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J Clin Invest ; 123(4): 1492-500, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23524969

RESUMO

Type II deiodinase (D2) activates thyroid hormone by converting thyroxine (T4) to 3,5,3'-triiodothyronine (T3). This allows plasma T4 to signal a negative feedback loop that inhibits production of thyrotropin-releasing hormone (TRH) in the mediobasal hypothalamus (MBH) and thyroid-stimulating hormone (TSH) in the pituitary. To determine the relative contributions of these D2 pathways in the feedback loop, we developed 2 mouse strains with pituitary- and astrocyte-specific D2 knockdown (pit-D2 KO and astro-D2 KO mice, respectively). The pit-D2 KO mice had normal serum T3 and were systemically euthyroid, but exhibited an approximately 3-fold elevation in serum TSH levels and a 40% reduction in biological activity. This was the result of elevated serum T4 that increased D2-mediated T3 production in the MBH, thus decreasing Trh mRNA. That tanycytes, not astrocytes, are the cells within the MBH that mediate T4-to-T3 conversion was defined by studies using the astro-D2 KO mice. Despite near-complete loss of brain D2, tanycyte D2 was preserved in astro-D2 KO mice at levels that were sufficient to maintain both the T4-dependent negative feedback loop and thyroid economy. Taken together, these data demonstrated that the hypothalamic-thyroid axis is wired to maintain normal plasma T3 levels, which is achieved through coordination of T4-to-T3 conversion between thyrotrophs and tanycytes.


Assuntos
Regulação da Expressão Gênica , Hipotálamo/enzimologia , Iodeto Peroxidase/metabolismo , Hipófise/enzimologia , Tireotropina/genética , Tri-Iodotironina/sangue , Animais , Astrócitos/enzimologia , Composição Corporal , Córtex Cerebral/metabolismo , Ativação Enzimática , Retroalimentação Fisiológica , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Hipotálamo/citologia , Hipotálamo/metabolismo , Iodeto Peroxidase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Especificidade de Órgãos , Hipófise/citologia , Glândula Tireoide/metabolismo , Glândula Tireoide/fisiologia , Tireotrofos/enzimologia , Tireotropina/sangue , Hormônio Liberador de Tireotropina , Tiroxina/sangue , Tiroxina/fisiologia , Tri-Iodotironina/fisiologia
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