Research Topic 1: Environmental Metabolic Disease – Discovery and Validation of Novel CNS Targets

ICEMED Publications – Research Topic 1: Environmental Metabolic Disease – Discovery and Validation of Novel CNS Targets; Leader: Mathias Treier

WP 1: Molecular mechanisms underlying brain control of food intake; Leaders: Giles Yeo, Stephen O’Rahilly

Chitrang Trivedi, Xiaoye Shan, Yi-Chun Loraine Tung, Dhiraj Kabra, Jenna Holland, Sarah Amburgy, Kristy Heppner, Henriette Kirchner, Giles S. H. Yeo, and Diego Perez-Tilve: Tachykinin-1 in the Central Nervous System Regulates Adiposity in Rodents. Endocrinology (2015) 156(5): 1714–23.

Y.C. Loraine Tung, Pawan Gulati, Che-Hsiung Liu, Debra Rimmington, Rowena Dennis, Marcella Ma,Vladimir Saudek, Stephen O’Rahilly, Anthony P. Coll, Giles S.H. Yeo: FTO is necessary for the induction of leptin resistance by high-fat feeding. Molecular Metabolism (2015) 4(4): 287-98.

Y.C. Loraine Tung, Giles S.H. Yeo, Stephen O’Rahilly, and Anthony P. Coll: Obesity and FTO: Changing Focus at a Complex Locus. Cell Metabolism (2014) 23;20(5): 710-718.

Pawan Gulati, Edward Avezov, Marcella Ma, Robin Antrobus, Paul Lehner, Stephen O’Rahilly and Giles S. H. Yeo: Fat mass and obesity-related (FTO) shuttles between the nucleus and cytoplasm. Bioscience Reports (2014) 34(5): e00144.

Giles S.H. Yeo: The role of the FTO (Fat Mass and Obesity Related) locus in regulating body size and composition. Mol Cell Endocrinol. (2014) 397(1-2): 34-41.

Ruth J.F. Loos and Giles S.H. Yeo: The bigger picture of FTO – the first GWAS-identified obesity gene. Nat Rev Endocrinol. (2014) 10(1): 51–61.

Pawan Gulatia, Man Ka Cheunga, Robin Antrobusc, Chris D. Churchd, Heather P. Hardinga, Yi-Chun Loraine Tunga, Debra Rimmingtona, Marcella Maa, David Rona, Paul J. Lehnerc, Frances M. Ashcrofte, Roger D. Coxd, Anthony P. Colla, Stephen O’Rahillya, and Giles S. H. Yeoa: Role for the obesity-related FTO gene in the cellular sensing of amino acids. Proc. Natl. Acad. Sci. U.S.A. (2013) 110(7): 2557-2562.

Fiona McMurray, Chris D. Church, Rachel Larder, George Nicholson, Sara Wells, Lydia Teboul, Y. C. Loraine Tung, Debra Rimmington, Fatima Bosch, Veronica Jimenez, Giles S. H. Yeo, Stephen O’Rahilly: Frances M. Ashcroft, Anthony P. Coll, Roger D. Cox: Adult Onset Global Loss of the Fto Gene Alters Body Composition and Metabolism in the Mouse. PLoS Genet (2013) 9(1): e1003166.

MK Cheung, P Gulati, S O’Rahilly, and GSH Yeo: FTO expression is regulated by availability of essential amino acids. International Journal of Obesity (2013) 37(5): 744–747.

Anthony P Coll and Giles SH Yeo: The hypothalamus and metabolism: integrating signals to control energy and glucose homeostasis. Current Opinion in Pharmacology (2013) 13(6): 970–976.

Pawan Gulati & Giles S. H. Yeo: The biology of FTO: from nucleic acid demethylase to amino acid sensor. Diabetologia (2013) 56(10): 2113–2121.

WP 2: Genetic and epigenetic regulatory networks controlling liver metabolism; Leader: Norbert Hübner

Sebastian Schafer, Eleonora Adami, Matthias Heinig, Katharina E. Costa Rodrigues, Franziska Kreuchwig, Jan Silhavy, Sebastiaan van Heesch, Deimante Simaite, Nikolaus Rajewsky, Edwin Cuppen, Michal Pravenec, Martin Vingron, Stuart A. Cook, & Norbert Hubner: Translational regulation shapes the molecular Landscape of complex disease phenotypes. Nature Communications (2015) 26(6): 7200.

