Downregulation of Type 3 Deiodinase in the Hypothalamus During Inflammation.

Background: Inflammation is associated with marked changes in cellular thyroid hormone (TH) metabolism in triiodothyronine (T3) target organs. In the hypothalamus, type 2 deiodinase (D2), the main T3 producing enzyme, increases upon inflammation, leading to an increase in local T3 availability, which in turn decreases thyrotropin releasing hormone expression in the paraventricular nucleus. Type 3 deiodinase (D3), the T3 inactivating enzyme, decreases during inflammation, which might also contribute to the increased T3 availability in the hypothalamus. While it is known that D2 is regulated by nuclear factor κB (NF-κB) during inflammation, the underlying mechanisms of D3 regulation are unknown. Therefore, the aim of the present study was to investigate inflammation-induced D3 regulation using in vivo and in vitro models. Methods: Mice were injected with a sublethal dose of bacterial endotoxin (lipopolysaccharide [LPS]) to induce a systemic acute-phase response. A human neuroblastoma (SK-N-AS) cell line was used to test the involvement of the thyroid hormone receptor alpha 1 (TRα1) as well as the activator protein-1 (AP-1) and NF-κB inflammatory pathways in the inflammation-induced decrease of D3. Results: D3 expression in the hypothalamus was decreased 24 hours after LPS injection in mice. This decrease was similar in mice lacking the TRα. Incubation of SK-N-AS cells with LPS robustly decreased both D3 mRNA expression and activity. This led to increased intracellular T3 concentrations. The D3 decrease was prevented when NF-κB or AP-1 was inhibited. TRα1 mRNA expression decreased in SK-N-AS cells incubated with LPS, but knockdown of the TRα in SK-N-AS cells did not prevent the LPS-induced D3 decrease. Conclusions: We conclude that the inflammation-induced D3 decrease in the hypothalamus is mediated by the inflammatory pathways NF-κB and AP-1, but not TRα1. Furthermore, the observed decrease modulates intracellular T3 concentrations. Our results suggest a concerted action of inflammatory modulators to regulate both hypothalamic D2 and D3 activities to increase the local TH concentrations.

Tissue thyroid hormone metabolism is differentially regulated during illness in mice.

Illness induces major modifications in central and peripheral thyroid hormone (TH) metabolism, so-called nonthyroidal illness syndrome (NTIS). As a result, organ-specific changes in local TH availability occur depending on the type and severity of illness. Local TH availability is of importance for the regulation of the tissue-specific TH target genes and determined by the interplay between deiodinating enzymes, TH transport and TH receptor (TR) expression. In the present study, we evaluated changes in TH transport, deiodination and TR expression, the resulting tissue TH concentrations and the expression of TH target genes in liver and muscle in three animal models of illness. We induced (1) acute systemic inflammation by intraperitoneal injection of bacterial endotoxin (LPS), (2) chronic local inflammation by a turpentine injection in the hind limb and (3) severe pneumonia and sepsis by intranasal inoculation with Streptococcus pneumoniae We found that all aspects of peripheral TH metabolism are differentially regulated during illness, depending on the organ studied and severity of illness. In addition, tissue TH concentrations are not equally affected by the decrease in serum TH concentrations. For example, the decrease in muscle TH concentrations is less severe than the decrease observed in liver. In addition, despite lower TH concentrations in muscle in all three models, muscle T3 action is differentially affected. These observations help to understand the complex nature of the nonthyroidal illness syndrome.

Leptin administration restores the fasting-induced increase of hepatic type 3 deiodinase expression in mice.

BACKGROUND: Decreased serum leptin has been proposed as a critical signal initiating the neuroendocrine response to fasting. Leptin administration partially reverses the fasting-induced suppression of the hypothalamus-pituitary-thyroid axis at the central level. It is, however, unknown to what extent leptin affects peripheral thyroid hormone metabolism. The aim of this study was to evaluate the effect of leptin administration on starvation-induced alterations of peripheral thyroid hormone metabolism in mice. METHODS: Three types of experiments were performed: (i) mice were fasted for 24 hours while leptin was administered twice (at 0 and 8 hours, 1 µg/g body weight [BW]), (ii) mice were fasted for 24 hours and, subsequently, leptin was given once at 24 hours (killed at 28 and 32 hours), and (iii) mice were fasted for 48 hours. All groups had appropriate controls. Serum triiodothyronine and thyroxine, liver type 1 deiodinase (D1), type 3 deiodinase (D3), thyroid hormone receptor (TR)ß1, TRα1 and α2 mRNA expression, and liver D1 and D3 activity were measured. RESULTS: Twenty-four hours of fasting decreased liver TRß1 mRNA expression, while liver TRα1, TRα2, and D1 mRNA expression and activity did not change. In contrast, 24 hours of fasting increased liver D3 mRNA. Leptin administration after fasting restored liver D3 expression, while serum thyroid hormone levels and liver TRß1 expression remained low. CONCLUSION: Leptin administration selectively restores starvation-induced increased hepatic D3 expression independently of serum thyroid hormone concentrations. The present study shows that fasting-induced changes in mRNA expression of genes involved in hepatic hormone metabolism are influenced not only by decreased serum thyroid hormone levels but also by serum leptin.