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.

Association of Type II 5′ Monodeiodinase Thr92Ala Single Nucleotide Gene Polymorphism and Circulating Thyroid Hormones Among Type 2 Diabetes Mellitus Patients

“…The blood concentration of TSH is increased due to suppressed negative feedback from TH's. Analysis of the HPT axis in D2 knockout mice demonstrated a 2-3 fold increase in the circulating TSH concentration and 27-40 % increase in the T 4 level accompanied by reducing clearance of T 4 from plasma, but at normal levels of T 3 [22][23][24]. Hypothyroidism in diabetics induces the secondary dyslipidemia; it is characterized as elevated levels of TAG, TC, LDL and altered levels of HDL.…”

Coordination of hypothalamic and pituitary T3 production regulates TSH expression

“…This indicates that in response to a disruption in pituitary T4 signaling, multiple adjustments take place in the HPT, eventually preserving systemic euthyroidism. In fact, the pit-D2 KO mouse model represented yet another example that the HPT is wired to maintain normal serum T3 levels, in addition to most animal models of isolated or combined deiodinase deficiency (19).…”

The type 2 deiodinase Thr92Ala polymorphism is associated with increased bone turnover and decreased femoral neck bone mineral density

“…This is in line with recent observations in C3H/HeJ D2 À/À compound mutant mice with D1 deficiency and deletion of D2, which were shown to maintain normal growth. (26) This notion is supported by a recent study suggesting that D2 may not play a physiologic role in growth plate chondrocytes. (27) The observed effects of the D2 Thr92Ala polymorphism on femoral neck BMD are in line with the importance of local availability of T 3 for bone formation.…”

“…Although earlier studies on the role and functional expression of iodothyronine deiodinase enzymes in the skeleton have been equivocal, (12,14,(22)(23)(24)(25) a recent study reported normal growth in mice with deficiencies in D1 and D2, indicating that D2 may not be critical in skeletal development. (26) This notion was supported in a recent study that demonstrated that D2 activity is restricted to mature osteoblasts, suggesting a possible role for D2 in mature osteoblast function. (27) Devising a study addressing the potential role of deiodinases, including D2, on skeletal metabolism is difficult in humans, but study of the effects of functional D2 polymorphisms on BMD and bone turnover in humans may shed light on this role.…”