title: Coordination of hypothalamic and pituitary T3 production regulates TSH expression.
abstract: 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.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
authors.forename: Tatiana L
authors.initials: TL
authors.lastname: Fonseca
authors.forename: Mayrin
authors.initials: M
authors.lastname: Correa-Medina
authors.forename: Maira P O
authors.initials: MP
authors.lastname: Campos
authors.forename: Gabor
authors.initials: G
authors.lastname: Wittmann
authors.forename: Joao P
authors.initials: JP
authors.lastname: Werneck-de-Castro
authors.forename: Rafael
authors.initials: R
authors.lastname: Arrojo e Drigo
authors.forename: Magda
authors.initials: M
authors.lastname: Mora-Garzon
authors.forename: Cintia Bagne
authors.initials: CB
authors.lastname: Ueta
authors.forename: Alejandro
authors.initials: A
authors.lastname: Caicedo
authors.forename: Csaba
authors.initials: C
authors.lastname: Fekete
authors.forename: Balazs
authors.initials: B
authors.lastname: Gereben
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Lechan
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Bianco
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology; D001823:Body Composition; D002540:Cerebral Cortex / Q000378:metabolism; D004789:Enzyme Activation; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007031:Hypothalamus / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D010902:Pituitary Gland / Q000166:cytology / Q000201:enzymology*; D013961:Thyroid Gland / Q000378:metabolism / Q000502:physiology; D052684:Thyrotrophs / Q000201:enzymology; D013972:Thyrotropin / Q000097:blood / Q000235:genetics*; D013973:Thyrotropin-Releasing Hormone; D013974:Thyroxine / Q000097:blood / Q000502:physiology; D014284:Triiodothyronine / Q000097:blood* / Q000502:physiology; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D005904:Glial Fibrillary Acidic Protein; D007453:Iodide Peroxidase; D013972:Thyrotropin; D013973:Thyrotropin-Releasing Hormone; D013974:Thyroxine; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II