SAT-393 Physiology Of A Thyroidally-Derived T3-Centric Hormonal Environment

Abstract Disclosure: C.E. Citterio: None. B. Morales-Rodriguez: None. X. Liao: None. C. Vu: None. R. Nguyen: None. J. Tsai: None. J. Le: None. I. Metawea: None. M. Liu: None. D.P. Olson: None. S. Refetoff: None. P. Arvan: None. Thyroid hormones (T4 and T3) are indispensable for sustaining vertebrate life, and their deficiency gives rise to a wide range of symptoms characteristic of hypothyroidism, affecting 5-10% of the world’s population. T3 and T4 may make distinct contributions to the physiology of different organ systems, and a subset of hypothyroid patients treated with T4 do not fully normalize their symptoms despite achieving normal TSH levels. The precursor for thyroid hormone synthesis is thyroglobulin (Tg), consisting of upstream regions I-II-III (responsible for synthesis of most T4) and the C-terminal CholinEsterase-Like (ChEL) domain (responsible for synthesis of most T3, which can also be generated extrathyroidally by T4 deiodination). Genetically-engineered mice with a thyroid gland designed for disproportionate T3 generation from the T3-forming ChEL domain of Tg, named ChEL-KI, are capable of thyroidal T3 synthesis but largely incompetent for T4 synthesis such that T4-to-T3 conversion contributes little. We have examined the physiology of a thyroidally-derived T3-centric hormonal environment. Compared to cog/cog mice with conventional hypothyroidism (low serum T4and T3), body size was greater in ChEL-KI mice; although these animals with profound T4 deficiency, despite normal circulating T3 levels, did exhibit a marked elevation of serum TSH and developed a large goiter. ChEL-KI mice exhibited normal expression of the hepatic markers of thyroid hormone action ME1 and D1, indicating that these markers do not require normal circulating levels of T4 but are supported by circulating levels of T3. In contrast with the liver, the CNS is thought to rely substantially on local T3 production from T4 via D2-mediated 5’-deiodination. We examined additional CNS functions that have been reported to be linked to phenotypes in hypothyroid rodents and humans. Both ChEL-KI and cog/cog mice exhibited similar behavioral abnormalities such as impaired motor activity and locomotion, as well as increased anxiety-like behavior compared to euthyroid controls. Thus, we conclude that normal circulating T3 cannot efficiently replace the role of T4 in supporting these behaviors that require local generation of T3 in the CNS. This work highlights tissue-specific differences in T3 versus T4 action, reflecting key considerations in hypothyroid patients receiving thyroid hormone replacement therapy. Presentation: Saturday, July 12, 2025