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Type 3 Deiodinase Deficiency Results in Functional Abnormalities at Multiple Levels of the Thyroid Axis

Departments of Medicine (A.H., M.E.M., D.L.S.G.) and Physiology (V.A.G., D.L.S.G.), Dartmouth Medical School, Lebanon, New Hampshire 03756; Departments of Medicine (X.-H.L., S.R.) and Pediatrics (S.R.) and the Committees on Genetics and Molecular Medicine, The University of Chicago, Chicago, Illinois 60637; and Institute de Recherche Interdisciplinaire (J.V.S.), Faculte de Medicine, Universite Libre de Bruxelles, 1070 Bruxelles, Belgium

Address all correspondence and requests for reprints to: Arturo Hernandez, Ph.D., Research Assistant Professor of Medicine, Dartmouth Medical School, Lebanon, New Hampshire 03756. E-mail: Arturo.Hernandez{at}Dartmouth.edu.

The type 3 deiodinase (D3) is a selenoenzyme that inactivates thyroid hormones and is highly expressed during development and in the adult central nervous system. We have recently observed that mice lacking D3 activity (D3KO mice) develop perinatal thyrotoxicosis followed in adulthood by a pattern of hormonal levels that is suggestive of central hypothyroidism. In this report we describe the results of additional studies designed to investigate the regulation of the thyroid axis in this unique animal model. Our results demonstrate that the thyroid and pituitary glands of D3KO mice do not respond appropriately to TSH and TRH stimulation, respectively. Furthermore, after induction of severe hypothyroidism by antithyroid treatment, the rise in serum TSH in D3KO mice is only 15% of that observed in wild-type mice. In addition, D3KO animals rendered severely hypothyroid fail to show the expected increase in prepro-TRH mRNA in the paraventricular nucleus of the hypothalamus. Finally, treatment with T₃ results in a serum T₃ level in D3KO mice that is much higher than that in wild-type mice. This is accompanied by significant weight loss and lethality in mutant animals. In conclusion, the absence of D3 activity results in impaired clearance of T₃ and significant defects in the mechanisms regulating the thyroid axis at all levels: hypothalamus, pituitary, and thyroid.