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Jacqueline E Siljee, Unga A Unmehopa, Andries Kalsbeek, Dick F Swaab, Eric Fliers and Anneke Alkemade


The melanocortin 4 receptor (MC4R) is an essential regulator of energy homeostasis and metabolism, and MC4R mutations represent the most prevalent monogenetic cause of obesity in humans known to date. Hypothalamic MC4Rs in rodents are well characterized in neuroanatomical and functional terms, but their expression pattern in the human hypothalamus is unknown.

Design and methods

To determine the topographic distribution and identity of cells expressing MC4R mRNA in the human hypothalamus, locked nucleic acid in situ hybridization was performed on nine human postmortem hypothalami. In addition, co-expression of MC4R with glial fibrillary acidic protein (GFAP), vasopressin/oxytocin (AVP/OXT), corticotropin-releasing hormone (CRH), neuropeptide Y (NPY), agouti-related protein (AgRP), and α-melanocyte stimulating hormone (α-MSH) was examined.


Most intense MC4R mRNA expression was present in the paraventricular nucleus (PVN), the supraoptic nucleus (SON), and the nucleus basalis of Meynert. Most MC4R-positive cells in the SON also expressed AVP/OXT. Co-expression with AVP/OXT in the PVN was less abundant. We did not observe co-expression of MC4R mRNA and GFAP, CRH, NPY, AgRP, or α-MSH. However, fiber-like staining of NPY, AgRP, and α-MSH was found adjacent to MC4R-positive cells in the PVN.


Expression of MC4R mRNA in the human hypothalamus is widespread and in close approximation to endogenous MC4R binding partners AgRP and α-MSH.

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Anneke Alkemade, Edith C Friesema, George G Kuiper, Wilmar M Wiersinga, Dick F Swaab, Theo J Visser and Eric Fliers

Objective: An increasing number of proteins appear to be involved in thyroid hormone feedback action at the level of the anterior pituitary, but the cell types expressing these proteins are largely unknown. The aim of the present study was to identify cell types in the human anterior pituitary that express type II and type III deiodinase (D2 and D3), the recently described thyroid hormone transporter (MCT8) and thyroid hormone receptor (TR) isoforms by means of double-labeling immunocytochemistry.

Results: We found TR isoforms to be expressed most prominently in gonadotropes and – although to a lesser extent – in thyrotropes, corticotropes, lactotropes and somatotropes. D3 staining showed a distribution pattern that was remarkably similar. By contrast, D2 immunoreactivity was observed exclusively in folliculostellate (FS) cells showing coexpression with human leukocyte antigen (HLA), a marker of major histocompatibility complex (MHC)-class II. MCT8 immunostaining was present in FS cells without HLA coexpression.

Conclusions: From these results, we propose a novel neuroanatomical model for thyroid hormone feedback on the human pituitary, with a central role for FS cells in thyroid hormone activation, which thus play an important role in the suppression of TSH secretion by circulating thyroxine (T4).

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Edith C H Friesema, Theo J Visser, Anke J Borgers, Andries Kalsbeek, Dick F Swaab, Eric Fliers and Anneke Alkemade


Thyroid hormone (TH) signaling in brain cells is dependent on transport of TH across the plasma membrane followed by intracellular deiodination and binding to the nuclear TH receptors. The aim of this study is to investigate the expression of the specific TH transporters monocarboxylate transporter 8 (MCT8 (SLC16A2)), MCT10, organic anion transporting polypeptide 1C1 (OATP1C1 (SLCO1C1)), and the types 2 and 3 deiodinases (D2 and D3) in the developing human hypothalamus.


Fifteen postmortem brain samples of fetuses and young children ranging between 17 weeks of gestation and 29 months of postnatal age including one child (28 months) with central congenital hypothyroidism were studied.


Sections of the different hypothalami were stained with polyclonal rabbit antisera against MCT8, MCT10, OATP1C1, D2, and D3.


We found MCT8 and D3 but not D2 protein expression to be present in our earliest sample of 17 weeks of gestation, indicating triiodothyronine degradation, but not production at this time of development. At term, expression of TH transporters and D2 decreased and D3 expression increased, suggesting decreased TH signaling just before birth. The child with central congenital hypothyroidism showed higher MCT8 and D2 expression compared with the other children of similar age.


This study reports the developmental timing of expression of components crucial for central TH signaling in the human hypothalamus. In general, during fetal hypothalamic development, the coordinated expression of D2 and D3 in combination with the different TH transporters suggests that proper TH concentrations are regulated to prevent untimely maturation of brain cells.