Different Hypothalamic Mechanisms Control Decreased Circulating Thyroid Hormone Levels in Infection and Fasting-Induced Non-Thyroidal Illness Syndrome in Male Thyroid Hormone Action Indicator Mice.

Background: Non-Thyroidal Illness Syndrome (NTIS) caused by infection or fasting is hallmarked by reduced circulating thyroid hormone (TH) levels. To better understand the role of local TH-action in the development of NTIS, we assessed tissue-specific changes of TH signaling in Thyroid Hormone Action Indicator (THAI) mice. Methods: NTIS was induced in young adult THAI mice by bacterial lipopolysaccharide (LPS)-administration or by 24 or 48 hours' fasting. Tissue-specific TH-action was assessed by the detection of changes of the Luciferase reporter of THAI mice with quantitative polymerase chain reaction along with tissue-specific examination of regulators of TH metabolism and signaling. Age dependence of revealed alterations of hypothalamic TH-action was also studied in 1-year-old male THAI mice. Results: LPS-treatment increased TH-action in the hypothalamic arcuate nucleus-median eminence (ARC-ME) region preceded by an increase of type 2 deiodinase (D2) expression in the same region and followed by the suppression of proTrh expression in the hypothalamic paraventricular nucleus (PVN). In contrast, LPS decreased both TH-action and D2 activity in the pituitary at both ages. Tshß expression and serum free thyroxine (fT4) and free triiodothyronine (fT3) levels decreased in LPS-treated young adults. Tshß expression and serum fT4 levels were not significantly affected by LPS treatment in aged animals. In contrast to LPS treatment, TH-action remained unchanged in the ARC-ME of 24 and 48 hours fasted animals accompanied with a modest decrease of proTrh expression in the PVN in the 24-hour group. Tshß expression and fT3 level were decreased in both fasted groups, but the fT4 decreased only in the 48 hours fasted animals. Conclusions: Although the hypothalamo-pituitary-thyroid (HPT) axis is inhibited both in LPS and fasting-induced NTIS, LPS achieves this by centrally inducing local hyperthyroidism in the ARC-ME region, while fasting acts without affecting hypothalamic TH signaling. Lack of downregulation of Tshß and fT4 in LPS-treated aged THAI mice suggests age-dependent alterations in the responsiveness of the HPT axis. The LPS-induced tissue-specific hypo-, eu-, and hyperthyroidism in different tissues of the same animal indicate that under certain conditions TH levels alone could be a poor marker of tissue TH signaling. In conclusion, decreased circulating TH levels in these two forms of NTIS are associated with different patterns of hypothalamic TH signaling.

Selenium involvement in mitochondrial function in thyroid disorders.

Selenium (Se), an important oligoelement, is a component of the antioxidant system. Over the last decade, it has been ever more frequently discussed in the context of thyroid disorders. Graves' disease and Hashimoto's thyroiditis, differentiated thyroid cancer, and even endemic goiter may have common triggers that are activated by excess reactive oxygen species (ROS), which are involved in various stages of the pathogenesis of thyroid disorders. Most oxidative events occur in mitochondria, organelles that contain enzymes with Se as a cofactor. Mitochondria are responsible for the production of ATP in the cell and are also a major site of ROS production. Thyroid hormone status (the thyroid being the organ with the highest concentration of Se in the body) has a profound impact on mitochondria biogenesis. In this review, we focus on the role of Se in mitochondrial function in thyroid disorders with impaired oxidative stress, since both thyroid hormone synthesis and thyroid dysfunction involve ROS. The role of Se deficiency or its excess in relation to mitochondrial dysfunction in the context of thyroid disorders is therefore of interest.

Is euthyroid sick syndrome a defensive mechanism against oxidative stress?

The body has a hierarchy of defence strategies to deal with oxidative stress. Among these arrays of defence mechanisms, the over expression and increased activity of glutathione peroxidases has been suggested as the first line of defence. The two main cofactors required for glutathione peroxidase activity are selenium and reduced glutathione. These two factors have been shown to be required for the deiodinase activity also. In vitro and in vivo studies have shown that oxidative stress decreases the activity of deiodinase. Thus, a decrease in deiodinase activity would facilitate the use of these cofactors by glutathione peroxidase in combating oxidative stress. Lowering of serum T3 is generally regarded as a valuable calorie-sparing economy. A decreased metabolic state of the cells as found in euthyroid sick syndrome indicates a decreased free radical generation from the mitochondria. For this reason, euthyroid sick syndrome could be considered as a physiological mechanism activated in response to oxidative stress.

Alterations in cardiac contractility and gene expression during low-T3 syndrome: prevention with T3.

The low-T3 syndrome is a metabolic response resulting in a decreased serum triiodothyronine (T3) concentration that has uncertain effects on thyroid hormone-responsive gene expression and function. We measured cardiac myocyte gene expression and cardiac contractility in young adult female rats using chronic calorie deprivation as a model of the low-T3 syndrome. Sarcoplasmic reticulum calcium adenosinetriphosphatase (SERCA2) and myosin heavy chain (MHC) isoform mRNA content were measured after 28 days on a 50% calorie-restricted diet (low T3) with or without T3 treatment (6 micrograms.kg body wt-1.day-1). The low-T3 animals had decreased maximal rates of contraction (-13%; P < 0.05) and relaxation (-18%; P < 0.05) compared with the control and the T3-treated groups. There was a 21% (P < 0.05) increase in left ventricular (LV) relaxation time in the low-T3 animals vs. both control and T3-treated groups. The LV content of the SERCA2 mRNA was decreased significantly (37%) in the low-T3 rats and was increased (P < 0.05) with T3 treatment vs. controls. The alpha-MHC mRNA isoform decreased in the low-T3 animals but was unchanged in the T3-treated animals. T3 supplementation normalized both cardiac function and phenotype of calorie-restricted animals, suggesting a role for the low-T3 syndrome in the pathophysiological response to calorie restriction.