Endocrine Abstracts

Thyroid hormone (TH) signalling regulates tissues function in virtually all organs and exerts a striking impact on brain development and function. The major secretory product of the human thyroid gland is thyroxine (T4), a stable pro-hormone. In order to bind the TH receptor TR, T4 needs to get converted to T3 by deiodination. The hypothalamo-pituitary-thyroid (HPT) axis controls circulating TH levels, that show remarkable stability. However, tissue TH action undergoes vigorous changes that is achieved by cell-type specific customization of TH availability by local TH metabolizing deiodinase enzymes and transporters. Region-specific regulation of TH action in the brain is critical to regulate TH-dependent brain function. Importantly, this process is also essential for the generation of T3-mediated negative feedback on hypophysiotropic TRH-synthesizing neurons that are located in the paraventricular nucleus. In the hypothalamus, regulation of region-specific TH action functionally overlaps with central regulation of the HPT axis. Therefore, regulation of hypothalamic TH economy is hallmarked by unique features represented by highly compartmentalised neuro-glial mechanisms. These include TH activation via type 2 deiodinase (D2) in tanycytes, lining the lateral wall and the floor of the third ventricle of the mediobasal hypothalamus; and type 3 deiodinase-mediated TH inactivation that fine tunes TH availability in neurosecretory neurons in a phenotype specific manner. We will discuss recent findings on neuropeptide and ubiquitination mediated regulation of hypothalamic TH metabolism. These studies allow better understanding of hypothalamus-specific TH activation; its impact on the HPT axis; and its hypothalamic and systemic consequences during TH supplementation. Finally, we will discuss the hypothalamic pathogenesis and tissue-specific TH availability during lipopolysaccharide-induced nonthyroidal illness syndrome based on data obtained on our recently generated TH action indicator (THAI) transgenic mouse, allowing the assessment of tissue-specific TH action in the intact context of endogenously expressed regulatory factors of TH economy.