituitary-thyroid axis, TH negative feedback at the pituitary was thought to be the primary regulator of serum TSH levels. However, study of transgenic animals showed an unexpected, dominant role for TRH in regulating the hypothalamic-pituitary-thyroid axis and an unanticipated involvement of the thyroid hormone receptor ligand-dependent activation function (AF-2) domain in TH negative regulation. These results are summarized in the review. The thyrotropin-releasing hormone neuron is well-positioned to integrate information about the environment as well as circulating TH levels and ultimately affect metabolism in response to these physiological changes.

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In Vivo Interaction of Steroid Receptor Coactivator (SRC)-1 and the Activation Function-2 Domain of the Thyroid Hormone Receptor (TR) β in TRβ E457A Knock-In and SRC-1 Knockout mice

Endocrinology ◽

10.1210/en.2009-0093 ◽

2009 ◽

Vol 150 (8) ◽

pp. 3927-3934 ◽

Cited By ~ 23

Author(s):

Manuela Alonso ◽

Charles Goodwin ◽

XiaoHui Liao ◽

Tania Ortiga-Carvalho ◽

Danielle S. Machado ◽

...

Keyword(s):

Thyroid Hormone ◽

Thyroid Hormone Receptor ◽

Steroid Receptor ◽

Activation Function ◽

Steroid Receptor Coactivator ◽

Pituitary Thyroid Axis ◽

Serum T4 ◽

Thyroid Axis

The activation function-2 (AF-2) domain of the thyroid hormone (TH) receptor (TR)-β is a TH-dependent binding site for nuclear coactivators (NCoA), which modulate TH-dependent gene transcription. In contrast, the putative AF-1 domain is a TH-independent region interacting with NCoA. We determined the specificity of the AF-2 domain and NCoA interaction by evaluating thyroid function in mice with combined disruption of the AF-2 domain in TRβ, due to a point mutation (E457A), and deletion of one of the NCoAs, steroid receptor coactivator (SRC)-1. The E457A mutation was chosen because it abolishes NCoA recruitment in vitro while preserving normal TH binding and corepressor interactions resulting in resistance to TH. At baseline, disruption of SRC-1 in the homozygous knock-in (TRβE457A/E457A) mice worsened the degree of resistance to TH, resulting in increased serum T4 and TSH. During TH deprivation, disruption of AF-2 and SRC-1 resulted in a TSH rise 50% of what was seen when AF-2 alone was removed, suggesting that SRC-1 was interacting outside of the AF-2 domain. Therefore, 1) during TH deprivation, SRC-1 is necessary for activating the hypothalamic-pituitary-thyroid axis; 2) ligand-dependent repression of TSH requires an intact AF-2; and 3) SRC-1 may interact with the another region of the TRβ or the TRα to regulate TH action in the pituitary. This report demonstrates the dual interaction of NCoA in vivo: the TH-independent up-regulation possibly through another domain and TH-dependent down-regulation through the AF-2 domain.

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MECHANISMS IN ENDOCRINOLOGY: Beyond the fixed setpoint of the hypothalamus–pituitary–thyroid axis

Acta Endocrinologica ◽

10.1530/eje-14-0285 ◽

2014 ◽

Vol 171 (5) ◽

pp. R197-R208 ◽

Cited By ~ 58

Author(s):

Eric Fliers ◽

Andries Kalsbeek ◽

Anita Boelen

Keyword(s):

Thyroid Hormone ◽

Negative Feedback ◽

Thyroid Hormone Receptor ◽

Feedback Regulation ◽

Tissue Level ◽

Serum Concentrations ◽

Negative Feedback Regulation ◽

Pituitary Thyroid Axis ◽

Thyroid Axis ◽

Hpt Axis

The hypothalamus–pituitary–thyroid (HPT) axis represents a classical example of an endocrine feedback loop. This review discusses dynamic changes in HPT axis setpoint regulation, identifying their molecular and cellular determinants, and speculates about their functional role. Hypothalamic thyrotropin-releasing hormone neurons were identified as key components of thyroid hormone (TH) setpoint regulation already in the 1980s, and this was followed by the demonstration of a pivotal role for the thyroid hormone receptor beta in negative feedback of TH on the hypothalamic and pituitary level. Gradually, the concept emerged of the HPT axis setpoint as a fixed entity, aiming at a particular TH serum concentration. However, TH serum concentrations appear to be variable and highly responsive to physiological and pathophysiological environmental factors, including the availability or absence of food, inflammation and clock time. During food deprivation and inflammation, TH serum concentrations decrease without a concomitant rise in serum TSH, reflecting a deviation from negative feedback regulation in the HPT axis. Surprisingly, TH action in peripheral organs in these conditions cannot be simply predicted by decreased serum TH concentrations. Instead, diverse environmental stimuli have differential effects on local TH metabolism, e.g. in liver and muscle, occurring quite independently from decreased TH serum concentrations. The net effect of these differential local changes is probably a major determinant of TH action at the tissue level. In sum, hypothalamic HPT axis setpoint regulation as well as TH metabolism at the peripheral organ level is flexible and dynamic, and may adapt the organism in an optimal way to a range of environmental challenges.

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Thyroid hormone receptor phosphorylation regulates acute fasting-induced suppression of the hypothalamic–pituitary–thyroid axis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2107943118 ◽

2021 ◽

Vol 118 (39) ◽

pp. e2107943118

Author(s):

Svetlana Minakhina ◽

Vanessa De Oliveira ◽

Sun Young Kim ◽

Haiyan Zheng ◽

Fredric E. Wondisford

Keyword(s):

Thyroid Hormone ◽

Hormone Receptor ◽

Thyroid Hormone Receptor ◽

Phosphorylation Site ◽

Nuclear Hormone Receptor ◽

Negative Regulator ◽

Common Mechanism ◽

Pituitary Thyroid Axis ◽

Hpt Axis

Fasting induces profound changes in the hypothalamic–pituitary–thyroid (HPT) axis. After binding thyroid hormone (TH), the TH receptor beta 2 isoform (THRB2) represses Trh and Tsh subunit genes and is the principle negative regulator of the HPT axis. Using mass spectrometry, we identified a major phosphorylation site in the AF-1 domain of THRB2 (serine 101, S101), which is conserved among many members of the nuclear hormone receptor superfamily. More than 50% of THRB2 is phosphorylated at S101 in cultured thyrotrophs (TαT1.1) and in the mouse pituitary. All other THR isoforms lack this site and exhibit limited overall levels of phosphorylation. To determine the importance of THRB2 S101 phosphorylation, we used the TαT1.1 cell line and S101A mutant knock-in mice (Thrb2S101A). We found that TH promoted S101 THRB2 phosphorylation and was essential for repression of the axis at physiologic TH concentrations. In mice, THRB2 phosphorylation was also increased by fasting and mimicked Trh and Tshb repression by TH. In vitro studies demonstrated that a master metabolic sensor, AMP-activated kinase (AMPK) induced phosphorylation at the same site and caused Tshb repression independent of TH. Furthermore, we identified cyclin-dependent kinase 2 (CDK2) as a direct kinase phosphorylating THRB2 S101 and propose that AMPK or TH increase S101 phosphorylation through the activity of CDK2. This study provides a physiologically relevant function for THR phosphorylation, which permits nutritional deprivation and TH to use a common mechanism for acute suppression of the HPT axis.

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