Carola Rintisch, Matthias Heinig, Anja Bauerfeind, Sebastian Schafer, Christin Mieth, Giannino Patone, Oliver Hummel, Wei Chen, Stuart Cook, Edwin Cuppen, Maria Colome´-Tatche´, Frank Johannes, Ritsert C. Jansen, Helen Neil, Michel Werner, Michal Pravenec, Martin Vingron, and Norbert Hubner: Natural variation of histone modification and its impact on gene expression in the rat genome. Genome Research (2014) 24(6): 942–953.

N. Henriette Uhlenhaut, Grant D. Barish, Ruth T. Yu, Michael Downes, Malith Karunasiri, Christopher Liddle, Petra Schwalie, Norbert Hübner, and Ronald M. Evans: Insights into Negative Regulation by the Glucocorticoid Receptor from Genome-Wide Profiling of Inflammatory Cistromes. Mol Cell. (2013) 49(1): 158 –171.

WP 3: Optogenetic deconstruction and functional characterisation of hypothalamic BSX circuits controlling metabolism; Leader: Mathias Treier

Fortin J, Boehm U, Deng CX, Treier M, Bernard DJ. Follicle-stimulating hormone synthesis and fertility depend on SMAD4 and FOXL2. FASEB J. 2014 Aug;28(8):3396-410. doi: 10.1096/fj.14-249532. Epub 2014 Apr 16.

Tran S, Zhou X, Lafleur C, Calderon MJ, Ellsworth BS, Kimmins S, Boehm U, Treier M, Boerboom D, Bernard DJ. Impaired fertility and FSH synthesis in gonadotrope-specific Foxl2 knockout mice. Mol Endocrinol. 2013 Mar;27(3):407-21. doi: 10.1210/me.2012-1286. Epub 2013 Jan 22.

WP 4: Functional characterisation of recently identified CNS targets relevant for the control of obesity and type 2 diabetes; Leader: Thomas Willnow

Schmidt et al.: SORLA facilitates insulin receptor signaling and exacerbates diet-induced obesity. Manuscript submitted (2015).
Dumanis et al.: Distinct functions of anterograde and retrograde sorting of SORLA. J Neuroscience in press.

Anne-Sophie Carlo & Anders Nykjaer & Thomas E. Willnow: Sorting receptor sortilin — a culprit in cardiovascular and neurological diseases. J Mol Med (2014) 92(9): 905–911.

Safak Caglayan, Shizuka Takagi-Niidome, Fan Liao, Anne-Sophie Carlo, Vanessa Schmidt, Tilman Burgert, Yu Kitago, Ernst-Martin Füchtbauer, Annette Füchtbauer, David M. Holtzman, Junichi Takagi, Thomas E. Willnow: Lysosomal Sorting of Amyloid-b by the SORLA Receptor Is Impaired by a Familial Alzheimer’s Disease Mutation. ScienceTranslationalMedicine (2014) 6(223): 223ra20.

Schmidt V, Carlo AS, Willnow TE: Apolipoprotein E receptor pathways in Alzheimer disease. Wiley Interdiscip Rev Syst Biol Med. (2014) 6(3): 255-270.

Tilman Burgert, Vanessa Schmidt, Safak Caglayan, Fuyu Lin, Annette Füchtbauer, Ernst-Martin Füchtbauer, Anders Nykjaer, Anne-Sophie Carlo, Thomas E. Willnow: SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes. Molecular and Cellular Biology (2013) 33(21): 4308-4320.

Anne-Sophie Carlo, Camilla Gustafsen, Guido Mastrobuoni, Morten S. Nielsen, Tilman Burgert, Daniela Hartl, Michael Rohe, Anders Nykjaer, Joachim Herz, Joerg Heeren, Stefan Kempa, Claus Munck Petersen, and Thomas E. Willnow: The pro-neurotrophin receptor sortilin is a major neuronal APOE receptor for catabolism of amyloid-β peptide in the brain. J Neurosci. (2013) 33(1): 358–370

WP 5: Discovery of key pathways mediating parental metabolic programing; Leaders: Johannes Beckers, Matthias Tschöp, Tamas Horvath

Peter Huypens, Daniela Dyckhoff, Moya Wu, Steffen Sass, Susan Marschall, Fabian Theis, Matthias Tschöp, Martin Hrabě de Angelis, and Johannes Beckers: Oocyte and sperm inherit diet-induced obesity and diabetes. Nature Communications, under revision.

