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Neuroanatomical Pathways for Thyroid Hormone Feedback in the Human Hypothalamus

Department of Endocrinology and Metabolism (A.A., W.M.W., E.F.), Academic Medical Center, University of Amsterdam, and Netherlands Institute for Brain Research (A.A., U.A.U., B.O.F., D.F.S., E.F.), 1105 AZ Amsterdam, The Netherlands; Department of Internal Medicine (E.C.F., G.G.K., T.J.V.), Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands; and Department of Cellular and Molecular Physiology (J.L.L.), University of Massachusetts Medical Center, Worcester, Massachusetts 01605

Address all correspondence and requests for reprints to: E. Fliers, Department of Endocrinology and Metabolism, Academic Medical Center of the University of Amsterdam, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands. E-mail: e.fliers{at}amc.uva.nl.

Context: Recent findings point to an increasing number of hypothalamic proteins involved in the central regulation of thyroid hormone feedback. The functional neuroanatomy of these proteins in the human hypothalamus is largely unknown at present.

Objective: The aim of this study was to report the distribution of type II and type III deiodinase (D2 and D3) as well as the recently identified T₃ transporter, monocarboxylate transporter 8 (MCT8), in the human hypothalamus.

Design: The study included enzyme activity assays, immunocytochemical studies, and mRNA in situ hybridizations in postmortem human hypothalamus (n = 9).

Results: D2 immunoreactivity is prominent in glial cells of the infundibular nucleus/median eminence, blood vessels, and cells lining the third ventricle. By contrast, both D3 and MCT8 are expressed by neurons of the paraventricular (PVN), supraoptic, and infundibular nucleus (IFN). In support of these immunocytochemical data, D2 and D3 enzyme activities are detectable in the mediobasal human hypothalamus. Combined D2, D3, MCT8, and thyroid hormone receptor immunohistochemistry and TRH mRNA in situ hybridization clearly showed that D3, MCT8, and thyroid hormone receptor isoforms are all expressed in TRH neurons of the PVN, whereas D2 is not.

Conclusions and Implications: Based on these findings, we propose three possible routes for thyroid hormone feedback on TRH neurons in the human PVN: 1) local thyroid hormone uptake from the vascular compartment within the PVN, 2) thyroid hormone uptake from the cerebrospinal fluid in the third ventricle followed by transport to TRH neurons in the PVN or IFN neurons projecting to TRH neurons in the PVN, and 3) thyroid hormone sensing in the IFN of the mediobasal hypothalamus by neurons projecting to TRH neurons in the PVN.

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