Endocrine Abstracts

Thyroid hormones (TH) play an important role in brain development, central nervous system functions and energy metabolism. In order to mediate these effects in the brain, TH are actively transported through the blood-brain barrier from the periphery to the brain. Tanycytes are specialized ependymal cells that line the wall and the base of the third ventricle in the mediobasal hypothalamus. The cell bodies are in contact with the cerebrospinal fluid and send their processes to hypothalamic nuclei (α-tanycytes) and the fenestrated vessels (β-tanycytes) in the median eminence (ME). Tanycytes projecting to the ME act as gatekeepers for the entry of peripheral substances (eg: leptin and ghrelin) and control hormonal release of hypophysiotropic hormones (eg: GnRH and TRH). They express the repertoire to transport and activate TH and respond to TH themselves. Our previous data suggested that TH modulates tanycytic functions and morphology, which in turn plays a role in the TH transport to the hypothalamus. However, the precise mechanism of how TH and their receptors modulate tanycytic functions is unclear. In this project we use specific genetic tools to manipulate the tanycytic TH transport as well as the tanycytic TH signalling pathway, to investigate the physiological relevance of the interaction between TH and tanycytes. We inhibit or activate TH receptor functions by either overexpressing a dominant negative mutant (TRα1^DN) or a dominant positive mutant (TRα1^VP16) of Thyroid hormone receptor α1 in tanycytes. We use qPCR, RNAscope and calcium imaging as tools to investigate the changes in the hormonal axes and gene expression on inhibiting or activating THRα specifically in tanycytes. We further probe into the possible metabolic changes in the mice by using indirect calorimetry. It has previously been shown that addition of the TRH analog taltirelin led to an increase in the size of the endfeet of tanycytes. To further understand the morphological changes of tanycytes due to TH, we performed scratch assays to track the migration patterns of primary tanycytes. Overall, we hypothesize that the modulation of the gatekeeper functions of tanycytes by inhibition or activation of TRα1 specifically in tanycytes and regulation of tanycytic endfeet morphology has an important impact on the central regulation of physiological functions and diseases. A better understanding of how local TH actions modulate tanycytic functions could provide the basis for an improved treatment opportunity of patients with central TH resistance.