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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.
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Abstract |
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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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Introduction |
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An increasing number of hypothalamic proteins appears to be involved in the neuroendocrine regulation of thyroid hormone feedback. We recently reported the distribution of thyroid hormone receptor isoforms (TRs) in the human hypothalamus by immunocytochemistry, showing intense immunoreactivity in neurons of the infundibular nucleus (IFN), which is the human equivalent of the arcuate nucleus (ARC), and in the PVN (5). Production and degradation of T3 in the central nervous system (CNS) occurs through deiodination by two separate enzymes (6). Type II deiodinase (D2) activates thyroid hormone by converting T4 into T3, whereas type III deiodinase (D3) inactivates thyroid hormone by converting T3 into T2 and T4 into rT3. Monocarboxylate transporter 8 (MCT8) has recently been identified in humans as a specific T3 transporter and plays a pivotal role in thyroid hormone metabolism in the CNS by providing cells expressing deiodinases with thyroid hormone (7). The functional importance of MCT8 was recently illustrated in several patients with severe psychomotor retardation who appeared to have mutations or deletions in the MCT8 gene (8, 9).
The concerted action of MCT8, deiodinases, and TRs may be essential for not only general thyroid hormone action in the CNS but also hypothalamic thyroid hormone feedback regulation. MCT8 has been identified in the brain, but no data are available on its hypothalamic distribution (7, 10). The distribution of deiodinase activity in the hypothalamus was first reported in hypothyroid rats by Riskind et al. (11), showing highest activity in punches of the ARC region, whereas expression in the PVN was very low. More recent studies in rats showed the hypothalamic D2 distribution in more detail using in situ hybridization, reporting D2 mRNA in ependymal cells lining the floor and inferolateral walls of the third ventricle, in the ARC and the median eminence (ME) (12). Cells showing D2 immunoreactivity were later identified as astrocytes and appeared to include tanycytes, which provide an extensive network of cellular processes into the ARC (13). The distribution of D3 mRNA in the rat hypothalamus appeared to be quite different with moderate neuronal D3 hybridization signal reported throughout the hypothalamus (14).
A functional role for D2 and D3 in thyroid hormone feedback regulation was suggested by a number of studies. Induction of hypothyroidism in rats results in increased pituitary and hypothalamic D2 enzyme activity (11). In situ hybridization studies also showed increased D2 mRNA in the ARC/ME region of hypothyroid rats, whereas D3 expression was undetectable in hypothyroid rat brain (12, 14). By contrast, during hyperthyroidism D3 is induced in hippocampus and cerebellum but not so in the hypothalamus except for a few animals showing increased D3 expression in the supraoptic nucleus (SON) (14).
Studies on the functional neuroanatomy of thyroid hormone transporters and deiodinases are likely to provide us with more insight in understanding thyroid hormone feedback regulation in humans. Because these data are largely unavailable at present, we set two aims for the present study: first, to uncover the distribution of D2, D3, and MCT8 in the human hypothalamus. For this aim, we used RT-PCR, immunocytochemistry, and enzyme activity assays in human hypothalamus and anterior pituitary. Our second aim was to investigate possible colocalization of TRH in PVN neurons in the human hypothalamus with D2, D3, MCT8, and TR isoforms, which have been described in TRH neurons in rat PVN (15) using combined immunocytochemistry and TRH mRNA in situ hybridization. On the basis of the data obtained we propose three neuroanatomical models for thyroid hormone feedback on TRH neurons in the human PVN.
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Patients and Methods |
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We studied nine human hypothalami, including one patient with documented hyperthyroidism [serum free T4 44.2 pmol/liter (normal range, 10–23 pmol/liter) and TSH < 0.01 mU/liter, who was started on methimazole 2 d before death], by means of immunocytochemistry and/or combined in situ hybridization. Tissues were obtained from The Netherlands Brain Bank at The Netherlands Institute for Brain Research in accordance with the formal permissions for a brain autopsy and the use of human brain material and clinical information for research purposes. Clinicopathological data are presented in Table 1
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Primers specific for D2 and D3 were designed. Primers for D2 were: forward, 5'-CATGTCTCCAGTACAGAAGG-3' and reverse, 5'-GCAGTTCTCCTCAGTGGC TGA-3' corresponding to the human sequence from nucleotide 662–854 (NM_000793). Primers for D3 were: forward, 5'-TGTGTATCCGCAAGCATTTC-3' and reverse, 5'-GCCCATCTGCGTGTCCGACG-3' corresponding to the human sequence from nucleotide 336–455 (NM_001362).
