Life without T4 to T3 conversion
Valerie Anne Galton, Donald St Germain & Arturo Hernandez
Abundant evidence indicates that the three deiodinases (D1, D2 and D3) function at the pre-receptor level to influence both extracellular and intracellular thyroid hormone levels and hence thyroid hormone action. Indirect evidence supports the concept that a major function of the D1 is to generate T3 for export to plasma whereas the D2 generates T3 primarily for local use. To obtain direct evidence concerning their individual physiological roles we have generated mice deficient in one, two or all three deiodinases. Data obtained in C57Bl/6 mice deficient in one or both 5′-deiodinases indicate that: i) maintenance of a normal serum T3 level is not dependent on the generation of T3 from T4 either in peripheral tissues or in the thyroid; ii) iodothyronines other than T4 are the principal substrates for the D1; iii) consistent with the conclusion based on indirect evidence, the D2 is important for local generation of T3 in pituitary, brown fat and the CNS. However, although brain T3 content in neonatal D2KO mice is reduced to a level comparable to that in age-matched hypothyroid WT mice, the molecular and functional phenotype of the D2KO mouse is much milder than that of the hypothyroid mouse. Possible reasons for this paradoxical finding include the potential importance of serum as a source of T3 for the developing brain and a direct action of T4 per se. The phenotype of the D3KO mouse is much more severe than that of mice deficient in D1 and D2, and is lethal in the C57Bl/6 strain. However, viability is improved if the D1 and D2 are also absent; many C57Bl/6 mice deficient in all three deiodinases thrive and can raise litters. In summary, mice maintained in a stress-free environment function very well in the absence of one or both of the 5′-deiodinases.