Startseite Alterations in rat adipose tissue transcriptome and proteome in response to prolonged fasting
Artikel
Lizenziert
Nicht lizenziert Erfordert eine Authentifizierung

Alterations in rat adipose tissue transcriptome and proteome in response to prolonged fasting

  • Marianne Ibrahim , Daniel Ayoub , Thierry Wasselin , Alain Van Dorsselaer , Yvon Le Maho , Thierry Raclot und Fabrice Bertile ORCID logo EMAIL logo
Veröffentlicht/Copyright: 13. August 2019

Abstract

Various pathophysiological situations of negative energy balance involve the intense depletion of the body’s energy reserves. White adipose tissue is a central place to store energy and a major endocrine organ. As a model of choice to better understand how the white adipose tissue dynamically responds to changes in substrate availability, we used the prolonged fasting paradigm, which is characterized by successive periods of stimulated (phase 2) and then reduced (phase 3) lipid mobilization/utilization. Using omics analyses, we report a regulatory transcriptional program in rat epididymal (EPI) adipose tissue favoring lipolysis during phase 2 and repressing it during phase 3. Changes in gene expression levels of lipases, lipid droplet-associated factors, and the proteins involved in cAMP-dependent and cAMP-independent regulation of lipolysis are highlighted. The mRNA and circulating levels of adipose-secreted factors were consistent with the repression of insulin signaling during prolonged fasting. Other molecular responses are discussed, including the regulation of leptin and adiponectin levels, the specific changes reflecting an increased fibrinolysis and a possible protein catabolism-related energy saving mechanism in late fasting. Finally, some differences between internal and subcutaneous (SC) adipose tissues are also reported. These data provide a comprehensive molecular basis of adipose tissue responses when facing a major energetic challenge.

Award Identifier / Grant number: ANR-05-BLAN-0069

Funding statement: This work was supported by the Agence Nationale de la Recherche (Funder Id: http://dx.doi.org/10.13039/501100001665, Programme Proteonutr ANR-05-BLAN-0069) and the French Proteomic Infrastructure (ProFI; ANR-10-INSB-08-03). During the tenure of this study, TW was supported by the Centre National de la Recherche Scientifique (CNRS) and the Bruker Daltonics Company. Technical assistance from Chrystel Husser and Dr. JM Strub was essential to DIGE experiment and plasma profiling, respectively. We also thank Drs. Christelle Thibault-Carpentier, Doulaye Dembele and Violaine Alunni for involvement in transcriptomics experiments, and Dr. Patrick Guterl for bioinformatics assistance in functional annotation analysis.

  1. Conflict of interest statement: The authors declare no competing financial interests.

References

Bertile, F. and Raclot, T. (2004a). Differences in mRNA expression of adipocyte-derived factors in response to fasting, refeeding and leptin. Biochim. Biophys. Acta 1683, 101–109.10.1016/j.bbalip.2004.05.001Suche in Google Scholar

Bertile, F. and Raclot, T. (2004b). mRNA levels of SREBP-1c do not coincide with the changes in adipose lipogenic gene expression. Biochem. Biophys. Res. Commun. 325, 827–834.10.1016/j.bbrc.2004.10.110Suche in Google Scholar

Bertile, F. and Raclot, T. (2006). Adipose-derived factors during nutritional transitions. Curr. Nutr. Food Sci. 2, 127–139.10.2174/157340106776818862Suche in Google Scholar

Bertile, F. and Raclot, T. (2008). Proteomics can help to gain insights into metabolic disorders according to body reserve availability. Curr. Med. Chem. 15, 2545–2558.10.2174/092986708785908950Suche in Google Scholar

Bertile, F. and Raclot, T. (2011). ATGL and HSL are not coordinately regulated in response to fuel partitioning in fasted rats. J. Nutr. Biochem. 22, 372–379.10.1016/j.jnutbio.2010.03.005Suche in Google Scholar

Bertile, F., Criscuolo, F., Oudart, H., Le Maho, Y., and Raclot, T. (2003). Differences in the expression of lipolytic-related genes in rat white adipose tissues. Biochem. Biophys. Res. Commun. 307, 540–546.10.1016/S0006-291X(03)01196-3Suche in Google Scholar

