The Role of Tanycytes in the Hypothalamus-Pituitary-Thyroid Axis and the Possibilities for Their Genetic Manipulation

2019 ◽  
Vol 128 (06/07) ◽  
pp. 388-394
Author(s):  
Helge Müller-Fielitz ◽  
Markus Schwaninger
Keyword(s):  
Energy Homeostasis ◽  
Genetic Manipulation ◽  
Heart Function ◽  
Feedback Regulation ◽  
Target Organs ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis ◽  
Hpt Axis ◽  
The Brain

AbstractThyroid hormone (TH) regulation is important for development, energy homeostasis, heart function, and bone formation. To control the effects of TH in target organs, the hypothalamus-pituitary-thyroid (HPT) axis and the tissue-specific availability of TH are highly regulated by negative feedback. To exert a central feedback, TH must enter the brain via specific transport mechanisms and cross the blood-brain barrier. Here, tanycytes, which are located in the ventral walls of the 3rd ventricle in the mediobasal hypothalamus (MBH), function as gatekeepers. Tanycytes are able to transport, sense, and modify the release of hormones of the HPT axis and are involved in feedback regulation. In this review, we focus on the relevance of tanycytes in thyrotropin-releasing hormone (TRH) release and review available genetic tools to investigate the physiological functions of these cells.

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

2014 ◽  
Vol 171 (5) ◽  
pp. R197-R208 ◽  
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.

scholarly journals 60 YEARS OF NEUROENDOCRINOLOGY: TRH, the first hypophysiotropic releasing hormone isolated: control of the pituitary–thyroid axis

2015 ◽  
Vol 226 (2) ◽  
pp. T85-T100 ◽  
Author(s):  
Patricia Joseph-Bravo ◽  
Lorraine Jaimes-Hoy ◽  
Rosa-María Uribe ◽  
Jean-Louis Charli
Keyword(s):  
Negative Energy ◽  
Feedback Effects ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis ◽  
Synthetic Hormones ◽  
Hpt Axis ◽  
Different Levels ◽  
Trh Receptor

This review presents the findings that led to the discovery of TRH and the understanding of the central mechanisms that control hypothalamus–pituitary–thyroid axis (HPT) activity. The earliest studies on thyroid physiology are now dated a century ago when basal metabolic rate was associated with thyroid status. It took over 50 years to identify the key elements involved in the HPT axis. Thyroid hormones (TH: T4and T3) were characterized first, followed by the semi-purification of TSH whose later characterization paralleled that of TRH. Studies on the effects of TH became possible with the availability of synthetic hormones. DNA recombinant techniques permitted the identification of all the elements involved in the HPT axis, including their mode of regulation. Hypophysiotropic TRH neurons, which control the pituitary–thyroid axis, were identified among other hypothalamic neurons which express TRH. Three different deiodinases were recognized in various tissues, as well as their involvement in cell-specific modulation of T3concentration. The role of tanycytes in setting TRH levels due to the activity of deiodinase type 2 and the TRH-degrading ectoenzyme was unraveled. TH-feedback effects occur at different levels, including TRH and TSH synthesis and release, deiodinase activity, pituitary TRH-receptor and TRH degradation. The activity of TRH neurons is regulated by nutritional status through neurons of the arcuate nucleus, which sense metabolic signals such as circulating leptin levels.Trhexpression and the HPT axis are activated by energy demanding situations, such as cold and exercise, whereas it is inhibited by negative energy balance situations such as fasting, inflammation or chronic stress. New approaches are being used to understand the activity of TRHergic neurons within metabolic circuits.

scholarly journals Interleukin-18, a proinflammatory cytokine, contributes to the pathogenesis of non-thyroidal illness mainly via the central part of the hypothalamus-pituitary-thyroid axis

2004 ◽  
pp. 497-502 ◽  
Author(s):  
A Boelen ◽  
J Kwakkel ◽  
M Platvoet-ter Schiphorst ◽  
B Mentrup ◽  
A Baur ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Mrna Expression ◽  
Proinflammatory Cytokine ◽  
Biological Properties ◽  
Thyroid Hormone Metabolism ◽  
Pituitary Thyroid Axis ◽  
Serum T3 ◽  
Thyroid Axis ◽  
Hpt Axis

