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Department of Endocrinology and Metabolism, Academic Medical Center University of Amsterdam, F5-165, Meibergdreef 9, 1105 AZ Amsterdam The Netherlands¹ INSERM U 577, Université Victor Segalen Bordeaux 2, Bordeaux 33076 France

(Correspondence should be addressed to J Kwakkel; Email: g.j.kwakkel{at}amc.uva.nl)

The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

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.