Physiological consequences of the TRα1 aporeceptor state

Mittag, Jens; Wallis, Karin; Vennström, Björn

doi:10.1007/s10741-008-9119-5

Cited by 16 publications

(9 citation statements)

References 34 publications

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“…However, more recent studies on TH control of cardiovascular function revealed an additional central mechanism originating in the hypothalamus. Mittag et al [70] reported that mice expressing the mutant TRα1 exhibit a slight decrease in heart rate and a severely impaired cardiovascular response to stress or an environmental temperature challenge. This cardiac dysfunction in TRα1-mutant mice was found to be due to an unbalanced sympatho-vagal tone from the brain [70].…”

Section: Systemic Effects Of Intrahypothalamic Thmentioning

confidence: 99%

“…Mittag et al [70] reported that mice expressing the mutant TRα1 exhibit a slight decrease in heart rate and a severely impaired cardiovascular response to stress or an environmental temperature challenge. This cardiac dysfunction in TRα1-mutant mice was found to be due to an unbalanced sympatho-vagal tone from the brain [70]. Further studies indicated that a previously unknown population of parvalbuminergic neurons in the anterior hypothalamic area may be responsible for this dysregulation of heart function.…”

Section: Systemic Effects Of Intrahypothalamic Thmentioning

confidence: 99%

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TRH Neurons and Thyroid Hormone Coordinate the Hypothalamic Response to Cold

Zhi¹,

Boelen²,

Kalsbeek³

et al. 2018

Eur Thyroid J

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Thyroid hormone (TH) plays a key role in regulating body temperature in mammals. Cold exposure stimulates the hypothalamus-pituitary-thyroid (HPT) axis at the hypothalamic level by activating hypophysiotropic thyrotropin-releasing hormone (TRH)-producing neurons, ultimately resulting in increased plasma TH concentrations. Importantly, the local TH metabolism within various cold-responsive organs enables tissue-specific action of TH on heat production and adaption to cold independently of the circulating TH levels. In addition to these neuroendocrine effects, TRH neurons in the hypothalamus also have neural connections with brown adipose tissue (BAT), probably contributing to regulation of thermogenesis by the autonomic nervous system. Recent studies have demonstrated that intrahypothalamic TH has profound metabolic effects on BAT, the liver, and the heart that are mediated via the autonomic nervous system. These effects originate in various hypothalamic nuclei, including the paraventricular nucleus (PVN), the ventromedial nucleus, and recently reported neurons in the anterior hypothalamic area, indicating a potential central function for TH on thermoregulation. Finally, although robust stimulation of the thermogenic program in BAT was shown upon TH administration in the ventromedial hypothalamus, the physiological relevance of these neurally mediated effects of TH is unclear at present. This review provides an overview of studies reporting the role of TH in cold defense, with a focus on recent literature evidencing the centrally mediated effects of TRH and TH.

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Section: Systemic Effects Of Intrahypothalamic Thmentioning

confidence: 99%

Section: Systemic Effects Of Intrahypothalamic Thmentioning

confidence: 99%

TRH Neurons and Thyroid Hormone Coordinate the Hypothalamic Response to Cold

Zhi¹,

Boelen²,

Kalsbeek³

et al. 2018

Eur Thyroid J

View full text Add to dashboard Cite

show abstract

“…Analyses of mice heterozygous for a mutant TRα1, however, suggest that these patients might display normal TH economy, which could hinder their identification [10]. Despite the several defects observed in the animals with a mutant TRα1 (for a review see [11]), a reliable biochemical marker for a large-scale screening approach is missing. Although recent studies on TRα1R384C mutant mice revealed a TRα1-specific regulation of serum selenium (Se) [12], this parameter alone is not suitable to predict or diagnose RTH as it varies with serum TH levels.…”

