title: Mice with impaired extrathyroidal thyroxine to 3,5,3'-triiodothyronine conversion maintain normal serum 3,5,3'-triiodothyronine concentrations.
abstract: For T(3) to mediate its biological effects, the prohormone T(4) must be activated by removal of an outer-ring iodine by the type 1 or 2 deiodinases (D1 and D2) with approximately 60% of the daily T(3) production in rodents being produced extrathyroidally through this pathway. To further define the role of these enzymes in thyroid hormone homeostasis, we backcrossed the targeted disruption of the Dio2 gene into C3H/HeJ (C3H) mice with genetically low D1 expression to create the C3H-D2KO mouse. Remarkably, these mice maintain euthyroid serum T(3) levels with normal growth and no decrease in expression of hepatic T(3)-responsive genes. However, serum T(4) is increased 1.2-fold relative to the already elevated C3H levels, and serum TSH is increased 1.4-fold. Despite these increases, thyroidal (125)I uptake indicates no difference in thyroidal activity between C3H-D2KO and C3H mice. Although C3H-D2KO hepatic and renal D1 activities were well below those observed in wild-type mice (approximately 0.1-fold for both), they were 8-fold and 2-fold higher, respectively, relative to C3H mice. Thyroidal D1 and cerebral cortical type 3 deiodinase activity were unchanged between C3H-D2KO and C3H mice. In conclusion, C3H-D2KO mice have notably elevated serum T(4) levels, and this, in conjunction with residual D1 activity, is likely an important role in the maintenance of euthyroid serum T(3) concentrations.
authors.affiliation: Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Christoffolete
authors.forename: Rafael
authors.initials: R
authors.lastname: Arrojo e Drigo
authors.forename: Fernanda
authors.initials: F
authors.lastname: Gazoni
authors.forename: Susana M
authors.initials: SM
authors.lastname: Tente
authors.forename: Vanessa
authors.initials: V
authors.lastname: Goncalves
authors.forename: Beatriz S
authors.initials: BS
authors.lastname: Amorim
authors.forename: P Reed
authors.initials: PR
authors.lastname: Larsen
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Bianco
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Zavacki
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D005260:Female; D007453:Iodide Peroxidase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013974:Thyroxine / Q000378:metabolism*; D014284:Triiodothyronine / Q000097:blood* / Q000378:metabolism*; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D013974:Thyroxine; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II