The Intrinsic Activity of Thyroxine Is Critical for Survival and Growth and Regulates Gene Expression in Neonatal Liver.
Level 5 - mechanism / opinion, no new human data
Bench and animal research using genetically modified mouse models.
PubMed 32791885 · doi:10.1089/thy.2020.0508
What was done
Researchers generated triple knockout mice lacking deiodinases 1 and 2 and the Pax8 gene, rendering them thyroidless and unable to convert thyroxine (T4) to triiodothyronine (T3). These mice were injected on alternate days with vehicle or physiological doses of T4, T3, or T3+T4 from postnatal days 2 to 14, followed by liver RNA-seq gene expression profiling at postnatal day 15. In an additional experiment, Pax8 knockout mice were treated with T3, T4, or T4+T3 to measure growth rate and survival to postnatal day 84.
What was found
Growth retardation in triple knockout mice was not improved by T3 or T4 alone but was significantly improved by T4+T3. T4 significantly regulated neonatal liver gene expression, with a higher proportion of negatively regulated genes compared to T3 treatment. Combined T4+T3 treatment identified genes regulated synergistically or exclusively by both hormones, enriched in pathways for cell proliferation and cholesterol physiology. All Pax8 knockout mice treated with T4 or T4+T3 survived to postnatal day 84, whereas survival with T3 alone was 50% at 3.5 weeks and 10% at 12 weeks.
Why it matters
This study demonstrates that T4 possesses intrinsic biological activity in vivo independent of conversion to T3, challenging the classic model that T4 is solely an inactive prohormone.
Limits
The study is conducted entirely in transgenic mouse models, which may not fully replicate human physiology. The abstract provides no sample sizes (n), exact dosage amounts, statistical variance estimates, or data on adult tissues beyond the neonatal liver.
Cited by
- context T4 is an inactive thyroid hormone, whereas T3 is the active thyroid hormone.