Section: Introductionmentioning

confidence: 99%

Serum copper as a novel biomarker for resistance to thyroid hormone

Mittag

Behrends

Nordström

et al. 2012

Biochemical Journal

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Thyroid hormone action is mediated by the thyroid hormone receptors TRα1 and TRβ. Defects in TRβ lead to RTH (resistance to thyroid hormone) β, a syndrome characterized by high levels of thyroid hormone and non-suppressed TSH (thyroid-stimulating hormone). However, a correct diagnosis of RTHβ patients is difficult as the clinical picture varies. A biochemical serum marker indicative of defects in TRβ signalling is needed and could simplify the diagnosis of RTHβ, in particular the differentiation to TSH-secreting pituitary adenomas, which present with clinically similar symptoms. In the present paper we show that serum copper levels are regulated by thyroid hormone, which stimulates the synthesis and the export of the hepatic copper-transport protein ceruloplasmin into the serum. This is accompanied by a concerted reduction in the mRNA levels of other copper-containing proteins such as metallothioneins 1 and 2 or superoxide dismutase 1. The induction of serum copper is abolished in genetically hyperthyroid mice lacking TRβ and human RTHβ patients, demonstrating an important role of TRβ for this process. Together with a previously reported TRα1 specific regulation of serum selenium, we show that the ratio of serum copper and selenium, which is largely independent of thyroid hormone levels, volume changes or sample degradation, can constitute a valuable novel biomarker for RTHβ. Moreover, it could also provide a suitable large-scale screening parameter to identify RTHα patients, which have not been identified to date.

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“…However, TH are thought to act principally by binding to their nuclear receptors, it is intriguing why TR knockout animals exhibit a much milder phenotype compared to hypothyroid animals (Gothe et al 1999). These differences in the phenotypes have been attributed to the unliganded TRs and their bound co-repressors in the pathogenesis of hypothyroidism-induced brain abnormalities (Hashimoto et al 2001, Morte et al 2002, Venero et al 2005, Kapoor et al 2010, Mittag et al 2010, Bernal & Morte 2013, Shi 2013. Since HDACs are associated with the co-repressors bound unliganded TRs, we hypothesized that inhibiting HDAC activity would block the negative regulation of target genes by unliganded TRs and may restore normal brain development under hypothyroidism.…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibition reduces hypothyroidism-induced neurodevelopmental defects in rats

Kumar

Mohan

Sinha

et al. 2015

Journal of Endocrinology

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Thyroid hormone (TH) through its receptor (TRa/b) influences spatio-temporal regulation of its target gene repertoire during brain development. Though hypothyroidism in WT rodent models of perinatal hypothyroidism severely impairs neurodevelopment, its effect on TRa/b knockout mice is less severe. An explanation to this paradox is attributed to a possible repressive action of unliganded TRs during development. Since unliganded TRs suppress gene expression through the recruitment of histone deacetylase (HDACs) via co-repressor complexes, we tested whether pharmacological inhibition of HDACs may prevent the effects of hypothyroidism on brain development. Using valproate, an HDAC inhibitor, we show that HDAC inhibition significantly blocks the deleterious effects of hypothyroidism on rat cerebellum, evident by recovery of TH target genes like Bdnf, Pcp2 and Mbp as well as improved dendritic structure of cerebellar Purkinje neurons. Together with this, HDAC inhibition also rescues hypothyroidism-induced motor and cognitive defects. This study therefore provides an insight into the role of HDACs in TH insufficiency during neurodevelopment and their inhibition as a possible therapeutics for treatment.

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Physiological consequences of the TRα1 aporeceptor state

Cited by 16 publications

References 34 publications

TRH Neurons and Thyroid Hormone Coordinate the Hypothalamic Response to Cold

TRH Neurons and Thyroid Hormone Coordinate the Hypothalamic Response to Cold

Serum copper as a novel biomarker for resistance to thyroid hormone

Histone deacetylase inhibition reduces hypothyroidism-induced neurodevelopmental defects in rats

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