UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl) UvA-DARE (Digital Academic Repository) Thyroid hormone metabolism during inflammation and fasting de Vries, E.M. Link to publication Citation for published version (APA): de Vries, E. M. (2015). Thyroid hormone metabolism during inflammation and fasting. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 07 Mar 2021
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UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)
UvA-DARE (Digital Academic Repository)
Thyroid hormone metabolism during inflammation and fasting
de Vries, E.M.
Link to publication
Citation for published version (APA):de Vries, E. M. (2015). Thyroid hormone metabolism during inflammation and fasting.
General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).
Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, statingyour reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Askthe Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,The Netherlands. You will be contacted as soon as possible.
Download date: 07 Mar 2021
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suMMaRy
Pathophysiological circumstances such as illness and fasting affect the hypothala-mus-pituitary-thyroid (HPT) axis. The illness induced alterations, collectively known as the non-thyroidal illness syndrome (NTIS) are characterized by decreased serum T₃ and T₄ concentrations, increased serum rT₃ concentrations and unaltered or inap-propriately low serum TSH, indicating profoundly altered negative feedback in the pituitary and hypothalamus. Similar changes are observed during fasting. We recently showed that besides alterations in serum thyroid hormone (TH) concentrations, both illness and fasting are accompanied by tissue specific changes in deiodinases, which determine the availability of TH in tissues.
In this thesis we have investigated the underlying mechanisms of the changes in type 2 deiodinase (D2) in the hypothalamus during inflammation (chapter 2 and 3) and the changes in type 3 deiodinase (D3) in the liver and white adipose tissue during fasting (chapter 4,5,6,7).
Central changes in thyroid hormone metabolism during inflammation.
D2 is an important source for T₃ in the brain. It is highly expressed in tanycytes, spe-cialized cells in the wall of the third ventricle. Tanycytes take up T₄ from the cerebro-spinal fluid and the blood, which is converted into T₃ by D2. T₃ can then be transported out of the tanycytes to adjacent neurons, e.g., in the paraventricular nucleus (PVN) of the hypothalamus. Acute inflammation in mice, induced by the administration of lipopolysaccharide (LPS), results in a decrease in serum T₄ and T₃ concentrations but also in an increase in D2 expression in tanycytes. Theoretically, this leads to a local increase in T₃ bio-availability, which may decrease TRH secretion from the PVN, and subsequently suppress the HPT axis. The mechanism involved in the inflammation induced D2 in-crease is currently incompletely understood. Our experiments regarding this question are described in the first part of this thesis.
LPS binds to the Toll Like receptor 4 (TLR4) which triggers activation of intracellu-lar signaling pathways including NF-κB. Activation of this pathway leads to nuclear translocation of subunits of the NF-κB family and subsequent activation of transcrip-tion. The D2 promoter is responsive to NF-κB and we hypothesized that NF-κB is important for the inflammation induced increase in D2. In order to investigate this we
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performed in vitro and in vivo experiments. Tanycytes were isolated from brains of rat pups, cultured and stimulated with LPS. LPS stimulation resulted in an increase in D2 expression, and activation of the NF-κB pathway. Inhibition of NF-κB with chemical inhibitors prevented the LPS induced D2 increase (chapter 2).
After showing a causal role for NF-κB in vitro we proceeded with in vivo experiments using mice that lack the p65 subunit of NF-κB (RelA) in tanycytes (chapter 3). This mouse has been developed in Jena, Germany, by Dr. Heike Heuer and Dr. Ronny Haenold. We assessed the reaction of the HPT axis to LPS administration in wild type (WT) and knock out (KO) mice. While D2 expression in tanycytes increased after LPS administration in WT mice, this effect was absent in KO mice. In addition, we observed a TRH decrease upon LPS administration in the WT mice but not in the KO mice. Surprisingly, the absence of RelA in tanycytes did not prevent the drop in pituitary TSHβ expression and serum T₄ and T₃ concentrations, as these decreased equally in WT and KO mice. Thus, although NF-κB in tanycytes is important for the increase in hypothalamic D2 expression after LPS administration, the changes in the pituitary and serum are not dependent on the D2 increase. It is therefore likely that due to the LPS-induced acute phase response, simultaneous changes occur at all levels of the HPT axis. We cannot exclude, however, that the observed decrease of serum TH levels in the chronic phase illness might be a result of prolonged suppres-sion of the central part of the HPT axis.
Alterations in peripheral TH metabolism during fasting.
Decreased food intake has similar effects on the HPT axis: low serum T₄ and T₃ and a paradoxically low TSH secretion by the pituitary. The underlying mechanisms, how-ever, are different from illness and probably partly dependent on changes in leptin and neuropeptides in de hypothalamus.
