FRI471 Regulation Of Adult Thyroid Hormone Homeostasis By Early Postnatal Hyperthyroidism In Male Mice

Abstract Disclosure: D. Kovári: None. A. Szilvásy-Szabó: None. V. Penksza: None. B. Gereben: None. C. Fekete: None. The thyroid hormone (TH) negative feedback regulation enables the hypothalamic-pituitary-thyroid (HPT) axis to maintain the relatively steady circulating TH levels. Internal and external factors influence the development of this feedback regulation and consequently evoke life-long changes of the HPT axis activity. The aim of our study was to reveal how perinatal alteration of TH status influences TH homeostasis of adult mice. Mice were treated with 1µg/bwg thyroxine (T4) or vehicle subcutaneously every day between postnatal day (P) 2-6 and sacrificed at adulthood. Early postnatal hyperthyroidism resulted in central hypothyroidism in adults, characterized by decreased thyrotropin releasing hormone (TRH) mRNA expression in the hypothalamic paraventricular nucleus (PVN) and lower serum free T4 level, accompanied by unchanged thyrotropin stimulating hormone β (TSHβ) mRNA expression in the pituitary and serum free triiodothyronine level. The two main regulators of the HPT axis are the hypophysiotropic TRH neurons and tanycytes. Tanycytes affect the feedback regulation of TRH neurons by type 2 deiodinase (D2) mediated TH activation. To understand how postnatal T4 treatment results in central hypothyroidism in adult mice, tanycytes and TRH neurons of the PVN were isolated by laser capture microdissection from control and postnatally T4 treated adult mice. Postnatal T4 treatment did not change D2 expression in the tanycytes. Furthermore, using Thyroid Hormone Action Indicator (THAI) mice, we showed that the treatment did not influence TH action in the mediobasal hypothalamus of adult mice. These data together indicate that tanycytes are not involved in mediation of the postnatal T4 treatment induced effects. In contrast, the early postnatal T4 treatment markedly changed the transcriptome of TRH neurons in the PVN of adult mice. The expression of TH receptors, most TH receptor-related coregulators, TH transporters and genes involved in the synthesis of TRH were decreased. Despite of the central hypothyroidism, the energy expenditure of these mice were not decreased and TH action also remained unchanged in most tissues indicating that the peripheral tissues are able to compensate the effect of the generated mild hypothyroidism. These results indicate that alteration of TH levels during the early postnatal period can cause life-long effects on the activity of the HPT-axis likely via epigenetic regulation of TRH neurons. Presentation: Friday, June 16, 2023