Bertile, F., Schaeffer, C., Le Maho, Y., Raclot, T., and Van Dorsselaer, A. (2009). A proteomic approach to identify differentially expressed plasma proteins between the fed and prolonged fasted states. Proteomics 9, 148–158.10.1002/pmic.200701001Suche in Google Scholar PubMed

Bertile, F., Fouillen, L., Wasselin, T., Maes, P., Le Maho, Y., Van Dorsselaer, A., and Raclot, T. (2016). The safety limits of an extended fast: lessons from a non-model organism. Sci. Rep. 6, 39008.10.1038/srep39008Suche in Google Scholar PubMed PubMed Central

Blüher, M. (2013). Importance of adipokines in glucose homeostasis. Diabetes Manage. 3, 389–400.10.2217/dmt.13.35Suche in Google Scholar

Bluher, M. and Mantzoros, C.S. (2015). From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century. Metabolism 64, 131–145.10.1016/j.metabol.2014.10.016Suche in Google Scholar PubMed

Carapito, C., Burel, A., Guterl, P., Walter, A., Varrier, F., Bertile, F., and Van Dorsselaer, A. (2014). MSDA, a proteomics software suite for in-depth mass spectrometry data analysis using grid computing. Proteomics 14, 1014–1019.10.1002/pmic.201300415Suche in Google Scholar

Chaston, T.B. and Dixon, J.B. (2008). Factors associated with percent change in visceral versus subcutaneous abdominal fat during weight loss: findings from a systematic review. Int. J. Obes. (Lond.) 32, 619–628.10.1038/sj.ijo.0803761Suche in Google Scholar

Chehimi, M. and Eljaafari, A. (2017). Beneficial effects of fasting on white adipose tissue inflammation and metabolic syndrome in obese subjects: review. Endocrinol. Metab. Int. J 4, 00105.10.15406/emij.2017.04.00105Suche in Google Scholar

Cherel, Y. and Le Maho, Y. (1991). Refeeding after the late increase in nitrogen excretion during prolonged fasting in the rat. Physiol. Behav. 50, 345–349.10.1016/0031-9384(91)90076-ZSuche in Google Scholar

Cherel, Y., Attaix, D., Rosolowska-Huszcz, D., Belkhou, R., Robin, J.P., Arnal, M., and Le Maho, Y. (1991). Whole-body and tissue protein synthesis during brief and prolonged fasting in the rat. Clin. Sci. (Lond.) 81, 611–619.10.1042/cs0810611Suche in Google Scholar PubMed

Collet, J.P., Moen, J.L., Veklich, Y.I., Gorkun, O.V., Lord, S.T., Montalescot, G., and Weisel, J.W. (2005). The alphaC domains of fibrinogen affect the structure of the fibrin clot, its physical properties, and its susceptibility to fibrinolysis. Blood 106, 3824–3830.10.1182/blood-2005-05-2150Suche in Google Scholar PubMed PubMed Central

de Hoon, M.J., Imoto, S., Nolan, J., and Miyano, S. (2004). Open source clustering software. Bioinformatics 20, 1453–1454.10.1093/bioinformatics/bth078Suche in Google Scholar PubMed

Ding, H., Zheng, S., Garcia-Ruiz, D., Hou, D., Wei, Z., Liao, Z., Li, L., Zhang, Y., Han, X., Zen, K., et al. (2016). Fasting induces a subcutaneous-to-visceral fat switch mediated by microRNA-149-3p and suppression of PRDM16. Nat. Commun. 7, 11533.10.1038/ncomms11533Suche in Google Scholar PubMed PubMed Central

Djurhuus, C.B., Gravholt, C.H., Nielsen, S., Mengel, A., Christiansen, J.S., Schmitz, O.E., and Möller, N. (2002). Effects of cortisol on lipolysis and regional interstitial glycerol levels in humans. Am. J. Physiol. 283, E172–E177.10.1152/ajpendo.00544.2001Suche in Google Scholar PubMed