During fasting, the expression and activity of deiodinases in tissues change; we and others have shown that fasting leads to an upregulation of type 3 deiodinase (D3), which is the main TH inactivating enzyme, in liver and white adipose tissue. In addi-tion to the deiodinases, other enzymes expressed in liver play a role in TH metabolism as well. Sulfotransferases (Sults) and UDP-glucuronyltransferases (UGTs) catalyze addition reactions of sulphate and glucuronide groups to TH, which increase the wa-ter solubility and enhances breakdown by deiodinases. The expression of these en-zymes is also changed during fasting.
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In chapter 4 we studied the expression of TH metabolizing enzymes either after 36 hours of fasting or after 3 weeks of 50% food restriction. We observed an increase in liver D3 during fasting and food restriction, while the expression of Sults and UGTs appeared to be differentially regulated. Hepatic T₃ concentrations decreased under both conditions indicating a minor role for Sults and UGTs in TH metabolism in the liver during fasting.
In chapter 5 and 6 we described experiments aimed to unravel the underlying mech-anisms of the fasting induced changes in hepatic TH metabolism. Earlier studies sug-gested a role for hypothalamic neuropeptides in the fasting induced alterations in hepatic TH metabolism. The liver is anatomically connected to the brain by the auto-nomic nervous system (ANS). We studied the role of the ANS in liver TH metabolism by selectively cutting either the sympathetic or parasympathetic input to the liver, followed by 36 hours of fasting. The response in TH metabolism to fasting was equal in the denervated and sham operated rats, indicating that the ANS input to the liver is not important for the changes in TH metabolism in the liver during fasting.
In chapter 6 we explored alternative mechanisms involved in the upregulation of D3 during fasting. Expression of Sults and UGTs is known to be regulated by the nuclear receptor CAR which is affected by fasting. CAR knock out mice were fasted for 24 hours and TH metabolism in the liver was assessed. We observed that the absence of CAR only slightly affected the fasting induced hepatic D3 increase while the re-sponse in serum TH did not differ between WT and KO mice. We therefore explored additional possible mechanisms for the regulation of D3.
Fasting results in a drop in plasma glucose and insulin secretion from the pancreas and a rise in free fatty acids in the blood. A protein that is important for the sensing and integration of these signals is mTOR. The absence of food related signals during fasting causes mTOR inhibition. We hypothesized that this might lead to an upregula-tion of D3. In primary hepatocytes, we inhibited mTOR with a chemical inhibitor and observed indeed that mTOR inhibition increases D3 expression in these cells (chap-ter 6). We thus concluded that mTOR plays a role in the fasting induced D3 increase in the liver.
White adipose tissue (WAT) is a key metabolic tissue during fasting. Free fatty acids are released from WAT to serve as alternative fuel for the body. T₃ is important in this process. In chapter 7 we described the effects of fasting on WAT of mice. We also
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used adipocytes to investigate possible mechanisms involved. Long term fasting in mice (48h) resulted in an increase in D3 expression in WAT. Inhibiting mTOR signal-ing in cultured 3T3-L1 adipocytes by a chemical inhibitor increased D3 expression indicating a role of mTOR.
Another protein that is known to be involved in the regulation of D3, especially dur-ing hypoxia, is HIF1α. Since there are similarities between hypoxia and fasting, we hypothesized HIF1α to be involved in the regulation of D3 during fasting. To test this, we stimulated the adipocytes with a chemical HIF1α stabilizer, however, we did not observe an increase in D3 expression. We therefore conclude that HIF1α does not play a role in the upregulation of D3 in adipocytes during fasting.
In chapter 8 the results summarized above are discussed in the context of existing literature.
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nEdERlandsE saMEnVaTTInG
Tijdens (patho)fysiologische omstandigheden verandert het setpoint van de hy-pothalamus-hypofyse-schildklier (HPT) as . Dit gebeurt bij ziekte of tijdens vasten. Bij ziekte noemen we dit het “non thyroidal illness syndrome” of NTIS. NTIS wordt gekarakteriseerd door lage triidodothronine- (T3) en thyroxine- (T4) concentraties in het bloed terwijl serum TSH en de TRH expressie in de hypothalamus niet stijgen. Deze veranderingen zien we ook tijdens vasten. Recent is aangetoond dat naast de veranderingen in schildklierhormoonwaarden in het bloed, er ook allerlei veranderin-gen optreden in schildklierhormoonmetabolisme in weefsels; met name in de expres-sie en activiteit van de dejodases, enzymen die T4 en T3 kunnen omzetten en daardoor mede de lokale weefselconcentraties van het schildklierhormoon bepalen.
In dit proefschrift hebben we gekeken naar de veranderingen in type 2 dejodase in de hypothalamus tijdens ontsteking (hoofdstuk 2 en 3) en de veranderingen in type 3 dejodase in de lever en wit vetweefsel (hoofdstuk 4, 5, 6 en 7) tijdens vasten met als doel de onderliggende mechanismen verantwoordelijk voor de veranderingen in de HPT-as te verklaren.
