Type 3 deiodinase deficiency results in functional abnormalities at multiple levels of the thyroid axis.
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 T(3) results in a serum T(3) 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 T(3) and significant defects in the mechanisms regulating the thyroid axis at all levels: hypothalamus, pituitary, and thyroid.
Hernandez
Arturo
A
Dartmouth Medical School, Lebanon, NH 03756, USA. Arturo.Hernandez@Dartmouth.edu
Martinez
M Elena
ME
Liao
Xiao-Hui
XH
Van Sande
Jacqueline
J
Refetoff
Samuel
S
Galton
Valerie Anne
VA
St Germain
Donald L
DL
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007037:Hypothyroidism / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism*; D013963:Thyroid Hormones / Q000008:administration & dosage / Q000494:pharmacology; D013972:Thyrotropin / Q000097:blood / Q000494:pharmacology; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology