@article{TEXTUAL,
      recid = {14503},
      author = {Sinkó, Richárd and Salas-Lucia, Federico and Mohácsik,  Petra and Halmos, Emese and Wittmann, Gábor and Egri, Péter  and Bocco, Barbara M. L. C. and Batistuzzo, Alice and  Fonseca, Tatiana L. and Fekete, Csaba and Bianco, Antonio  C. and Gereben, Balázs},
      title = {Variable transduction of thyroid hormone signaling in  structures of the mouse brain},
      journal = {PNAS},
      address = {2025-02-04},
      number = {TEXTUAL},
      abstract = {L-thyroxine (L-T4) monotherapy is the standard treatment  for hypothyroidism, administered daily to normalize TSH  levels. Once absorbed, T4 is converted to T3 to alleviate  most symptoms. However, this treatment abnormally elevates  plasma T4 levels in over 50% of patients. Using  L-T4-treated Thyroid Hormone (TH) Action Indicator mice,  which express a T3-regulated luciferase (Luc) reporter, we  examined whether these T4 elevations disrupt TH signaling.  Hypothyroid mice exhibited reduced Luc expression across  brain regions, and L-T4 treatment failed to restore T3  signaling uniformly. There was also variability in the  activity of type 2 deiodinase (D2), the enzyme that  generates most brain T3. Intracerebroventricular T4  administration achieved higher elevation of Luc expression  in the mediobasal hypothalamus compared to the cortex, and  studies on cultured cortical astrocytes and hypothalamic  tanycytes revealed cell-type-specific responses to T4. In  tanycytes, exposure to T4 sustained D2 activity, leading to  progressive T3 signaling, whereas in astrocytes, T4  exposure triggered a drop in D2 activity, limiting T3  production through a ubiquitin-dependent, self-limiting  mechanism. The sustained D2 activity in tanycytes was  linked to rapid deubiquitination by USP33, as confirmed  using a ubiquitin-specific protease (USP) pan-inhibitor and  USP33 knockout mice. In conclusion, the brain’s response to  L-T4 treatment is heterogeneous, influenced by  cell-specific regulation of D2-mediated T3 production.  While cortical astrocytes exhibit limited T3 signaling due  to D2 ubiquitination, tanycytes coexpressing USP33 amplify  T3 signaling by rescuing ubiquitinated D2 from proteasomal  degradation. These findings provide mechanistic insights  into the limitations of L-T4 therapy and highlight the need  for tailored approaches to managing hypothyroidism.},
      url = {http://knowledge.uchicago.edu/record/14503},
}