Veranderingen in centraal schildklierhormoon metabolisme tijdens ontsteking.
Type 2 dejodase komt in de hypothalamus vooral tot expressie in tanycyten gelegen in de wand van de derde ventrikel. In de tanycyten wordt T4 door D2 omgezet naar T3, het actieve schildklierhormoon. T3 wordt vervolgens de tanycyten uit getransporteerd naar de omliggende neuronen van de hypothalamus. Hiermee is D2 dus een belan-grijke bron van T3 voor de hypothalamus.
Het was lang onbekend waarom gedurende NTIS de negatieve feedback van de HPT-as verstoord is. De ontwikkeling van proefdiermodellen heeft bijgedragen aan meer kennis over dit onderwerp. Wanneer aan ratten en muizen bacterieel endotox-ine (lipopolysaccharide, LPS) wordt gegeven, ontstaat er een immuunrespons. Deze immuunrespons gaat samen met eenzelfde verstoring in de HPT-as als bij mensen met NTIS (lage T4 en T3 waarden, normaal/laag TSH). Het bleek bij zowel ratten als muizen dat in de hypothalamus en meer specifiek in de tanycyten, de hoeveelheid D2 na LPS verhoogd was. Dit zou een stijging van de hoeveelheid T3 in de hypothalamus tot gevolg moeten hebben. De TRH neuronen in de hypothalamus “zien” vervolgens de lokale hoge T3 waarden, waardoor de TRH afgifte onderdrukt wordt. Dit leidt dan
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tot de onderdrukking van de HPT as zoals we zien bij NTIS. Het bleef echter de vraag waarom de expressie van D2 omhoog gaat. Hierover gaat het eerste deel van dit proefschrift.
LPS bindt aan een specifieke receptor op het celoppervlak, de Toll Like Receptor 4 (TLR4). Binding van LPS aan de TLR4 leidt tot activatie van verschillende ontstek-ings-routes in de cel, waaronder de NF-κB pathway. Activatie van deze route zorgt ervoor dat NF-κB actief wordt en naar de celkern gaat. Hier kan het fungeren als een transcriptiefactor die de expressie van genen beïnvloedt. Al eerder is onderzocht dat het D2 gen gevoelig is voor NF-κB. Daarom hebben we ons gericht op de rol van NF-κB in de ontstekings- gemedieerde verhoging van D2 expressie in tanycyten.
Om te onderzoeken of NF-κB inderdaad verantwoordelijk is voor de verhoging van D2 expressie tijdens ontsteking, hebben we zowel in vitro als in vivo experimenten gedaan. Uit de hersenen van ratten pups hebben we tanycyten geïsoleerd, deze in kweek gebracht en vervolgens gestimuleerd met LPS. We zagen dat na LPS stimu-latie de expressie van D2 omhoog ging. Vervolgens hebben we de activatie van NF-κB geremd met een chemische remmer. Het resultaat hiervan was dat de verhog-ing van D2 na LPS stimulatie achterwege bleef (hoofdstuk 2). Hiermee hebben we aangetoond dat in tanycyten NF-κB belangrijk is voor de regulatie van D2 expressie tijdens ontsteking.
De volgende stap was om aan te tonen of NF-κB een rol speelt bij de LPS-geïnduceerde D2 stijging in vivo, in het intacte dier. Hiervoor hebben we een muis gebruikt die geen NF-κB heeft in de tanycyten (hoofdstuk 3). Deze muis is ontwikkeld in Jena (Heike Heuer en Ronny Haenold). Door de muizen LPS toe te dienen, hebben we aange-toond dat NF-κB essentieel is voor de reactie van D2 en TRH op de ontsteking: de D2 expressie in de tanycyten ging niet omhoog in de knockout muizen maar wel in de controle muizen. Ook was er geen daling van TRH in de hypothalamus te zien in de knockout muizen. Verrassend genoeg zagen we in zowel de controle als de knockout muizen wel een daling van de TSH afgifte en een daling van de T4 en T3 concentra-ties in het bloed. Deze resultaten laten zien dat hoewel NF-κB ook in vivo belangrijk is voor de D2 verhoging tijdens ontsteking, en indirect ook voor de TRH verlaging, dit niet belangrijk is voor acute reactie van de hypofyse en de schildklier op ontsteking. Waarschijnlijk treden er als gevolg van de LPS toediening gelijktijdige veranderingen op in de gehele HPT-as. De snelle verlaging van schildkierhormoon in het bloed lijkt in eerste instantie een consequentie van een veranderd metabolisme van de schildklier.
