scholarly journals The Thyroid Hormone Transporter Mct8 Restricts Cathepsin-Mediated Thyroglobulin Processing in Male Mice through Thyroid Auto-Regulatory Mechanisms That Encompass Autophagy

2021 ◽  
Vol 22 (1) ◽  
pp. 462
Author(s):  
Vaishnavi Venugopalan ◽  
Alaa Al-Hashimi ◽  
Maren Rehders ◽  
Janine Golchert ◽  
Vivien Reinecke ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Cathepsin L ◽  
Cathepsin K ◽  
Regulatory Mechanisms ◽  
Classical Pathway ◽  
Phenotypic Differences ◽  
Pituitary Thyroid Axis ◽  
Data Points ◽  
Thyroid Axis ◽  
Deficient Mice

The thyroid gland is both a thyroid hormone (TH) generating as well as a TH responsive organ. It is hence crucial that cathepsin-mediated proteolytic cleavage of the precursor thyroglobulin is regulated and integrated with the subsequent export of TH into the blood circulation, which is enabled by TH transporters such as monocarboxylate transporters Mct8 and Mct10. Previously, we showed that cathepsin K-deficient mice exhibit the phenomenon of functional compensation through cathepsin L upregulation, which is independent of the canonical hypothalamus-pituitary-thyroid axis, thus, due to auto-regulation. Since these animals also feature enhanced Mct8 expression, we aimed to understand if TH transporters are part of the thyroid auto-regulatory mechanisms. Therefore, we analyzed phenotypic differences in thyroid function arising from combined cathepsin K and TH transporter deficiencies, i.e., in Ctsk-/-/Mct10-/-, Ctsk-/-/Mct8-/y, and Ctsk-/-/Mct8-/y/Mct10-/-. Despite the impaired TH export, thyroglobulin degradation was enhanced in the mice lacking Mct8, particularly in the triple-deficient genotype, due to increased cathepsin amounts and enhanced cysteine peptidase activities, leading to ongoing thyroglobulin proteolysis for TH liberation, eventually causing self-thyrotoxic thyroid states. The increased cathepsin amounts were a consequence of autophagy-mediated lysosomal biogenesis that is possibly triggered due to the stress accompanying intrathyroidal TH accumulation, in particular in the Ctsk-/-/Mct8-/y/Mct10-/- animals. Collectively, our data points to the notion that the absence of cathepsin K and Mct8 leads to excessive thyroglobulin degradation and TH liberation in a non-classical pathway of thyroid auto-regulation.

scholarly journals Neuropeptide Y1 and Y5 Receptors Mediate the Effects of Neuropeptide Y on the Hypothalamic-Pituitary-Thyroid Axis

Endocrinology ◽  
2002 ◽  
Vol 143 (12) ◽  
pp. 4513-4519 ◽  
Author(s):  
Csaba Fekete ◽  
Sumit Sarkar ◽  
William M. Rand ◽  
John W. Harney ◽  
Charles H. Emerson ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Paraventricular Nucleus ◽  
Receptor Agonist ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis ◽  
Ad Libitum ◽  
Thyroid Hormone Levels ◽  
Hpt Axis

Abstract Neuropeptide Y (NPY) is one of the most important hypothalamic-derived neuropeptides mediating the effects of leptin on energy homeostasis. Central administration of NPY not only markedly stimulates food intake, but simultaneously inhibits the hypothalamic-pituitary-thyroid axis (HPT axis), replicating the central hypothyroid state associated with fasting. To identify the specific NPY receptor subtypes involved in the action of NPY on the HPT axis, we studied the effects of the highly selective Y1 ([Phe7,Pro34]pNPY) and Y5 ([chicken pancreatic polypeptide1–7, NPY19–23, Ala31, Aib32 (aminoisobutyric acid), Q34]human pancreatic polypeptide) receptor agonists on circulating thyroid hormone levels and proTRH mRNA in hypophysiotropic neurons of the hypothalamic paraventricular nucleus. The peptides were administered continuously by osmotic minipump into the cerebrospinal fluid (CSF) over 3 d in ad libitum-fed animals and animals pair-fed to artificial CSF (aCSF)-infused controls. Both Y1 and Y5 receptor agonists nearly doubled food intake compared with that of control animals receiving aCSF, similar to the effect observed for NPY. NPY, Y1, and Y5 receptor agonist administration suppressed circulating levels of thyroid hormones (T3 and T4) and resulted in inappropriately normal or low TSH levels. These alterations were also associated with significant suppression of proTRH mRNA in the paraventricular nucleus, particularly in the Y1 receptor agonist-infused group [aCSF, NPY, Y1, and Y5 (density units ± sem), 97.2 ± 8.6, 39.6 ± 8.4, 19.9 ± 1.9, and 44.6 ± 8.4]. No significant differences in thyroid hormone levels, TSH, or proTRH mRNA were observed between the agonist-infused FSanimals eating ad libitum and the agonist-infused animals pair-fed with vehicle-treated controls. These data confirm the importance of both Y1 and Y5 receptors in the NPY-mediated increase in food consumption and demonstrate that both Y1 and Y5 receptors can mediate the inhibitory effects of NPY on the HPT axis.