Isolated pituitary mRNA and mRNA from the periventricular area, containing the PVN and the central lining of the third ventricle, was in vitro reverse transcribed after DNase treatment and subjected to PCR using the above primers. PCR products were checked by gel electrophoresis As a positive control, we isolated mRNA from placenta. Negative controls consisted of reactions without template or reverse transcription.
Immunocytochemistry
Histology.
Hypothalami were fixed in phosphate-buffered 10% formalin at room temperature (RT) for 4–21 wk (Table 1
). Tissues were dehydrated in a graded ethanol series, cleared in xylene, and embedded in paraffin. Coronal sections of 6 µm were made. From the hypothalamus, sections were cut from the level of the lamina terminalis to the mammillary bodies. Every 100th section was collected on a chromealum gelatin-coated slide with 0.5% BSA (Sigma, Zwijndrecht, The Netherlands) in distilled water and dried overnight at 37 C. Nissl staining was performed for anatomical orientation.
Antisera
For immunocytochemical staining, we used polyclonal rabbit antisera raised against synthetic peptides derived from rat D2 [no. 763: amino acids 247–266 and no. 762: 247–262 (13, 16)] and human D3 (no. 676, 265–278) and MCT8 (no. 1305 and no. 1306: 527–539). D2 antiserum specificity has already been described (16). Polyclonal antisera for D3 and MCT8 were raised in rabbits by Eurogentec SA (Herstal, Belgium) after conjugation of the synthetic peptide to keyhole limpet hemocyanin. The D3 antiserum has already been published (17). Antiserum from the final bleed was used without further purification. Antisera against TR isoforms and their specificity were published earlier (5, 18, 19).
Specificity tests
Specificity of the antisera was supported by: 1) staining with preimmune antiserum, 2) preadsorption with the homologous peptide, 3) assessment of cross-reactivity of the deiodinase antibodies by preadsorption with heterologous peptides, and 4) Western blotting.
Preimmune staining. Staining was performed with the preimmune serum of the D3 and MCT8 antibodies on hypothalamus and pituitary sections. The staining procedure was identical with the immunocytochemical staining. No preimmune sera were available for D2 antibodies.
Preadsorptions. Antisera were preadsorbed with the homologous peptide as described by van der Beek et al. (20). Peptides were dissolved (500 ng/µl), spotted and fixed on gelatin-coated nitrocellulose and subsequently incubated with the antibody diluted in supermix [SUMI, 0.05 M Tris, 0.15 M NaCl, 0.5% Triton X-100 (Sigma), and 0.25% gelatin (Merck, Darmstadt, Germany) (pH 7.6) (D2, 1:125; D3, 1:90; MCT8, 1:50)]. Nitrocellulose sheets were immunocytochemically stained to check antigen-antibody binding. The preadsorbed antisera were tested on human hypothalamus sections, using the immunocytochemical staining procedure described below. Nonpreadsorbed antiserum was used as a positive control in adjacent sections.
Cross-reactivity. To investigate cross-reaction of the antisera, peptides were spotted and fixed on gelatin-coated nitrocellulose membranes. MCT8 and D2 antisera were preadsorbed with the D3 peptide and the D3 antiserum was preadsorbed with the D2 peptide. Adsorption was performed according to the same protocol as for preadsorption with the homologous peptides. The preadsorbed antisera were used for immunocytochemical staining on human pituitary sections.
Western blotting. Fifty-micrometer sections were cut from fresh frozen human hypothalami and pituitaries. From these sections SON, PVN, and infundibular (IF)/ME region were dissected. Protein was isolated and used for Western blotting. Samples were run on a 15% SDS-PAGE gel (10% for MCT8) and electroblotted onto nitrocellulose membrane (BA45, Schleicher & Schuell, Dassel, Germany). Blots were incubated with the antisera (D2, no. 763 and 762, 1:1000 in SUMI; D3, no. 676, 1:500 in SUMI-1% BSA; MCT8, no. 1306 and 1305, 1:500 in SUMI) for 1 h at RT and overnight at 4 C. Blots were washed 3 x 10 min in Tris-buffered saline [TBS, 0.05 M Tris (Biosolve, Valkenswaard, The Netherlands) and 0.15 M NaCl (Merck) (pH 7.6)] with 0.1% Tween and incubated in horseradish peroxidase-coupled porcine-antirabbit (1:1000 in SUMI) for 1 h at RT. Bands were detected by chemiluminescence, using Western Lightning chemiluminescence reagents (PerkinElmer, Groningen, The Netherlands).