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We kunnen echter niet uitsluiten dat de chronische verlaging van serum schildklier-hormoonconcentraties tijdens ziekte een gevolg is van de (langdurige) repressie van de HPT-as.
Veranderingen in perifeer schildklier hormoon metabolisme tijdens vasten.
Verlaagde voedselinname heeft dezelfde uitwerking op de HPT-as als ziekte; verlag-ing van T4 en T3 in het bloed, en een niet-passende TSH afgifte door de hypofyse. De onderliggende mechanismen zijn echter anders dan bij ziekte; mogelijk spelen hormonen geassocieerd met de energiebalans een belangrijke rol.
Tijdens vasten vinden er veranderingen plaats in de activiteit van dejodases in or-ganen en weefsels leidend tot veranderingen in lokale T3 concentraties. Er is onder andere een verhoging in type 3 dejodase (D3) in lever en wit vetweefsel aangetoond. Aangezien D3 belangrijk is voor de afbraak van T4 en T3, is lang aangenomen dat de verhoging van D3 bij zou kunnen bijdragen aan de verlaging van T4 en T3 in het bloed tijdens vasten. Naast de dejodases bevinden zich in de lever nog andere enzymen die betrokken zijn bij de afbraak en klaring van schildklierhormoon. De sulfotrans-ferases en UDP-glucuronyltransferases katalyseren reacties waarbij een sulfaat of een glucuronide groep aan schildklierhormoon wordt gekoppeld. Hierdoor verandert de wateroplosbaarheid en de affiniteit voor dejodases waardoor ze sneller worden uitgescheiden of omgezet. De expressie van deze enzymen verandert tijdens vasten.
In hoofdstuk 4 hebben we al deze aspecten van schildklierhormoonmetabolisme in de lever bestudeerd tijdens twee verschillende modellen: 36 uur vasten en 3 weken voedselrestrictie waarbij de ratten 50% van hun normale voedselinname kregen. Uit deze studie konden we concluderen dat in beide modellen de activiteit van D3 in de lever verhoogd was, terwijl de expressie van de sulfotransferases en UDP-glucuronyltransferases in de lever verschillend was gereguleerd. In beide modellen zagen we echter een verlaging van T3 concentraties in de lever. Het lijkt er dus op dat de veranderingen in sulfotransferases en UDP-glucuronyltransferases niet bepalend zijn voor de verlaging van T3 in de lever.
In hoofdstuk 5 en 6 worden experimenten beschreven die gedaan zijn om meer inzicht te krijgen in de manier waarop schildklierhormoonmetabolisme gereguleerd wordt tijdens vasten.
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Uit de literatuur is gebleken dat neuropeptides aanwezig in de hypothalamus belan-grijk kunnen zijn voor de veranderingen in schildklierhormoonmetabolisme in de lever tijdens vasten. De lever is met de hersenen verbonden door het autonome zenuwstel-sel (ANS). We hebben de rol van het ANS onderzocht in ratten door de zenuwbanen van de hersenen naar de lever selectief door te knippen, en de ratten vervolgens te vasten (hoofdstuk 5). De veranderingen in lever schildklierhormoonmetabolisme als gevolg van vasten waren niet verschillend in ratten die nog wel een intact ANS had-den vergeleken met ratten die dat niet meer hadden. Hieruit concludeerden we dat de verbinding tussen de hersenen en de lever via het autonome zenuwstelsel niet belangrijk is voor de veranderingen in schildklierhormoonmetabolisme tijdens vasten in de lever.
Welke signalen zijn dan wel verantwoordelijk voor de veranderingen in D3, sulfotrans-ferases (Sult’s) en UDP-glucuronosyltransferases (Ugt’s) in de lever? Van Sult’s en Ugt’s weten we dat de expressie wordt gereguleerd door de receptor CAR. De expres-sie van CAR verandert tijdens vasten, en dit zou dus een manier kunnen zijn waarop de verminderde voedselinname wordt “gezien” door de lever. Om dit te onderzoeken gebruikten we muizen die geen CAR eiwit tot expressie brengen, de CAR knockout muizen (hoofdstuk 6). De resultaten lieten zien dat dat de afwezigheid van CAR maar een marginaal effect had op de veranderingen in D3 expressie in de lever als we deze muizen lieten vasten. We zochten daarom verder naar een mogelijk ander mechanisme. Tijdens vasten verandert er veel in het lichaam. De hoeveelheid glu-cose daalt, er is minder afgifte van insuline door de alvleesklier, de hoeveelheid vrije vetzuren stijgt om als alternatieve brandstof te dienen, en zo voorts. Al deze signalen moeten door de levercellen worden geïnterpreteerd en geïntegreerd, zodat de juiste processen worden aan en uitgezet.