scholarly journals The TRH Gene Is Regulated by Thyroid Hormone at the Level of Transcription in Vivo

2010 ◽  
Vol 31 (1) ◽  
pp. 136-136
Author(s):  
Michelle L. Sugrue ◽  
Kristen R. Vella ◽  
Crystal Morales ◽  
Marisol E. Lopez ◽  
Anthony N. Hollenberg
Keyword(s):  
Thyroid Hormone ◽  
Genomic Region ◽  
Model System ◽  
Model Systems ◽  
In Vivo Model ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis ◽  
Normal Production

ABSTRACT The expression of the TRH gene in the paraventricular nucleus (PVH) of the hypothalamus is required for the normal production of thyroid hormone (TH) in rodents and humans. In addition, the regulation of TRH mRNA expression by TH, specifically in the PVH, ensures tight control of the set point of the hypothalamic-pituitary-thyroid axis. Although many studies have assumed that the regulation of TRH expression by TH is at the level of transcription, there is little data available to demonstrate this. We used two in vivo model systems to show this. In the first model system, we developed an in situ hybridization (ISH) assay directed against TRH heteronuclear RNA to measure TRH transcription directly in vivo. We show that in the euthyroid state, TRH transcription is present both in the PVH and anterior/lateral hypothalamus. In the hypothyroid state, transcription is activated in the PVH only and can be shut off within 5 h by TH. In the second model system, we employed transgenic mice that express the Cre recombinase under the control of the genomic region containing the TRH gene. Remarkably, TH regulates Cre expression in these mice in the PVH only. Taken together, these data affirm that TH regulates TRH at the level of transcription in the PVH only and that genomic elements surrounding the TRH gene mediate its regulation by T3. Thus, it should be possible to identify the elements within the TRH locus that mediate its regulation by T3 using in vivo approaches.

scholarly journals Minireview: The Neural Regulation of the Hypothalamic-Pituitary-Thyroid Axis

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4128-4135 ◽  
Author(s):  
Ricardo H. Costa-e-Sousa ◽  
Anthony N. Hollenberg
Keyword(s):  
Thyroid Hormone ◽  
Adult Life ◽  
Feedback System ◽  
Primary Hypothyroidism ◽  
Neural Regulation ◽  
Pituitary Thyroid Axis ◽  
Genes Encoding ◽  
Thyroid Axis ◽  
Hpt Axis

Thyroid hormone (TH) signaling plays an important role in development and adult life. Many organisms may have evolved under selective pressure of exogenous TH, suggesting that thyroid hormone signaling is phylogenetically older than the systems that regulate their synthesis. Therefore, the negative feedback system by TH itself was probably the first mechanism of regulation of circulating TH levels. In humans and other vertebrates, it is well known that TH negatively regulates its own production through central actions that modulate the hypothalamic-pituitary-thyroid (HPT) axis. Indeed, primary hypothyroidism leads to the up-regulation of the genes encoding many key players in the HPT axis, such as TRH, type 2 deiodinase (dio2), pyroglutamyl peptidase II (PPII), TRH receptor 1 (TRHR1), and the TSH α- and β-subunits. However, in many physiological circumstances, the activity of the HPT axis is not always a function of circulating TH concentrations. Indeed, circadian changes in the HPT axis activity are not a consequence of oscillation in circulating TH levels. Similarly, during reduced food availability, several components of the HPT axis are down-regulated even in the presence of lower circulating TH levels, suggesting the presence of a regulatory pathway hierarchically higher than the feedback system. This minireview discusses the neural regulation of the HPT axis, focusing on both TH-dependent and -independent pathways and their potential integration.

