Life without Thyroxine to 3,5,3′-Triiodothyronine Conversion: Studies in Mice Devoid of the 5′-Deiodinases

Abstract

Considerable indirect evidence suggests that the type 2 deiodinase (D2) generates T(3) from T(4) for local use in specific tissues including pituitary, brown fat, and brain, whereas the type I deiodinase (D1) generates T(3) from T(4) in the thyroid and peripheral tissues primarily for export to plasma. From studies in deiodinase-deficient mice, the importance of the D2 for local T(3) generation has been confirmed. However, the phenotypes of these D1 knockout (KO) and D2KO mice are surprisingly mild and their serum T(3) level, general health, and reproductive capacity are unimpaired. To explore further the importance of 5'deiodination in thyroid hormone economy, we used a mouse devoid of both D1 and D2 activity. In general, the phenotype of the D1/D2KO mouse is the sum of the phenotypes of the D1KO and D2KO mice. It appears healthy and breeds well, and most surprisingly its serum T(3) level is normal. However, impairments in brain gene expression and possibly neurological function are somewhat greater than those seen in the D2KO mouse, and the serum rT(3) level is elevated 6-fold in the D1/D2KO mouse but only 2-fold in the D1KO mouse and not at all in the D2KO mouse. The data suggest that whereas D1 and D2 are not essential for the maintenance of the serum T(3) level, they do serve important roles in thyroid hormone homeostasis, the D2 being critical for local T(3) production and the D1 playing an important role in iodide conservation by serving as a scavenger enzyme in peripheral tissues and the thyroid.

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…To further illustrate the potency of the homeostatic system preserving tissue T3 levels, mice lacking D1 or D2 (D1/D2 knock out mice) surprisingly, have normal circulating T3 levels due to TSH-induced T3 secretion from the thyroid, without a change in D3 mediated degradation, confirming the capacity of the hypothalamic-pituitary-thyroid axis to compensate for the lack of peripheral T4-to-T3 conversion (30).…”

“…For example, in mice with D1 and D2 deficiency, the fact that serum T3 remains normal despite the absence of both the deiodinases, is related to the fact that the thyroid, rather than T4, is a much more important source of plasma T3 in rodents (30). Furthermore, hypothalamic-pituitary suppression occurs much sooner during illness or fasting in rodents than in humans, making extrapolation to the human situation even more difficult.…”

Influence of Iodine-Deficiency on Thyroid Hormones Homeostasis in Rats

“…7,8) It has been reported that the optimum dose of levothyroxine sodium for hypothyroid patients was related to body weight. 9) The homeostatic mechanisms for stabilizing thyroid hormone activity are complex and vary based on disease etiology, with many of the details unknown. Thus, therapeutic dosage should be optimized not only by body weight but also considering the variation of supply and turnover rates associated with the condition etiology.…”

Role of type 1 and 2 deiodinases in thyroid metabolism (review)

“…У мышей D1KO введение Т3 повышало его уровень в сыворотке и обусловливало более высокую сте-пень гипертиреоза, чем у мышей дикого типа. Сле-довательно, Д1 способна сглаживать последствия гипертиреоза и дефицита йода [16].…”