Een eiwit wat heel belangrijk is voor de integratie van al deze signalen is mTOR. Tijdens vasten komen er minder voedings-gerelateerde signalen binnen in de cel, en hierdoor wordt mTOR geremd. Dit gegeven heeft geleid tot onze hypothese dat rem-ming van mTOR belangrijk zou kunnen zijn voor de stijging van de D3 expressie in de lever. In hoofdstuk 6 hebben we deze hypothese onderzocht door in gekweekte levercellen mTOR te remmen met een chemische remmer. We zagen vervolgens dat hierdoor de expressie van D3 omhoog ging net zoals bij vasten. Hieruit concluderen we dat de integratie van alle voedings-gerelateerde signalen door mTOR een belan-grijke rol speelt bij de veranderingen in D3 expressie tijdens vasten.
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Naast de lever, speelt ook wit vetweefsel een belangrijk rol tijdens vasten. Vanuit het vet worden tijdens vasten vrije vetzuren vrij gemaakt om te dienen als alternatieve brandstof voor ons lichaam. T3 is hiervoor erg belangrijk. In hoofdstuk 7 hebben we onderzocht of vasten ook leid tot veranderingen in D3 expressie in wit vet. We zagen dat alleen een lange periode van vasten (48 uur in muizen) leidt tot een verhoging van D3 expressie in vet. Om te onderzoeken wat hieraan ten grondslag ligt hebben we vetcellen in kweek gebracht en mTOR geremd met een chemische remmer. Net zoals in de levercel bracht dit een stijging van D3 expressie teweeg wat er op wijst dat mTOR ook in vet mogelijk betrokken is bij de regulatie van D3.
Een ander eiwit wat bekend is betrokken te zijn bij D3 regulatie is HIF1α, dit eiwit speelt een belangrijke rol bij hypoxie. Aangezien er overeenkomsten zijn in de cel tussen hypoxie en vasten, was de hypothese dat HIF1α ook tijdens vasten D3 zou kunnen verhogen. Dit hebben we getest door met een chemische stabilisator HIF1α te activeren en het effect op D3 expressie te bestuderen. We hebben echter geen aanwijzingen gevonden dat HIF1α betrokken is bij de regulatie van D3 in vetcellen.
In hoofdstuk 8 zijn de resultaten tenslotte bediscussieerd in de context van de bestaande literatuur.
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auThoR aFFIlIaTIons
Mariette T. ackermansDepartment of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, The Netherlands.
PerryBarretRowett institute for Nutrition and Health, University of Aberdeen, United Kingdom.
Herminac.vanBeerenDepartment of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, The Netherlands.
EvitaBelegriDepartment of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, The Netherlands.
AnitaBoelenDepartment of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, The Netherlands.
Pierre ChambonDepartment of Functional Genomics, IGBMC, Collège de France, Illkirch,France.
leslie EggelsDepartment of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, The Netherlands.
Eric FliersDepartment of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, The Netherlands.
Ronny haenoldLeibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
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heike heuerLeibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany. Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
sigrun hornLeibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
andries KalsbeekDepartment of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, The Netherlands. Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
Joan KwakkelDepartment of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, The Netherlands.
Marinus a.W. MaasDepartment of Experimental Surgery, Academic Medical Center, University of Amsterdam, The Netherlands.
Frank W. PfriegerInstitute of Cellular and Integrative Neurosciences, University of Strasbourg, France.
Marc J. TolDepartment of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands.
arthur J. VerhoevenDepartment of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands.
Falk WeihLeibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
albert C.W.a. van WijkDepartment of Experimental Surgery, Academic Medical Center, University of Amsterdam, The Netherlands.
