The downregulation of liver deiodinase type 1 (D1) is supposed to be one of the mechanisms behind the decrease in serum tri-iodothyronine (T₃) observed during non-thyroidal illness (NTI). Liver D1 mRNA expression is positively regulated by T₃, mainly via the thyroid hormone receptor (TR)β1. One might thus expect that lacking the TRβ gene would result in diminished downregulation of liver D1 expression and a smaller decrease in serum T₃ during illness. In this study, we used TRβ^−/− mice to evaluate the role of TRβ in lipopolysaccharide (LPS, a bacterial endotoxin)-induced changes in thyroid hormone metabolism. Our results show that the LPS-induced serum T₃ and thyroxine and liver D1 decrease takes place despite the absence of TRβ. Furthermore, we observed basal differences in liver D1 mRNA and activity between TRβ^−/− and wild-type mice and TRβ^−/− males and females, which did not result in differences in serum T₃. Serum T₃ decreased rapidly after LPS administration, followed by decreased liver D1, indicating that the contribution of liver D1 during NTI may be limited with respect to decreased serum T₃ levels. Muscle D2 mRNA did not compensate for the low basal liver D1 observed in TRβ^−/− mice and increased in response to LPS in TRβ^−/− and WT mice. Other (TRβ independent) mechanisms like decreased thyroidal secretion and decreased binding to thyroid hormone-binding proteins probably play a role in the early decrease in serum T₃ observed in this study.

In addition to the direct effects of thyroid hormone (TH) on peripheral organs, recent work showed metabolic effects of TH on the liver and brown adipose tissue via neural pathways originating in the hypothalamic paraventricular and ventromedial nucleus (PVN and VMH). So far, these experiments focused on short-term administration of TH. The aim of this study is to develop a technique for chronic and nucleus-specific intrahypothalamic administration of the biologically active TH tri-iodothyronine (T₃). We used beeswax pellets loaded with an amount of T₃ based on in vitro experiments showing stable T₃ release (∼5 nmol l⁻¹) for 32 days. Upon stereotactic bilateral implantation, T₃ concentrations were increased 90-fold in the PVN region and 50-fold in the VMH region after placing T₃-containing pellets in the rat PVN or VMH for 28 days respectively. Increased local T₃ concentrations were reflected by selectively increased mRNA expression of the T₃-responsive genes Dio3 and Hr in the PVN or in the VMH. After placement of T₃-containing pellets in the PVN, Tshb mRNA was significantly decreased in the pituitary, without altered Trh mRNA in the PVN region. Plasma T₃ and T₄ concentrations decreased without altered plasma TSH. We observed no changes in pituitary Tshb mRNA, plasma TSH, or plasma TH in rats after placement of T₃-containing pellets in the VMH. We developed a method to selectively and chronically deliver T₃ to specific hypothalamic nuclei. This will enable future studies on the chronic effects of intrahypothalamic T₃ on energy metabolism via the PVN or VMH.

We have previously shown that skeletal muscle deiodinase type 2 (D2) mRNA (listed as Dio2 in MGI Database) is upregulated in an animal model of acute illness. However, human studies on the expression of muscle D2 during illness report conflicting data. Therefore, we evaluated the expression of skeletal muscle D2 and D2-regulating factors in two mouse models of illness that differ in timing and severity of illness: 1) turpentine-induced inflammation, and 2) Streptococcus pneumoniae infection. During turpentine-induced inflammation, D2 mRNA and activity increased compared to pair-fed controls, most prominently at day 1 and 2, whereas after S. pneumoniae infection D2 mRNA decreased. We evaluated the association of D2 expression with serum thyroid hormones, (de-)ubiquitinating enzymes ubiquitin-specific peptidase 33 and WD repeat and SOCS box-containing 1 (Wsb1), cytokine expression and activation of inflammatory pathways and cAMP pathway. During chronic inflammation the increased muscle D2 expression is associated with the activation of the cAMP pathway. The normalization of D2 5 days after turpentine injection coincides with increased Wsb1 and tumor necrosis factor α expression. Muscle interleukin-1β (Il1b) expression correlated with decreased D2 mRNA expression after S. pneumoniae infection. In conclusion, muscle D2 expression is differentially regulated during illness, probably related to differences in the inflammatory response and type of pathology. D2 mRNA and activity increases in skeletal muscle during the acute phase of chronic inflammation compared to pair-fed controls probably due to activation of the cAMP pathway. In contrast, muscle D2 mRNA decreases 48 h after a severe bacterial infection, which is associated with local Il1b mRNA expression and might also be due to diminished food-intake.

A variety of illnesses that leads to profound changes in the hypothalamus–pituitary–thyroid (HPT) are axis collectively known as the nonthyroidal illness syndrome (NTIS). NTIS is characterized by decreased tri-iodothyronine (T₃) and thyroxine (T₄) and inappropriately low TSH serum concentrations, as well as altered hepatic thyroid hormone (TH) metabolism. Spontaneous caloric restriction often occurs during illness and may contribute to NTIS, but it is currently unknown to what extent. The role of diminished food intake is often studied using experimental fasting models, but partial food restriction might be a more physiologically relevant model. In this comparative study, we characterized hepatic TH metabolism in two models for caloric restriction: 36 h of complete fasting and 21 days of 50% food restriction. Both fasting and food restriction decreased serum T₄ concentration, while after 36-h fasting serum T₃ also decreased. Fasting decreased hepatic T₃ but not T₄ concentrations, while food restriction decreased both hepatic T₃ and T₄ concentrations. Fasting and food restriction both induced an upregulation of liver D3 expression and activity, D1 was not affected. A differential effect was seen in Mct10 mRNA expression, which was upregulated in the fasted rats but not in food-restricted rats. Other metabolic pathways of TH, such as sulfation and UDP-glucuronidation, were also differentially affected. The changes in hepatic TH concentrations were reflected by the expression of T₃-responsive genes Fas and Spot14 only in the 36-h fasted rats. In conclusion, limited food intake induced marked changes in hepatic TH metabolism, which are likely to contribute to the changes observed during NTIS.