OBJECTIVE: Proinflammatory cytokines are involved in the pathogenesis of non-thyroidal illness (NTI), as shown by studies with IL-6-/- and IL-12-/- mice. Interleukin (IL)-6 changes peripheral thyroid hormone metabolism, and IL-12 seems to be involved in the regulation of the central part of the hypothalamic-pituitary-thyroid (HPT) axis during illness. IL-18 is a proinflammatory cytokine which shares important biological properties with IL-12, such as interferon (IFN)-gamma-inducing activity. DESIGN: By studying the changes in the HPT-axis during bacterial lipopolysaccharide (LPS)-induced illness in IL-18-/-, IFNgammaR-/- and wild-type (WT) mice, we wanted to unravel the putative role of IL-18 and IFNgamma in the pathogenesis of NTI. RESULTS: LPS induced a decrease in pituitary type 1 deiodinase (D1) activity (P<0.05, ANOVA) in WT mice, but not in IL-18-/- mice, while the decrease in D2 activity was similar in both strains. LPS decreased serum thyroid hormone levels and liver D1 mRNA within 24 h similarly in IL-18-/-, and WT mice. The expression of IL-1, IL-6 and IFNgamma mRNA expression was significantly lower in IL-18-/- mice than in WT, while IL-12 mRNA expression was similar. IFNgammaR-/- mice had higher basal D1 activity in the pituitary than WT mice (P<0.05); LPS induced a decrease of D2, but not of D1, activity in the pituitary which was similar in both strains. In the liver, the LPS-induced increase in cytokine expression was not different between IFNgammaR-/- mice and WT mice, and the decrease in serum T3 and T4 levels and hepatic D1 mRNA was also similar. CONCLUSIONS: The relative decrease in serum T3 and T4 and liver D1 mRNA in response to LPS is similar in IL-18-/-, IFNgammaR-/- and WT mice despite significant changes in hepatic cytokine induction. However, the LPS-induced decrease in D1 activity in the pituitary of WT mice is absent in IL-18-/- mice; in contrast, LPS did not decrease pituitary D1 activity in the IFNgammaR-/- mice or their WT, which might be due to the genetic background of the mice. Our results suggest that IL-18 is also involved in the regulation of the central part of the HPT axis during illness.

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 Distinct Roles of Deiodinases on the Phenotype of Mct8 Defect: A Comparison of Eight Different Mouse Genotypes

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 1180-1191 ◽  
Author(s):  
Xiao-Hui Liao ◽  
Caterina Di Cosmo ◽  
Alexandra M. Dumitrescu ◽  
Arturo Hernandez ◽  
Jacqueline Van Sande ◽  
...  
Keyword(s):  
Growth Response ◽  
Pituitary Thyroid Axis ◽  
Severe Impairment ◽  
Serum T3 ◽  
Serum T4 ◽  
Thyroid Axis ◽  
Mct8 Deficiency ◽  
The Brain ◽  
Insight Into ◽  
Serum Tsh

Mice deficient in the thyroid hormone (TH) transporter Mct8 (Mct8KO) have increased 5′-deiodination and impaired TH secretion and excretion. These and other unknown mechanisms result in the low-serum T4, high T3, and low rT3 levels characteristic of Mct8 defects. We investigated to what extent each of the 5′-deiodinases (D1, D2) contributes to the serum TH abnormalities of the Mct8KO by generating mice with all combinations of Mct8 and D1 and/or D2 deficiencies and comparing the resulting eight genotypes. Adding D1 deficiency to that of Mct8 corrected the serum TH abnormalities of Mct8KO mice, normalized brain T3 content, and reduced the impaired expression of TH-responsive genes. In contrast, Mct8D2KO mice maintained the serum TH abnormalities of Mct8KO mice. However, the serum TSH level increased 27-fold, suggesting a severely impaired hypothalamo-pituitary-thyroid axis. The brain of Mct8D2KO manifested a pattern of more severe impairment of TH action than Mct8KO alone. In triple Mct8D1D2KO mice, the markedly increased serum TH levels produced milder brain defect than that of Mct8D2KO at the expense of more severe liver thyrotoxicosis. Additionally, we observed that mice deficient in D2 had an unexplained marked reduction in the thyroid growth response to TSH. Our studies on these eight genotypes provide a unique insight into the complex interplay of the deiodinases in the Mct8 defect and suggest that D1 contributes to the increased serum T3 in Mct8 deficiency, whereas D2 mainly functions locally, converting T4 to T3 to compensate for distinct cellular TH depletion in Mct8KO mice.

The Neuroendocrine System and General Mechanisms of Endocrine Disruption

2017 ◽  
Author(s):  
Heather B. Patisaul ◽  
Scott M. Belcher
Keyword(s):  
Feedback Regulation ◽  
Neuroendocrine System ◽  
Negative Feedback Regulation ◽  
Adrenal Hormone ◽  
Aryl Hydrocarbon ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis ◽  
Environmental Sensor ◽  
Exogenous Compounds ◽  
Primary Focus

The neuroendocrine system is the interface between the endocrine and nervous systems. This chapter presents an overview of the neuroendocrine system and endogenous hormones, with a primary focus on the hypothalamic-pituitary-gonadal (HPG) axis, the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-thyroid axis (HPT). The importance of impacts of exogenous compounds, both natural and man-made, on the neuroendocrine system is discussed, with a focus on endocrine-disruptive actions of plant-derived phytoestrogens and the role of the aryl hydrocarbon receptor as an environmental sensor. The impacts of EDCs on feed-forward and negative feedback regulation of neuroendocrine functions, including those mediated by estrogen, androgen, and thyroid pathways, as well as other less studied pathways of hormonal signaling that involve disruption of neurosteroids, peptide hormones, and adrenal hormone signaling are also presented.

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 Dominant Role of Thyrotropin-releasing Hormone in the Hypothalamic-Pituitary-Thyroid Axis

2005 ◽  
Vol 281 (8) ◽  
pp. 5000-5007 ◽  
Author(s):  
Amisra A. Nikrodhanond ◽  
Tania M. Ortiga-Carvalho ◽  
Nobuyuki Shibusawa ◽  
Koshi Hashimoto ◽  
Xiao Hui Liao ◽  
...  
Keyword(s):  
Dominant Role ◽  
Thyrotropin Releasing Hormone ◽  
Releasing Hormone ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis
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