Duncan, R.E., Ahmadian, M., Jaworski, K., Sarkadi-Nagy, E., and Sul, H.S. (2007). Regulation of lipolysis in adipocytes. Annu. Rev. Nutr. 27, 79–101.10.1146/annurev.nutr.27.061406.093734Suche in Google Scholar PubMed PubMed Central

Duszka, K., Bogner-Strauss, J.G., Hackl, H., Rieder, D., Neuhold, C., Prokesch, A., Trajanoski, Z., and Krogsdam, A.M. (2013). Nr4a1 is required for fasting-induced down-regulation of Ppar gamma 2 in white adipose tissue. Mol. Endocrinol. 27, 135–149.10.1210/me.2012-1248Suche in Google Scholar PubMed PubMed Central

Fasshauer, M. and Bluher, M. (2015). Adipokines in health and disease. Trends Pharmacol. Sci. 36, 461–470.10.1016/j.tips.2015.04.014Suche in Google Scholar

Faulconnier, Y., Chilliard, Y., Torbati, M.B.M., and Leroux, C. (2011). The transcriptomic profiles of adipose tissues are modified by feed deprivation in lactating goats. Comp. Biochem. Physiol. D Genomics Proteomics 6, 139–149.10.1016/j.cbd.2010.12.002Suche in Google Scholar

Fruhbeck, G., Mendez-Gimenez, L., Fernandez-Formoso, J.A., Fernandez, S., and Rodriguez, A. (2014). Regulation of adipocyte lipolysis. Nutr. Res. Rev. 27, 63–93.10.1017/S095442241400002XSuche in Google Scholar

Groscolas, R. and Robin, J.P. (2001). Long-term fasting and re-feeding in penguins. Comp. Biochem. Physiol. A. Mol. Integr. Physiol. 128, 645–655.10.1016/S1095-6433(00)00341-XSuche in Google Scholar

Houser, D.S., Champagne, C.D., and Crocker, D.E. (2013). A non-traditional model of the metabolic syndrome: the adaptive significance of insulin resistance in fasting-adapted seals. Front. Endocrinol. 4, 164.10.3389/fendo.2013.00164Suche in Google Scholar PubMed PubMed Central

Huber, R., Nauck, M., Basler, N., Haas, B., Mattern, M., Ludtke, R., and Peter, K. (2005). Effects of subtotal fasting on plasmatic coagulation, fibrinolytic status and platelet activation: a controlled pilot study in healthy subjects. Nut. Metab. Cardiovasc. Dis. 15, 212–218.10.1016/j.numecd.2004.12.003Suche in Google Scholar PubMed

Ji, B., Ernest, B., Gooding, J.R., Das, S., Saxton, A.M., Simon, J., Dupont, J., Metayer-Coustard, S., Campagna, S.R., and Voy, B.H. (2012). Transcriptomic and metabolomic profiling of chicken adipose tissue in response to insulin neutralization and fasting. BMC Genomics 13, 441.10.1186/1471-2164-13-441Suche in Google Scholar PubMed PubMed Central

Kwok, K.H., Lam, K.S., and Xu, A. (2016). Heterogeneity of white adipose tissue: molecular basis and clinical implications. Exp. Mol. Med. 48, e215.10.1038/emm.2016.5Suche in Google Scholar PubMed PubMed Central

Lafontan, M. and Langin, D. (2009). Lipolysis and lipid mobilization in human adipose tissue. Prog. Lipid Res. 48, 275–297.10.1016/j.plipres.2009.05.001Suche in Google Scholar PubMed

Li, R.Y., Zhang, Q.H., Liu, Z., Qiao, J., Zhao, S.X., Shao, L., Xiao, H.S., Chen, J.L., Chen, M.D., and Song, H.D. (2006). Effect of short-term and long-term fasting on transcriptional regulation of metabolic genes in rat tissues. Biochem. Biophys. Res. Commun. 344, 562–570.10.1016/j.bbrc.2006.03.155Suche in Google Scholar PubMed

Long, Y., Tsai, W.B., Wang, D., Hawke, D.H., Savaraj, N., Feun, L.G., Hung, M.C., Chen, H.H., and Kuo, M.T. (2017). Argininosuccinate synthetase 1 (ASS1) is a common metabolic marker of chemosensitivity for targeted arginine- and glutamine-starvation therapy. Cancer Lett. 388, 54–63.10.1016/j.canlet.2016.11.028Suche in Google Scholar PubMed