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Phd PoRTFolIo
Name: E.M. de VriesPhD period: 2010-2014Promotores: Prof. E. Fliers and Prof. A. Kalsbeek
1. Phd training
year Workload(hours/ECTs)
General courses - Laboratory animal course- Reference manager- Pubmed Biomedical sciences- Basic course Practical Biostatistics - Scientific writing- Career development
201020112011201120132013
3.90.10.11.11.50.8
specific courses - Advanced Immunology
2012 2.9
seminars, workshops and master classes- Weekly research meeting Endocrinology- ACM annual phD symposium (2 days)- ACM annual phD symposium (2 days)- ACM annual phD symposium (2 days)
oral Presentations- Annual symposium of the Dutch thyroid club- Annual symposium of the Dutch thyroid club- Annual symposium of the Dutch thyroid club- Annual meeting Nederlandse vereniging voor Endocrinologie
- American thyroid association annual meeting- European thyroid association annual meeting- European thyroid association annual meeting
2010-2014201120122013
2011201320142014
201220132014
4111
0.50.50.50.5
0.50.50.5
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Poster Presentations:- BSN meeting Cambridge- BSN meeting Manchester- Endocrine society meeting
(Inter)national conferences- Annual symposium of the Dutch thyroid club- Annual symposium of the Dutch thyroid club- Annual symposium of the Dutch thyroid club- Annual symposium of the Dutch thyroid club- Annual meeting Nederlandse vereniging voor
Endocrinologie- American thyroid association annual meeting- European thyroid association annual meeting- European thyroid association annual meeting- BSN meeting Cambridge- BSN meeting Aberdeen- BSN meeting Manchester
201120132014
20112012201320142014 201220132014201120122013
0.50.50.5
0.250.250.250.251
11.251.250.50.50.5
other- Organising committee ACM meeting
2013 0.5
2. Teaching
lecturing- Master course Endocrinology- Master course Pathology, Neurogenetics and Endocrinology
20122014
0.10.1
supervising - Internship student Neeltje van Wijk (6 months)- Internship student Amber Lakeman (9 months)
20122013/2014
23
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3. Parameters of Esteem
Grants- Travel grant BSN 2013
awards and Prizes- Poster prize at the Annual BSN meeting in Cambridge- Poster prize at the Annual BSN meeting in Manchester
20112013
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LIstOFPUBLIcAtIONs
Herwig A, de Vries EM, Bolborea M, Wilson D, Mercer JG, Ebling FJ, Morgan PJ, Barrett P.Hypothalamic ventricular ependymal thyroid hormone deiodinases are an important element of circannual timing in the Siberian hamster (Phodopus sungorus).PLoS One. 2013 Apr 18;8(4)
Kwakkel J, Surovtseva OV, de Vries EM, Stap J, Fliers E, Boelen A.A novel role for the thyroid hormone-activating enzyme type 2 deiodinase in the in-flammatory response of macrophages.Endocrinology. 2014 Jul;155(7)
de Vries EM, Kwakkel J, Eggels L, Kalsbeek A, Barrett P, Fliers E, Boelen A.NFκB signaling is essential for the lipopolysaccharide-induced increase of type 2 deiodinase in tanycytes.Endocrinology. 2014 May;155(5)
de Vries EM, Eggels L, van Beeren HC, Ackermans MT, Kalsbeek A, Fliers E, Boelen A.Fasting-induced changes in hepatic thyroid hormone metabolism in male rats are independent of autonomic nervous input to the liver.Endocrinology. 2014 Dec;155(12)
de Vries EM, van Beeren HC, Ackermans MT, Kalsbeek A, Fliers E, Boelen A.Differential effects of fasting vs food restriction on liver thyroid hormone metabolism in male rats.Journal of Endocrinology. 2015 Jan;224(1)
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ABOUttHEAUtHOR
Emmely Marije de Vries was born 1 month to early on the 15th of March 1987 in Delft. She grew up in Naaldwijk and Bosch en Duin, where she finished her primary educa-tion at “Oud Zandbergen”. She went to the Stedelijk Gymnasium in Utrecht, where she received her diploma in 2005, and not unimportant, met her boyfriend during Biology class, with whom she is together ever since. From the age of 6 till 25 years old, she has been an enthousiastic amateur ballet dancer. During a lecture of Prof. Gispen at the Stedelijk Gymnasium about the human memory, she got fascinated by the brain. This curiosity led to the decision to study Biomedical Sciences at the University of Utrecht, where she graduated in 2008. After this she proceeded with the master “Experimental and Clinical Neuroscience” at the same University. During her studies she was a member of the educational committee of the bachelor Biomedical sciences, and was a student member of the “Dier experimenten commissie” (DEC). As a part of her master studies, she worked as an internship student for 9 months in the group of Prof. Adan at the Rudolf Magnus institute in Utrecht, and for 6 months she moved to Scotland to do an internship in the group of Dr. P. Barrett at the Rowett institute for Nutrition and Health in Aberdeen. After obtaining her master’s degree cum laude she started in September 2010 with her PhD research in the group of Prof. Andries Kalsbeek and Prof. E. Fliers at the department of Endocrinology and Metabolism in the AMC Amsterdam studying thyroid hormone metabolism in tissues during inflammation and fasting. The results of this work are presented in this thesis.
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danKWooRd
Het hebben van leuke collega’s maakt naar het werk gaan zoveel meer waard! Grappig genoeg vind ik het dankwoord bijna het moeilijkste stuk van dit proefschrift, want hoe breng je onder woorden hoeveel mensen voor je hebben betekend? Ik waag toch een poging..
