Anita Boelen

Beyond Low Plasma T3: Local Thyroid Hormone Metabolism during Inflammation and Infection

Decreased serum thyroid hormone concentrations in severely ill patients were first reported in the 1970s, but the functional meaning of the observed changes in thyroid hormone levels, together known as nonthyroidal illness syndrome (NTIS), remains enigmatic. Although the common view was that NTIS results in overall down-regulation of metabolism in order to save energy, recent work has shown a more complex picture. NTIS comprises marked variation in transcriptional and translational activity of genes involved in thyroid hormone metabolism, ranging from inhibition to activation, dependent on the organ or tissue studied. Illness-induced changes in each of these organs appear to be very different during acute or chronic inflammation, adding an additional level of complexity. Organ- and timing-specific changes in the activity of thyroid hormone deiodinating enzymes (deiodinase types 1, 2, and 3) highlight deiodinases as proactive players in the response to illness, whereas the granulocyte is a novel and potentially important cell type involved in NTIS during bacterial infection. Although acute NTIS can be seen as an adaptive response to support the immune response, NTIS may turn disadvantageous when critical illness enters a chronic phase necessitating prolonged life support. For instance, changes in thyroid hormone metabolism in muscle during critical illness may be relevant for the pathogenesis of myopathy associated with prolonged ventilator dependence. This review focuses on NTIS as a timing-related and organ-specific response to illness, occurring independently from the decrease in serum thyroid hormone levels and potentially relevant for disease progression.

Thyroid hormone modulates glucose production via a sympathetic pathway from the hypothalamic paraventricular nucleus to the liver

Thyrotoxicosis increases endogenous glucose production (EGP) and induces hepatic insulin resistance. We have recently shown that these alterations can be modulated by selective hepatic sympathetic and parasympathetic denervation, pointing to neurally mediated effects of thyroid hormone on glucose metabolism. Here, we investigated the effects of central triiodothyronine (T3) administration on EGP. We used stable isotope dilution to measure EGP before and after i.c.v. bolus infusion of T3 or vehicle in euthyroid rats. To study the role of hypothalamic preautonomic neurons, bilateral T3 microdialysis in the paraventricular nucleus (PVN) was performed for 2 h. Finally, we combined T3 microdialysis in the PVN with selective hepatic sympathetic denervation to delineate the involvement of the sympathetic nervous system in the observed metabolic alterations. T3 microdialysis in the PVN increased EGP by 11 ± 4% (P = 0.020), while EGP decreased by 5 ± 8% (ns) in vehicle-treated rats (T3 vs. Veh, P = 0.030). Plasma glucose increased by 29 ± 5% (P = 0.0001) after T3 microdialysis versus 8 ± 3% in vehicle-treated rats (T3 vs. Veh, P = 0.003). Similar effects were observed after i.c.v. T3 administration. Effects of PVN T3 microdialysis were independent of plasma T3, insulin, glucagon, and corticosterone. However, selective hepatic sympathectomy completely prevented the effect of T3 microdialysis on EGP. We conclude that stimulation of T3-sensitive neurons in the PVN of euthyroid rats increases EGP via sympathetic projections to the liver, independently of circulating glucoregulatory hormones. This represents a unique central pathway for modulation of hepatic glucose metabolism by thyroid hormone.

Fasting-induced changes in the hypothalamus-pituitary-thyroid axis.

Fasting induces profound changes in the hypothalamus-pituitary-thyroid (HPT) axis. The alterations observed in humans and rodents are similar in many ways, although they may be more pronounced and more acute in rodents. The molecular mechanisms underlying the resetting of HPT axis regulation in the framework of caloric deprivation are still incompletely understood. Fascinating studies in rats and mice have shown a dramatic downregulation of thyrotropin-releasing hormone (TRH) gene expression in hypophysiotropic paraventricular nucleus (PVN) neurons during fasting. Direct and indirect effects of decreased serum leptin, as well as effects of increased local triiodothyronine (T3) concentrations, in the hypothalamus during food deprivation contribute to the decreased activity of TRH neurons in the PVN. However, the relative contributions of these complex determinants remain to be defined in more detail. Pituitary thyroid-stimulating hormone (TSH) beta mRNA expression decreases during fasting, and this may be relatively independent of leptin and/or TRH, since leptin administration in this setting does not fully restore pituitary TSH expression, while it does restore TRH expression in the PVN. There may be a role for pituitary peptides, such as neuromedin B, in altered TSH gene expression during fasting. The observed decrease in serum thyroid hormone concentrations results to some extent from diminished thyroidal secretion of thyroid hormones, especially in rodents. Decreased thyroxine (T4) and T3 contribute to the downregulation of T3-responsive genes such as liver D1. The overall result of these complex HPT axis changes in various tissues during fasting is downregulation of the HPT axis, which is assumed to represent an energy-saving mechanism, instrumental in times of food shortage.

Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis

Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with abnormal thyroid hormone (TH) parameters, is linked to mutations in the TH-specific monocarboxylate transporter MCT8. In mice, deletion of Mct8 (Mct8 KO) faithfully replicates AHDS-associated endocrine abnormalities; however, unlike patients, these animals do not exhibit neurological impairments. While transport of the active form of TH (T3) across the blood-brain barrier is strongly diminished in Mct8 KO animals, prohormone (T4) can still enter the brain, possibly due to the presence of T4-selective organic anion transporting polypeptide (OATP1C1). Here, we characterized mice deficient for both TH transporters, MCT8 and OATP1C1 (Mct8/Oatp1c1 DKO). Mct8/Oatp1c1 DKO mice exhibited alterations in peripheral TH homeostasis that were similar to those in Mct8 KO mice; however, uptake of both T3 and T4 into the brains of Mct8/Oatp1c1 DKO mice was strongly reduced. Evidence of TH deprivation in the CNS of Mct8/Oatp1c1 DKO mice included highly decreased brain TH content as well as altered deiodinase activities and TH target gene expression. Consistent with delayed cerebellar development and reduced myelination, Mct8/Oatp1c1 DKO mice displayed pronounced locomotor abnormalities. Intriguingly, differentiation of GABAergic interneurons in the cerebral cortex was highly compromised. Our findings underscore the importance of TH transporters for proper brain development and provide a basis to study the pathogenic mechanisms underlying AHDS.

Both immunisation with a formalin-inactivated respiratory syncytial virus (RSV) vaccine and a mock antigen vaccine induce severe lung pathology and a Th2 cytokine profile in RSV-challenged mice.

Respiratory syncytial virus (RSV) is the most important cause of bronchiolitis and pneumonia in infants and young children. Immunopathology may play a role in RSV-induced disease and a severe RSV infection may also be associated with an increased risk of developing asthma. Vaccination with formalin-inactivated RSV (FI-RSV) prior to infection resulted both in human and in the mouse model in extensive lung pathology. In the mouse model, it has been shown that this aggravation of disease was associated with a shift in the balance between Th1 and Th2 cytokines towards a Th2-type response. The aim of the present study was to characterise the immunological and inflammatory responses in BALB/c mice upon RSV infection with or without prior vaccination with aluminium-adjuvanted FI-RSV or control antigens (FI-Mock). As previously reported by others, we also observed that a primary RSV infection in BALB/c mice resulted in a predominant Th1-type cytokine response, which was associated with slight bronchiolitis and alveolitis. FI-RSV vaccination prior to RSV challenge prevented virus replication and was associated with an aggravation of pulmonary histopathology and a shift towards a Th2-type response. Vaccination with FI-Mock did not prevent RSV replication in the lung but resulted in an even more pronounced Th2 response after infection while these mice were not sensitised to specific viral antigens. Thus, viral replication in a Th2 responding animal (induced by aluminium-adjuvanted mock vaccine) appears to boost the Th2 response upon RSV infection.

Effects of thyrotoxicosis and selective hepatic autonomic denervation on hepatic glucose metabolism in rats

Thyrotoxicosis is known to induce a broad range of changes in carbohydrate metabolism. Recent studies have identified the sympathetic and parasympathetic nervous system as major regulators of hepatic glucose metabolism. The present study aimed to investigate the pathogenesis of altered endogenous glucose production (EGP) in rats with mild thyrotoxicosis. Rats were treated with methimazole in drinking water and l-thyroxine (T(4)) from osmotic minipumps to either reinstate euthyroidism or induce thyrotoxicosis. Euthyroid and thyrotoxic rats underwent either a sham operation, a selective hepatic sympathetic denervation (Sx), or a parasympathetic denervation (Px). After 10 days of T(4) administration, all animals were submitted to a hyperinsulinemic euglycemic clamp combined with stable isotope dilution to measure EGP. Plasma triiodothyronine (T(3)) showed a fourfold increase in thyrotoxic compared with euthyroid animals. EGP was increased by 45% in thyrotoxic compared with euthyroid rats and correlated significantly with plasma T(3). In thyrotoxic rats, hepatic PEPCK mRNA expression was increased 3.5-fold. Relative suppression of EGP during hyperinsulinemia was 34% less in thyrotoxic than in euthyroid rats, indicating hepatic insulin resistance. During thyrotoxicosis, Sx attenuated the increase in EGP, whereas Px resulted in increased plasma insulin with unaltered EGP compared with intact animals, compatible with a further decrease in hepatic insulin sensitivity. We conclude that chronic, mild thyrotoxicosis in rats increases EGP, whereas it decreases hepatic insulin sensitivity. Sympathetic hepatic innervation contributes only to a limited extent to increased EGP during thyrotoxicosis, whereas parasympathetic hepatic innervation may function to restrain EGP in this condition.