Luo, L. and Liu, M. (2016). Adipose tissue in control of metabolism. J. Endocrinol. 231, R77–R99.10.1530/JOE-16-0211Suche in Google Scholar PubMed PubMed Central

Manzoni, C., Kia, D.A., Vandrovcova, J., Hardy, J., Wood, N.W., Lewis, P.A., and Ferrari, R. (2016). Genome, transcriptome and proteome: the rise of omics data and their integration in biomedical sciences. Brief Bioinform. 19, 286–302.10.1093/bib/bbw114Suche in Google Scholar PubMed PubMed Central

Martinez, B. and Ortiz, R.M. (2017). Thyroid hormone regulation and insulin resistance: insights from animals naturally adapted to fasting. Physiology (Bethesda) 32, 141–151.10.1152/physiol.00018.2016Suche in Google Scholar PubMed

Martinez, B., Khudyakov, J., Rutherford, K., Crocker, D.E., Gemmell, N., and Ortiz, R.M. (2018). Adipose transcriptome analysis provides novel insights into molecular regulation of prolonged fasting in northern elephant seal pups. Physiol. Genomics 50, 495–503.10.1152/physiolgenomics.00002.2018Suche in Google Scholar PubMed PubMed Central

Muliar, L.A., Mishchenko, V.P., Loban, G.A., Goncharenko, L.L., and Bobyrev, V.N. (1984). Effect of complete fasting on the coagulative and antioxidative properties of blood. Vopr. Pitan. 4, 20–23.Suche in Google Scholar

Nakai, Y., Hashida, H., Kadota, K., Minami, M., Shimizu, K., Matsumoto, I., Kato, H., and Abe, K. (2008). Up-regulation of genes related to the ubiquitin-proteasome system in the brown adipose tissue of 24-h-fasted rats. Biosci. Biotechnol. Biochem. 72, 139–148.10.1271/bbb.70508Suche in Google Scholar PubMed

Nielsen, T.S., Jessen, N., Jorgensen, J.O., Moller, N., and Lund, S. (2014). Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease. J. Mol. Endocrinol. 52, R199–R222.10.1530/JME-13-0277Suche in Google Scholar PubMed

Owen, O.E., Smalley, K.J., D’Alessio, D.A., Mozzoli, M.A., and Dawson, E.K. (1998). Protein, fat, and carbohydrate requirements during starvation: anaplerosis and cataplerosis. Am. J. Clin. Nutr. 68, 12–34.10.1093/ajcn/68.1.12Suche in Google Scholar PubMed

Palou, M., Sanchez, J., Priego, T., Rodriguez, A.M., Pico, C., and Palou, A. (2010). Regional differences in the expression of genes involved in lipid metabolism in adipose tissue in response to short- and medium-term fasting and refeeding. J. Nutr. Biochem. 21, 23–33.10.1016/j.jnutbio.2008.10.001Suche in Google Scholar PubMed

Plumel, M.I., Stier, A., Thierse, D., van Dorsselaer, A., Criscuolo, F., and Bertile, F. (2014). Litter size manipulation in laboratory mice: an example of how proteomic analysis can uncover new mechanisms underlying the cost of reproduction. Front. Zool. 11, 41.10.1186/1742-9994-11-41Suche in Google Scholar PubMed PubMed Central

Purnell, J.Q., Kahn, S.E., Samuels, M.H., Brandon, D., Loriaux, D.L., and Brunzell, J.D. (2009). Enhanced cortisol production rates, free cortisol, and 11β-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss. Am. J. Physiol. Endocrinol. Metab. 296, E351–E357.10.1152/ajpendo.90769.2008Suche in Google Scholar PubMed PubMed Central

Qi, L., Heredia, J.E., Altarejos, J.Y., Screaton, R., Goebel, N., Niessen, S., Macleod, I.X., Liew, C.W., Kulkarni, R.N., Bain, J., et al. (2006). TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. Science 312, 1763–1766.10.1126/science.1123374Suche in Google Scholar PubMed