Als eerste anita, co-promoter en meer! Na een niet helemaal succesvol eerste jaar heb je me opgenomen in jouw groep en ben ik full time schildklier AIO bij jou ge-worden. Met als resultaat een proefschrift waar ik trots op ben! Met jou zesde zintuig voor dipjes, onrust en frustraties weet jij altijd precies hoe ik er aan toe ben. Even zit-ten, prioriteiten stellen, lijstjes maken en een positieve draai aan de resultaten geven, vaak voelde ik me na een gesprek met jou weer klaar om er tegenaan te gaan. Maar ook voor alle positieve berichten kon ik altijd bij jou terecht. Ik ben blij dat ik nog een paar jaartjes als postdoc in het lab bij jou door mag, bedankt voor alles!
Mijn promotores, Prof. E. Fliers en Prof. a. Kalsbeek. Beste Eric, jou deur staat altijd open. Dat heb ik als zeer prettig ervaren. Jouw rust heeft zeker positief op mij afgestraald Dries, bedankt dat je me de kans hebt gegeven op de afdeling aan mijn promotietraject te beginnen. Je hebt me de tijd gegeven en dat heeft zeker invloed gehad op mijn beslissing.
Ik wil graag Prof.dr.t.J.Visser,Prof.dr.G.vandenBerghe,Prof.dr.J.A.Romijn,Prof. dr. a.J. Verhoeven, Prof. dr. T. van der Poll en dr. W.s. simonides hartelijk bedankten voor het plaatsnemen in mijn promotiecommissie en het doorlezen van het manuscript. Met een speciaal woord van dank voor Prof Romijn: Beste Hans, dankjewel voor de kans om nog 3 jaar in het AMC als postdoc onderzoek te mogen doen!
Lieve Paranimfen, Lieve Joan en anne. Ik ben blij en vereerd dat jullie mijn paran-imfen willen zijn! Joan, jij bent een van de liefste mensen die ik ken. Ik kan denk ik wel zeggen dat jij voor een groot deel verantwoordelijk bent voor mijn lab-opvoeding. Toen je het lab verliet om bij inkoop te gaan werken was dat wel even een schok! Inmiddels zijn we redelijk gewend, en het is mooi om te zien hoe jij op je plek bent bij Inkoop. Als toch niets meer lukt kunnen we altijd nog samen een opruim en organi-satie bedrijf beginnen ;). Anne, jij kwam met jou eigen nuchtere levenshouding ons lab binnen waaien, en was in record tijd ingeburgerd. Koffie drinken, naar congressen
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gaan, deiodases meten; met jou is het altijd gezellig. Je werkt super hard, daar kan niets anders dan een prachtig proefschrift uit rollen.
En dan, de pijlers van het lab! Lieve Marianne, dat jij eerder met pensioen zou gaan dan dat ik zou promoveren wist ik natuurlijk wel, maar toch kwam dat moment on-verwacht. Je wordt gemist! Bedankt voor de gezelligheid en steun, en voor het hele servies dat je voor me bij elkaar gespaard hebt! Lieve Mieke, jij bent het jongste “oude wijf” (jouw woorden, niet de mijne) dat ik ken! Als rechtgeaarde research analist heb ik veel van jou geleerd. Al was het maar de correcte samenstelling van de fosfaat buffer ;). En dan olga, schatje! Je bent altijd een plezier om mee te werken en te kletsen, dankjewel voor al je hulp. Lieve unga, jij bent nog niet zo heel lang bij ons, maar het voelt al alsof het nooit anders geweest is. Je bent een aanwinst voor het lab!
susanne, via jou ben ik in het AMC binnen gekomen, en zonder jou had mijn pro-ject er heel anders uit gezien. Bedankt voor de steun op het kritieke “ik-ben-1-jaar-bezig-maar-het-lukt-voor-geen-meter-kan-ik-dat-stomme-virus-niet-het-raam-uit-gooien”punt!
leslie, ik kan jou niet genoeg bedanken voor al je hulp bij het dier werk de afgelopen jaren. Je weet dat het niet mijn favoriete experimenten zijn, maar gelukkig hoefde ik het niet alleen te doen!
Door de jaren heen heb ik heel wat kamergenootjes gehad. Wat is het fijn om lief en leed met elkaar te kunnen delen, al werd het soms wat al te gezellig. Charlene, Rianne, Eveline, Jacqueline, Jose, Merel, anne, hannah en Evita, jullie waren en zijn geweldige kamergenootjes! Ik hoop dat ik als postdoc nog even in de aio kamer mag blijven ☺
Alle stafleden en analisten van F2: an, andre, angeline, arja, Carla, Cecilia, david, dewi, Els, Ephraim, Erik, Fred, henk s, henk W, henny, Ivy, Jacquelien, Jose, li, luc, Mariette, Marja v.V., Marja n., Marjo, Ruud, shreyas, yasin, yvonne en alle oud-collega’s: bedankt voor de gezelligheid, de hulp met alle T3 en T4 metingen, en de praatjes her en der op het lab.