Staining procedure
Immunocytochemistry was performed throughout the hypothalamus. At intervals of 100 sections, we mounted sections for D2, D3, and MCT8 staining, which was performed according to the following protocol:
For D2 and MCT8 staining, sections were mounted on chrome alum-coated or Superfrost Plus Plus slides (Merck) and subsequently dried for at least 2 d at 37 C. After deparaffinization in xylene and rehydration through a graded ethanol series, sections were rinsed in distilled water and in TBS (3 x 10 min). For D3 staining, sections were microwave treated in TBS for 10 min at 700 W (21). Immunocytochemistry was performed using the avidine-biotinylated complex (Vector Laboratories, Peterborough, UK) technique (22) and consisted of the following steps: 1) incubation with the first antibody (D2: 1:1250; MCT8, 1:500 in SUMI; D3: 1:900 in SUMI containing 1% BSA) for 1 h at RT and subsequently overnight at 4 C; 2) rinsing in TBS (3 x 10 min); 3) incubation in biotinylated goat-antirabbit (1:400 in SUMI) for 1 h at RT; 4) rinsing in TBS (3 x 10 min); 5) incubation in avidine-biotinylated complex (1:800 in SUMI) for 1 h at RT; 6) rinsing in TBS (3 x 10 min); 7) incubation in a solution of 0.5 mg/ml 3,3-diaminobenzidine (Sigma) in a total volume of 15 ml TBS containing 0.01% H2O2 (Merck) and 0.035 g/ml ammonium nickel sulfate (BDH, Poole, UK), for approximately 15 min at RT. The enzyme reaction was stopped in distilled water. Subsequently the sections were dehydrated through a graded ethanol series, cleared in xylene, and coverslipped with Entellan (Merck).
For identification of cell types expressing deiodinases and MCT8, we combined staining with NeuN as a neuronal marker (Chemicon, Hampshire, UK) and vimentin (Chemicon) as a marker for tanycytes.
Combined immunocytochemistry and in situ hybridization
Sections containing the PVN were stained using immunocytochemistry for D2, D3, MCT8, or TR isoforms under RNase-free conditions. Antigen retrieval was applied for D3 and TR isoform staining. The specificity of the TR isoform-specific antisera and the staining protocol has been described before (5). Staining intensity was amplified using biotinylated tyramide and DAB was used for visualization. After immunocytochemistry, in situ hybridization was performed for TRH mRNA. The procedure for in situ hybridization has been described earlier (23).
Activity assays
D2 activities were analyzed in hypothalamic microsomes (n = 2) and pituitary homogenates (n = 6) and D3 activities in hypothalamic (n = 6) and pituitary (n = 6) homogenates of unfixed, snap-frozen brain material. Clinicopathological data of the patients are presented in Table 1. The techniques for determining deiodinase activities have been described before (24).
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Results |
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). Testing of preimmune sera on Western blots did not show any bands at the expected molecular weight. Testing of preimmune and preadsorbed antisera (D2, D3, and MCT8) resulted in completely negative staining of cells, fibers, and blood vessels. After adsorption of D2, D3, and MCT8 with heterologous peptides, staining was still present and unchanged.
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) and showed a strong interindividual variation, which is illustrated in Table 2. Prominent D2 immunoreactivity was observed throughout the ependymal layer of the third ventricle. D2 staining was also present in glial cells within the IFN/ME region, which showed clear colocalization with vimentin (Fig. 5). Intense D2 staining was found surrounding blood vessels, including the vasculature of the PVN (Fig. 2). In the present study, we could not clearly distinguish between D2 staining in blood vessel walls and D2 staining in tanycyte processes ending on blood vessels. Staining intensity showed a marked variation between vessels. In addition to glial staining, occasional neuronal staining was observed in the IFN and SON. Different D2 antisera showed an identical distribution of D2 immunoreactivity. The topographic distribution of D2 immunoreactivity is schematically represented in Fig. 6.
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). Staining showed clear colocalization with NeuN (Fig. 5). The distribution of D3 immunoreactivity throughout the hypothalamus is schematically presented in Fig. 7.
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). Staining showed clear colocalization with both vimentin and NeuN (Fig. 5). The distribution of MCT8 is presented schematically in Fig. 8. Immunocytochemical stainings in a patient with biochemically documented hyperthyroidism (Table 1) showed only moderate D2, D3, and MCT8 staining, whereas intense D2 immunoreactivity was observed surrounding blood vessels.