R Development Core Team. (2008). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria, ISBN 3-900051-07-0, URL: http://www.R-project.org.Suche in Google Scholar

Reilly, S.M. and Saltiel, A.R. (2017). Adapting to obesity with adipose tissue inflammation. Nat. Rev. Endocrinol. 13, 633–643.10.1038/nrendo.2017.90Suche in Google Scholar PubMed

Revollo, J.R., Korner, A., Mills, K.F., Satoh, A., Wang, T., Garten, A., Dasgupta, B., Sasaki, Y., Wolberger, C., Townsend, R.R., et al. (2007). Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab. 6, 363–375.10.1016/j.cmet.2007.09.003Suche in Google Scholar PubMed PubMed Central

Salameh, A., Daquinag, A.C., Staquicini, D.I., An, Z., Hajjar, K.A., Pasqualini, R., Arap, W., and Kolonin, M.G. (2016). Prohibitin/annexin 2 interaction regulates fatty acid transport in adipose tissue. JCI Insight 1, e86351.10.1172/jci.insight.86351Suche in Google Scholar PubMed PubMed Central

Schupp, M., Chen, F., Briggs, E.R., Rao, S., Pelzmann, H.J., Pessentheiner, A.R., Bogner-Strauss, J.G., Lazar, M.A., Baldwin, D., and Prokesch, A. (2013). Metabolite and transcriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissues. BMC Genomics 14, 758.10.1186/1471-2164-14-758Suche in Google Scholar PubMed PubMed Central

Schweiger, M., Paar, M., Eder, C., Brandis, J., Moser, E., Gorkiewicz, G., Grond, S., Radner, F.P., Cerk, I., Cornaciu, I., et al. (2012). G0/G1 switch gene-2 regulates human adipocyte lipolysis by affecting activity and localization of adipose triglyceride lipase. J. Lipid Res. 53, 2307–2317.10.1194/jlr.M027409Suche in Google Scholar PubMed PubMed Central

Sethi, J.K. and Vidal-Puig, A.J. (2007). Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J. Lipid Res. 48, 1253–1262.10.1194/jlr.R700005-JLR200Suche in Google Scholar PubMed PubMed Central

Shibuya, M. (2011). Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer 2, 1097–1105.10.1177/1947601911423031Suche in Google Scholar PubMed PubMed Central

Soomro, A.Y., Guerchicoff, A., Nichols, D.J., Suleman, J., and Dangas, G.D. (2016). The current role and future prospects of D-dimer biomarker. Eur. Heart J. Cardiovasc. Pharmacother. 2, 175–184.10.1093/ehjcvp/pvv039Suche in Google Scholar PubMed

Sugden, M.C., Grimshaw, R.M., Lall, H., and Holness, M.J. (1994). Regional variations in metabolic responses of white adipose tissue to food restriction. Am. J. Physiol. 267, E892–E899.10.1152/ajpendo.1994.267.6.E892Suche in Google Scholar PubMed

Sun, Z., Lei, H., and Zhang, Z. (2013). Pre-B cell colony enhancing factor (PBEF), a cytokine with multiple physiological functions. Cytokine Growth Factor Rev. 24, 433–442.10.1016/j.cytogfr.2013.05.006Suche in Google Scholar PubMed PubMed Central

Takahashi, Y., Shinoda, A., Kamada, H., Shimizu, M., Inoue, J., and Sato, R. (2016). Perilipin2 plays a positive role in adipocytes during lipolysis by escaping proteasomal degradation. Sci. Rep. 6, 20975.10.1038/srep20975Suche in Google Scholar PubMed PubMed Central

Tang, H.N., Tang, C.Y., Man, X.F., Tan, S.W., Guo, Y., Tang, J., Zhou, C.L., and Zhou, H.D. (2017). Plasticity of adipose tissue in response to fasting and refeeding in male mice. Nutr. Metab. (Lond.) 14, 3.10.1186/s12986-016-0159-xSuche in Google Scholar PubMed PubMed Central