Lieve collega’s van het NIN: Ewout, Yan, Zhi,Anneloes en Remi, bedankt jullie belangstelling en alle steun!
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Alle AIO’s van “boven” bedankt voor alle gezellige AIO lunches, waarbij we denk ik heel goed zijn geslaagd in het bij elkaar brengen van alle verschillende groepjes binnen de groep. Ik ben bang dat als ik alle namen ga noemen ik er ook weer veel vergeet, want onze groep blijft maar groeien! Het is altijd leuk om jullie bij “ons” op het lab te zien, en ik heb warme herinneringen aan ons gezamenlijke ski-weekend, nu al weer 3 jaar geleden! Dank aan alle andere collega’s van F5, met een speciaal woord van dank aan Birgit voor alle praktische hulp bij het afronden van mijn proefschrift.
Aan alle studenten die in de loop der jaren in onze groep stage hebben gelopen ook een woord van dank! Evita (toen nog student, nu collega!), neeltje, heleen, arjen, david, amber en Kim: dank jullie wel voor de gezelligheid en voor jullie bijdragen aan het lab en mijn experimenten.
Dank aan alle geweldige AMC collega’s die mij in de loop der jaren te hulp zijn ge-schoten en met wie ik heb samengewerkt. Speciaal albert, adri en lindy van de experimentele chirurgie voor alle primaire hepatocyten en Marc en arthur van de biochemie voor het vele werk aan de adipocyten!
Special thanks to my colleagues in Jena from group Heuer and group Weih with whom we have collaborated the last years on the RelA knock out experiments. heike, thanks for setting up this collaboration and for welcoming me in your lab. Ronny, thanks for all the breedings you’ve done and the fruitful discussions. sigrun, a lot of thanks for all the in situ’s that you’ve done for this project! sabine, thanks for the help with the mice. I’m sure it will result in a beautiful publication!
I would also like to take the opportunity to thank my fantastic colleagues from the Rowett Institute in Aberdeen. I have doubted for quite a while whether I wanted to move abroad for six months, but it has been one of the best choices I ever made and it was the foundation for my decision to start a PhD project. Perry, thanks for welcoming me in your lab and for teaching me the tanycyte isolation technique. Thanks to annika, Gisela, Tina, Imke, sylvia and all the others for making my stay unforgettable!
Naast al mijn collega’s, ben ik ook gezegend met geweldige vrienden en familie.
Lieve Nerdies; Eljo, lianne, Ischa en Jacobine. Bedankt voor alle gezellige dagen, de liters thee en de gesprekken over de wetenschap en onze (wetenschappelijke) carrières. Best bijzonder dat ik nu als eerste mag gaan promoveren! Ik kijk uit naar de
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volgende twee promoties en naar nog vele uitjes, lekkere hapjes en mooie feestjes. Lieve Margreet, dankjewel voor alles! lin, zo tof dat je de tekening voor op de cover voor me wilde maken, kus!! En aan alle vrienden die ik hier niet bij naam noem: bedankt voor de belangstelling in mijn werk, het zal vaak als abracadabra hebben geklonken!
Wat ben ik blij met mijn lieve familie! opa enOma’s,oomsen tantes, neefjes en nichtjes: jullie belangstelling in mijn onderzoek is altijd warm en oprecht geweest. Ook al ging het onderwerp jullie misschien wat te ver! Ik hoop dat er nog vele waarde-volle momenten met jullie zullen volgen.
Lieve Karin en Ton, mijn tweede ouders! Bedankt voor alle steun en hulp in de afgelo-pen jaren en in het bijzonder ook in de maanden waarin ik en even mijn proefschrift af moest maken en we ook nog even gingen verhuizen. Ik voel me ook echt een beetje jullie kind. Lieve Rox en huib, ook aan jullie dank voor de hulp in die drukke tijden!
Brothers from another mother and father, Casimir en Vincent: bedankt voor de bel-angstelling, steun en gezelligheid die ons gezin 1 maakt. En Martijn, mijn lieve bro-ertje, ik ben zo trots op jou! Ik vind het geweldig dat je ook gaat promoveren.
Lieve Zofia: bedankt voor je steun, trots, liefde en wijze woorden. Je trok me over de streep om een PhD te gaan doen, ik heb er geen moment spijt van gehad.
Mijn allerliefste papa, bedankt voor je onvoorwaardelijke steun en liefde. Zonder jou was ik niet geweest wie ik nu ben. Ik hou heel veel van je.
En dan mijn lieve mama, aan wie ik dit proefschrift opgedragen heb. Je bent de basis voor alles geweest. Hoe ouder ik word, hoe meer ik je mis.
Lieve Bob, nerd van me, al zoveel jaren mag ik met jou mijn leven delen! Je maakt me heel gelukkig, ik kijk uit naar een toekomst samen met jou. Ik hou van je!
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