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and -ß isoforms, D3, and MCT8 (Fig. 9) but not with D2 immunoreactivity.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In the hypothalamus, D2 staining appeared to be present in glial cells lining the third ventricle and in the IFN/ME. This distribution pattern is generally in agreement with earlier studies in rats in which subsequent studies using electron microscopy identified D2 immunoreactive cells as astrocytes, including tanycytes (12, 13). Tanycytes are cells lining the third ventricle establishing contacts with blood vessels of the ME, and they have been proposed to be involved in providing T3 to the CNS after T4 uptake from the cerebrospinal fluid (CSF) (12). In addition, we observed D2 staining surrounding blood vessels. Although in our study we could not clearly distinguish between D2 staining in blood vessel walls and D2 staining in tanycyte processes, staining in tanycytes surrounding blood vessels has been described in rats (12, 26). D2 expression in rats was reported to be confined to the infralateral walls of the third ventricle (12, 13). In the present study, we observed D2 expression over the entire height of the lining of the third ventricle in the human hypothalamus, which may represent a different expression level or, alternatively, an interspecies difference. In contrast to the expression pattern of D2, we found D3 immunoreactivity to be mainly neuronal and to be present throughout the human hypothalamus with a preferential expression in the PVN, IFN, and SON (14). Thus, expression of D3 showed a strong overlap with TR expression reported earlier by us in the human PVN, IFN, and SON (5). These neuroanatomical data suggest that D3 is expressed in T3-responsive neurons to terminate T3 action.
Staining intensity varied among patients. We had the unique opportunity to study deiodinase and MCT8 expression in the hypothalamus of a patient with biochemically documented hyperthyroidism just before death (no. 93121, see Table 1). This patient was found earlier to have extremely low TRH mRNA expression in the PVN (27), in keeping with negative feedback action of thyroid hormone on TRH gene expression in the human PVN. In the present study, the hypothalamus of this patient showed rather weak D2 immunostaining and unremarkable D3 and MCT8 staining. Studies performed earlier in rats showed occasionally increased D3 expression in the SON during hyperthyroidism, whereas extrahypothalamic areas reacted strongly to altered thyroid status. Furthermore, hypothyroidism was reported to induce up-regulation of hypothalamic D2 enzyme activity and mRNA expression in rats (11, 12, 28) with reversed changes seen in hyperthyroidism (29). Therefore, our observations in the patient with hyperthyroidism (i.e. markedly decreased TRH mRNA expression in the PVN, low D2, and unchanged D3 immunoreactivity) point to similar regulation of hypothalamic TRH and deiodinase by thyroid hormone in human and rat hypothalamus. For obvious reasons, it is unlikely that these preliminary data on effects of hyperthyroidism in the human hypothalamus will be extended in the future.
Based on the results reported in the present study, we hypothesize the existence of various neuroanatomical routes for feedback of thyroid hormone on TRH neurons in the human PVN (Fig. 10). Several aspects of these models have been proposed by other investigators for thyroid hormone feedback regulation in the rat hypothalamus (12, 13, 30, 31). The classical scheme for feedback of thyroid hormone on TRH neurons of the PVN has traditionally focused on direct intrahypothalamic effects of thyroid hormone on TRH neurons. Indeed, unilateral stereotaxic implants of T3 within the anterior hypothalamus was reported to induce a marked reduction of proTRH mRNA in the PVN of rats (32). Based on our present data, T4 might be taken up locally within the PVN from the blood by astrocytes. This process may require active T4 transport, e.g. by organic anion transporter 1C1, which has been proposed to serve as a high affinity T4 transporter in human brain (24). In rats, organic anion transporter 1C1 is localized in brain capillaries and may be particularly important for transport of T4 across the blood-brain barrier (BBB) (33, 34). After uptake, T4 is converted to T3 by D2 in astrocytes and subsequently transported to TRH neurons by MCT8 (Fig. 10A). Coexpression of D3, MCT8, and TRs with TRH in the PVN as evident in this neuroanatomical study certainly supports the existence of this route for thyroid hormone feedback action in the human hypothalamus.
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). This route has been proposed earlier by other investigators based on neuroanatomical studies in rats (12, 13, 30, 31). Specifically, thyroid hormone might be taken up from the CSF in the third ventricle and transported by tanycytes to neurons in the ARC that project to TRH cells in the PVN. T3 action in IFN neurons may induce an altered firing pattern, affecting TRH gene expression in PVN neurons via monosynaptic pathways demonstrated earlier by tracing studies in the rat hypothalamus (35). Alternatively, T3 may be transported from IFN neurons to TRH neurons in the PVN by anterograde axonal transport as proposed in the locus coeruleus by Gordon et al. (36). Our observations in the human hypothalamus supports uptake from the CSF as a possible route for thyroid hormone feedback on TRH neurons on the basis of immunostaining of D2 expressing glial cells along the lining of the basal part of the third ventricle and MCT8, TR, and D3 expression by neurons in the IFN, which is the human homolog of the rat ARC. In addition, similar uptake followed by transport to TRH cells in the PVN appears to be a possibility in view of D2-positive glial cells along the ependyma of the third ventricle in close approximation of the PVN.