Tao, C., Sifuentes, A., and Holland, W.L. (2014). Regulation of glucose and lipid homeostasis by adiponectin: effects on hepatocytes, pancreatic beta cells and adipocytes. Best Pract. Res. Clin. Endocrinol. Metab. 28, 43–58.10.1016/j.beem.2013.11.003Suche in Google Scholar PubMed PubMed Central

Thomas, G., Brown, A.L., and Brown, J.M. (2014). In vivo metabolite profiling as a means to identify uncharacterized lipase function: recent success stories within the alpha beta hydrolase domain, (ABHD) enzyme family. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1841, 1097–1101.10.1016/j.bbalip.2014.01.004Suche in Google Scholar PubMed PubMed Central

Viscarra, J.A. and Ortiz, R.M. (2013). Cellular mechanisms regulating fuel metabolism in mammals: role of adipose tissue and lipids during prolonged food deprivation. Metabolism 62, 889–897.10.1016/j.metabol.2012.12.014Suche in Google Scholar PubMed PubMed Central

Vizcaino, J.A., Csordas, A., del-Toro, N., Dianes, J.A., Griss, J., Lavidas, I., Mayer, G., Perez-Riverol, Y., Reisinger, F., Ternent, T., et al. (2016). 2016 Update of the PRIDE database and its related tools. Nucleic Acids Res. 44, D447–D456.10.1093/nar/gkv1145Suche in Google Scholar PubMed PubMed Central

Wasselin, T., Zahn, S., Maho, Y.L., Dorsselaer, A.V., Raclot, T., and Bertile, F. (2014). Exacerbated oxidative stress in the fasting liver according to fuel partitioning. Proteomics 14, 1905–1921.10.1002/pmic.201400051Suche in Google Scholar PubMed

Yamawaki, Y., Oue, K., Shirawachi, S., Asano, S., Harada, K., and Kanematsu, T. (2017). Phospholipase C-related catalytically inactive protein can regulate obesity, a state of peripheral inflammation. Jpn. Dent. Sci. Rev. 53, 18–24.10.1016/j.jdsr.2016.06.001Suche in Google Scholar PubMed PubMed Central

Yang, X., Lu, X., Lombes, M., Rha, G.B., Chi, Y.I., Guerin, T.M., Smart, E.J., and Liu, J. (2010). The G(0)/G(1) switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. Cell Metab. 11, 194–205.10.1016/j.cmet.2010.02.003Suche in Google Scholar PubMed PubMed Central

Yang, L., Vaitheesvaran, B., Hartil, K., Robinson, A.J., Hoopmann, M.R., Eng, J.K., Kurland, I.J., and Bruce, J.E. (2011). The fasted/fed mouse metabolic acetylome: N6-acetylation differences suggest acetylation coordinates organ-specific fuel switching. J. Proteome Res. 10, 4134–4149.10.1021/pr200313xSuche in Google Scholar PubMed PubMed Central

Yang, R.Y., Havel, P.J., and Liu, F.T. (2012). Galectin-12: a protein associated with lipid droplets that regulates lipid metabolism and energy balance. Adipocyte 1, 96–100.10.4161/adip.19465Suche in Google Scholar PubMed PubMed Central

Yasar Yildiz, S., Kuru, P., Toksoy Oner, E., and Agirbasli, M. (2014). Functional stability of plasminogen activator inhibitor-1. Sci. World J. 2014, 858293.10.1155/2014/858293Suche in Google Scholar PubMed PubMed Central

Zhang, X., Xie, X., Heckmann, B.L., Saarinen, A.M., Czyzyk, T.A., and Liu, J. (2014). Targeted disruption of G0/G1 switch gene 2 enhances adipose lipolysis, alters hepatic energy balance, and alleviates high-fat diet-induced liver steatosis. Diabetes 63, 934–946.10.2337/db13-1422Suche in Google Scholar PubMed PubMed Central


Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2019-0184).


Received: 2019-03-11
Accepted: 2019-07-18
Published Online: 2019-08-13
Published in Print: 2020-02-25

©2020 Walter de Gruyter GmbH, Berlin/Boston

Heruntergeladen am 23.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/hsz-2019-0184/html
Button zum nach oben scrollen