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

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.

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

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1065-1855 ◽

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.

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

Endocrinology ◽

10.1210/en.2012-1467 ◽

2012 ◽

Vol 153 (9) ◽

pp. 4128-4135 ◽

Cited By ~ 77

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.

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

Acta Endocrinologica ◽

10.1530/eje.0.1510497 ◽

2004 ◽

pp. 497-502 ◽

Cited By ~ 21

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.

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Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice

Journal of Endocrinology ◽

10.1677/joe.0.1820315 ◽

2004 ◽

Vol 182 (2) ◽

pp. 315-323 ◽

Cited By ~ 95

Author(s):

A Boelen ◽

J Kwakkel ◽

DC Thijssen-Timmer ◽

A Alkemade ◽

E Fliers ◽

...

Keyword(s):

Thyroid Hormone ◽

Mrna Expression ◽

Time Course ◽

Acute Illness ◽

Hormone Metabolism ◽

Thyroid Hormone Metabolism ◽

Pituitary Thyroid Axis ◽

Thyroid Axis ◽

Hpt Axis

During illness, major changes in thyroid hormone metabolism and regulation occur; these are collectively known as non-thyroidal illness and are characterized by decreased serum triiodothyronine (T(3)) and thyroxine (T(4)) without an increase in serum TSH. Whether alterations in the central part of the hypothalamus-pituitary-thyroid (HPT) axis precede changes in peripheral thyroid hormone metabolism instead of vice versa, or occur simultaneously, is presently unknown. We therefore studied the time-course of changes in thyroid hormone metabolism in the HPT axis of mice during acute illness induced by bacterial endotoxin (lipopolysaccharide; LPS).LPS rapidly induced interleukin-1beta mRNA expression in the hypothalamus, pituitary, thyroid and liver. This was followed by almost simultaneous changes in the pituitary (decreased expression of thyroid receptor (TR)-beta2, TSHbeta and 5'-deiodinase (D1) mRNAs), the thyroid (decreased TSH receptor mRNA) and the liver (decreased TRbeta1 and D1 mRNA). In the hypothalamus, type 2 deiodinase mRNA expression was strongly increased whereas preproTRH mRNA expression did not change after LPS. Serum T(3) and T(4) fell only after 24 h.Our results suggested almost simultaneous involvement of the whole HPT axis in the downregulation of thyroid hormone metabolism during acute illness.

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Faculty Opinions recommendation of Critical role of the hypothalamic-pituitary-thyroid axis in bone.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1124537.581743 ◽

2008 ◽

Author(s):

Gordon Klein

Keyword(s):

Critical Role ◽

Pituitary Thyroid Axis ◽

Thyroid Axis

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

Endocrinology ◽

10.1210/en.2002-220574 ◽

2002 ◽

Vol 143 (12) ◽

pp. 4513-4519 ◽

Cited By ~ 56

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.

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The Hypothalamic-Pituitary Thyroid Axis : Studies on the Regulatory Role of Thyrotropin Releasing Hormone (TRH)

Folia Endocrinologica Japonica ◽

10.1507/endocrine1927.52.9_908 ◽

1976 ◽

Vol 52 (9) ◽

pp. 908-925

Author(s):

Yoshifumi HIROOKA

Keyword(s):

Thyrotropin Releasing Hormone ◽

Regulatory Role ◽

Releasing Hormone ◽

Pituitary Thyroid Axis ◽

Thyroid Axis

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

Journal of Biological Chemistry ◽

10.1074/jbc.m511530200 ◽

2005 ◽

Vol 281 (8) ◽

pp. 5000-5007 ◽

Cited By ~ 67

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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The role of leptin in the regulation of TSH secretion in the fed state: in vivo and in vitro studies

Journal of Endocrinology ◽

10.1677/joe.0.1740121 ◽

2002 ◽

Vol 174 (1) ◽

pp. 121-125 ◽

Cited By ~ 78

Author(s):

TM Ortiga-Carvalho ◽

KJ Oliveira ◽

BA Soares ◽

CC Pazos-Moura

Keyword(s):

Fold Increase ◽

Adult Rats ◽

Fed State ◽

Rat Pituitary ◽

Pituitary Thyroid Axis ◽

Tsh Secretion ◽

Thyroid Axis

Leptin has been shown to stimulate the hypothalamus-pituitary-thyroid axis in fasting rodents; however, its role in thyroid axis regulation under physiological conditions is still under investigation. Here it was investigated in freely fed rats whether leptin modulates thyrotroph function in vivo and whether leptin has direct pituitary effects on TSH release. Since leptin is produced in the pituitary, the possibility was also investigated that leptin may be a local regulator of TSH release. TSH was measured by specific RIA. Freely fed adult rats 2 h after being injected with a single s.c. injection of 8 microg leptin/100 g body weight showed a 2-fold increase in serum TSH (P<0.05). Hemi-pituitary explants incubated with 10(-9) and 10(-7) M leptin for 2 h showed a reduced TSH release of 40 and 50% respectively (P<0.05). Conversely, incubation of hemi-pituitary explants with antiserum against leptin, aiming to block the action of locally produced leptin, resulted in higher TSH release (45%, P<0.05). In conclusion, also in the fed state, leptin has an acute stimulatory effect on TSH release in vivo, acting probably at the hypothalamus. However, the direct pituitary effect of leptin is inhibitory and data also provide evidence that in the rat pituitary leptin may act as an autocrine/paracrine inhibitor of TSH release.

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