Finally, thyroid hormone may have direct access from the circulation to the IFN in view of the absence of the BBB in this part of the mediobasal hypothalamus (Fig. 10C). That cells in the ARC sense intravascular thyroid hormone concentrations is supported by increased D2 activity and mRNA in the ARC/ME after induction of hypothyroidism in rats (11, 12). In addition, TRß2 is predominantly expressed in ARC neurons (37, 38). These neurons may, therefore, be able to sense T3 produced by glial cells expressing D2. Neuropeptide Y- (NPY), proopiomelanocortin-, and agouti gene-related peptide-containing neurons from the ARC project to TRH neurons in the PVN (39, 40). The present finding of D2 in the human IFN in conjunction with our earlier observation of TRß2 expression in the same area (5) is suggestive of a similar pathway in the human hypothalamus. Interestingly, functional connections between the ARC and TRH neurons in the PVN have convincingly been demonstrated to be instrumental for the leptin-mediated down-regulation of the central part of the hypothalamic-pituitary-thyroid axis in rats and mice after food deprivation by altering the sensitivity for feedback inhibition by thyroid hormone (41, 42). In addition, a role for up-regulation of D2 in tanycytes inducing locally increased T3 production and thereby leading to inhibition of hypophysiotropic TRH neurons in animal models with experimental infection was recently proposed by Lechan and Fekete (30). Interestingly, a positive correlation between total NPY immunoreactivity in the IFN and total TRH mRNA expression in the PVN was reported in patients with the nonthyroidal illness syndrome, suggesting a role for decreased NPY input from the IFN in the resetting of thyroid hormone feedback on hypothalamic TRH cells in nonthyroidal illness (NTI) (43). Whether indeed thyroid hormone itself acts via the vascular compartment-IFN-PVN route in the hypothalamus remains, however, hypothetical at this stage.
Surprisingly, most prominent MCT8 staining was observed in the perifornical area and the LHA. In rats D2 activity was reported in the LHA (44), but in the human LHA we found no D2 and only sporadic D3 immunoreactivity. The LHA in rats is innervated by leptin sensitive neurons from the ARC and is implicated in regulating food intake and body weight (45, 46, 47). A recent study in rats reported that T3 stimulates food intake in rats via the hypothalamic ventromedial nucleus (48). The presence of dense TRH fiber networks in the human perifornical area (49) in combination with presently found marked MCT8 and sparse D3 immunoreactivity may suggest a neuroanatomical basis for effects of thyroid hormone on feeding behavior in humans as well.
In the present study, both immunocytochemical staining and activity assays showed a strong interindividual variation in signals in both hypothalamus and pituitary samples, which may be caused by a large number of variables, e.g. variation in duration and severity of fatal illness, use of medication before death, and postmortem delay. During illness, serum T3 levels decrease without giving rise to higher TSH levels, a phenomenon that is known as NTI (50). The pathogenesis of NTI is still incompletely understood, but the decrease in TRH mRNA in the hypophysiotropic neurons of the PVN reported earlier suggests a major change in hypothalamic-pituitary-thyroid axis feedback regulation (4). Evidence for a role of D2 in the mediobasal hypothalamus in the resetting of thyroid hormone feedback has been proposed in rats after lipopolysaccharide injection, which is an animal model for acute infection (51). The present study design does not allow for comparison of deiodinase and MCT8 expression levels between patients who died either acutely or after protracted illness. The relationships in the human hypothalamus between TRs, deiodinases, and MCT8 on the one hand and NTI on the other will be the subject of our further studies.
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Acknowledgments |
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Footnotes |
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First Published Online April 19, 2005
Abbreviations: ARC, Arcuate nucleus; BBB, blood-brain barrier; CNS, central nervous system; CSF, cerebrospinal fluid; D2, type II deiodinase; D3, type III deiodinase; IF, infundibular; IFN, IF nucleus; LHA, lateral hypothalamus; MCT8, monocarboxylate transporter 8; ME, median eminence; NPY, neuropeptide Y; NTI, nonthyroidal illness; NTL, tuberolateral nucleus; PVN, paraventricular nucleus; RT, room temperature; SCN, suprachiasmatic nucleus; SON, supraoptic nucleus; SUMI, supermix; TBS, Tris-buffered saline; TMN, tuberomamillary nucleus; TR, thyroid hormone receptor isoform.
Received December 30, 2004.
Accepted April 7, 2005.
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