scholarly journals The Nuclear Receptor Corepressor (NCoR) Controls Thyroid Hormone Sensitivity and the Set Point of the Hypothalamic-Pituitary-Thyroid Axis

2011 ◽  
Vol 25 (2) ◽  
pp. 212-224 ◽  
Author(s):  
Inna Astapova ◽  
Kristen R. Vella ◽  
Preeti Ramadoss ◽  
Kaila A. Holtz ◽  
Benjamin A. Rodwin ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Nuclear Receptor ◽  
Hormone Sensitivity ◽  
Set Point ◽  
Nuclear Receptor Corepressor ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis

scholarly journals The Thyrotropin-Releasing Hormone Gene Is Regulated by Thyroid Hormone at the Level of Transcription in Vivo

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 793-801 ◽  
Author(s):  
Michelle L. Sugrue ◽  
Kristen R. Vella ◽  
Crystal Morales ◽  
Marisol E. Lopez ◽  
Anthony N. Hollenberg
Keyword(s):  
Thyroid Hormone ◽  
Genomic Region ◽  
Model System ◽  
Model Systems ◽  
In Vivo Model ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis ◽  
Normal Production

The expression of the TRH gene in the paraventricular nucleus (PVH) of the hypothalamus is required for the normal production of thyroid hormone (TH) in rodents and humans. In addition, the regulation of TRH mRNA expression by TH, specifically in the PVH, ensures tight control of the set point of the hypothalamic-pituitary-thyroid axis. Although many studies have assumed that the regulation of TRH expression by TH is at the level of transcription, there is little data available to demonstrate this. We used two in vivo model systems to show this. In the first model system, we developed an in situ hybridization (ISH) assay directed against TRH heteronuclear RNA to measure TRH transcription directly in vivo. We show that in the euthyroid state, TRH transcription is present both in the PVH and anterior/lateral hypothalamus. In the hypothyroid state, transcription is activated in the PVH only and can be shut off within 5 h by TH. In the second model system, we employed transgenic mice that express the Cre recombinase under the control of the genomic region containing the TRH gene. Remarkably, TH regulates Cre expression in these mice in the PVH only. Taken together, these data affirm that TH regulates TRH at the level of transcription in the PVH only and that genomic elements surrounding the TRH gene mediate its regulation by T3. Thus, it should be possible to identify the elements within the TRH locus that mediate its regulation by T3 using in vivo approaches.

scholarly journals Thyroid hormone-mediated negative transcriptional regulation of Necdin expression

2006 ◽  
Vol 36 (3) ◽  
pp. 517-530 ◽  
Author(s):  
Maria Nygård ◽  
Nathalie Becker ◽  
Barbara Demeneix ◽  
Katarina Pettersson ◽  
Maria Bondesson
Keyword(s):  
Thyroid Hormone ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptors ◽  
Developmentally Regulated ◽  
Hormone Response Elements ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis ◽  
Sequence Position

Unliganded thyroid hormone receptors (apoTRs) repress transcription of hormone-activated genes by recruiting corepressors to the promoters. In contrast, on promoters containing so-called negative thyroid hormone response elements (nTREs), apoTRs activate transcription. A number of different molecular mechanisms have been described as to how apoTRs activate transcription varying with the target gene of the study. Here we demonstrate that thyroid hormone regulates the transcription of the Necdin gene, a developmentally regulated candidate gene for the genomic imprinting-associated neurobehavioural disorder, Prader–Willi syndrome. ApoTRs activate Necdin expression through an nTRE in its promoter, downstream of the transcription start site. The nTRE of the Necdin gene resembles the nTREs of the TSHβ genes of the hypothalamus–pituitary–thyroid axis in the sequence, position in the promoter, and mode of activation. We show that this group of nTRE-driven genes shares the requirements for binding of the retinoic X receptor and nuclear receptor corepressor/silencing mediator of retinoid and thyroid hormone receptors (NCoR/SMRT) for full ligand-independent activation, whereas there is no need for association of the p160 family of coactivators. In accordance with the requirement for corepressors, Necdin expression is influenced by deacetylase activity, suggesting that histone deacetylases and corepressors as well could function as activators of transcription, depending on the promoter context.

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