Thyroid function in critically ill patients

Patients in the intensive care unit (ICU) typically present with decreased concentrations of plasma tri-iodothyronine, low thyroxine, and normal range or slightly decreased concentration of thyroid-stimulating hormone. This ensemble of changes is collectively known as non-thyroidal illness syndrome (NTIS). The extent of NTIS is associated with prognosis, but no proof exists for causality of this association. Initially, NTIS is a consequence of the acute phase response to systemic illness and macronutrient restriction, which might be beneficial. Pathogenesis of NTIS in long-term critical illness is more complex and includes suppression of hypothalamic thyrotropin-releasing hormone, accounting for persistently reduced secretion of thyroid-stimulating hormone despite low plasma thyroid hormone. In some cases distinguishing between NTIS and severe hypothyroidism, which is a rare primary cause for admission to the ICU, can be difficult. Infusion of hypothalamic-releasing factors can reactivate the thyroid axis in patients with NTIS, inducing an anabolic response. Whether this approach has a clinical benefit in terms of outcome is unknown. In this Series paper, we discuss diagnostic aspects, pathogenesis, and implications of NTIS as well as its distinction from severe, primary thyroid disorders in patients in the ICU.

MECHANISMS IN ENDOCRINOLOGY: Beyond the fixed setpoint of the hypothalamus–pituitary–thyroid 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.

Photoperiod and acute energy deficits interact on components of the thyroid hormone system in hypothalamic tanycytes of the Siberian hamster

In the Siberian hamster, seasonal weight loss occurs gradually over many weeks during autumn and winter. This is driven by a regulatory mechanism that is able to integrate duration of exposure to short days (SDs) with the size of body energy reserves. After food restriction in SDs, followed by ad libitum refeeding, body weight of the hamster does not return to its former level; rather, it increases to a level defined by the length of time spent in SDs. In this report, we show that components of the thyroid hormone system that are involved in seasonal weight loss change expression in response to 48 h of starvation. Eight weeks in an SD photoperiod induced weight loss in the Siberian hamster. In the hypothalamus of these hamsters, type II deiodinase expression was decreased and type III deiodinase expression was induced, but there was no change in hypothalamic neuropeptide Y or thyrotropin-releasing hormone gene expression. For the first time, we show that the thyroid hormone transporter monocarboxylate transporter 8 is expressed in tanycytes and is increased in response to an SD photoperiod. Food restriction (48 h of starvation) reversed the direction of gene expression change for type II and III deiodinase and monocarboxylate transporter 8 induced by SD photoperiods. Furthermore, fasting increased neuropeptide Y expression and decreased thyrotropin-releasing hormone expression. VGF, a gene upregulated in SDs in the dorsal region of the medial posterior area of the arcuate nucleus, was not changed by starvation. These data point to a mechanism whereby energy deprivation can interact with an SD photoperiod on hypothalamic tanycytes to regulate components of the thyroid hormone system involved in photoperiodic regulation of seasonal physiology.

Respiratory syncytial virus, pneumonia virus of mice, and influenza A virus differently affect respiratory allergy in mice

Background Respiratory viral infections in early childhood may interact with the immune system and modify allergen sensitization and/or allergic manifestations. In mice, respiratory syncytial virus (RSV) infection during allergic provocation aggravates the allergic T helper (Th) 2 immune response, characterized by the production of IL‐4, IL‐5, and IL‐13, and inflammatory infiltrates. However, it is unclear whether the RSV‐enhanced respiratory allergic response is a result of non‐specific virus‐induced damage of the lung, or virus‐specific immune responses.