Clemens Bönisch, Martin Irmler, Laura Brachthäuser, Frauke Neff, Mareike T. Bamberger, Susan Marschall, Martin Hrabě de Angelis, and Johannes Beckers: Dexamethasone alters insulin, leptin and adiponectin plasma levels but does not lead to epigenetic inheritance of metabolic phenotypes in mice. Mammalian Genome, under review.

Lucia Berti, Martin Irmler, Marty Zdichavsky, Tobias Meile, Anja Böhm, Norbert Stefan, Andreas Fritsche, Johannes Beckers, Alfred Königsrainer, Hans-Ulrich Häring, Martin Hrabe de Angelis, Harald Staiger: Fibroblast growth factor 21 is elevated in metabolically unhealthy obesity and affects lipid deposition, adipogenesis, and adipokine secretion of human abdominal subcutaneous adipocytes. MOLECULAR METABOLISM (2015) 4(7): 519-527.

Tao Deng, Z. Iris Zhu, Shaofei Zhang, Yuri Postnikov, Di Huang, Marion Horsch, Takashi Furusawa, Johannes Beckers, Jan Rozman, Martin Klingenspor, Oana Amarie, Jochen Graw, Birgit Rathkolb, Eckhard Wolf, Thure Adler, Dirk H. Busch, Valérie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Arjan van der Velde, Lino Tessarollo, Ivan Ovcherenko, David Landsman, and Michael Bustin: Functional compensation among HMGN variants modulates the DNase I hypersensitive sites at enhancers. Genome Research (2015) 25(9): 1295–1308.

Jakob S. Hansen & Xinjie Zhao & Martin Irmler & Xinyu Liu & Miriam Hoene & Mika Scheler & Yanjie Li & Johannes Beckers & Martin Hrabĕ de Angelis & Hans-Ulrich Häring & Bente K. Pedersen & Rainer Lehmann & Guowang Xu & Peter Plomgaard & Cora Weigert: Type 2 diabetes alters metabolic and transcriptional signatures of glucose and amino acid metabolism during exercise and recovery. Diabetologia (2015) 58(8): 1845–1854.

Sonja Hartwig, Silja Raschke, Birgit Knebel, Mika Scheler, Martin Irmler, Waltraud Passlack, Stefan Muller, Franz-Georg Hanisch, Thomas Franz, Xinping Li, Hans-Dieter Dicken, Kristin Eckardt, Johannes Beckers, Martin Hrabe de Angelis, CoraWeigert, Hans-Ulrich Häring, Hadi Al-Hasani, D. Margriet Ouwens, Jürgen Eckel, Jorg Kotzka, Stefan Lehr: Secretome profiling of primary human skeletal muscle cells. Biochimica et Biophysica Acta (2014) 1844(5): 1011–1017.

Marion Horsch, Juan Antonio Aguilar-Pimentel1, Clemens Bönisch, Christophe Côme, Cathrine Kolster-Fog, Klaus T. Jensen, Anders H. Lund, Icksoo Lee, Lawrence I. Grossman, Christopher Sinkler, Maik Hüttemann, Erwin Bohn, Helmut Fuchs, Markus Ollert, Valérie Gailus-Durner, Martin Hrabĕ de Angelis, Johannes Beckers: Cox4i2, Ifit2, and Prdm11 Mutant Mice: Effective Selection of Genes Predisposing to an Altered Airway Inflammatory Response from a Large Compendium of Mutant Mouse Lines. PLOS ONE (2015) 10(8): e0134503.

Limei Jua, Jonathan Winga, Elaine Taylora, Renata Brandtb, Predrag Slijepcevic c, Marion Horschd, Birgit Rathkolbd, Ildikó Ráczd, Lore Beckerd, Wolfgang Hansd, Thure Adlerd, Johannes Beckersd, Jan Rozmand, Martin Klingensporj, Eckhard Wolfe, Andreas Zimmerf, Thomas Klopstockg, Dirk H. Buschh, Valérie Gailus-Durnerd, Helmut Fuchsd, Martin Hrabe de Angelis, Gilbertus van der Horstb, Alan R. Lehmanna: SMC6 is an essential gene in mice, but a hypomorphic mutant in the ATPase domain has a mild phenotype with a range of subtle abnormalities. DNA Repair (2013) 12(5): 356– 366.

Melanie Kahle, Marion Horsch, Barbara Fridrich, Anett Seelig, Jürgen Schultheiß, Jörn Leonhardt, Martin Irmler, Johannes Beckers, Birgit Rathkolb, Eckhard Wolf, Nicole Franke, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe de Angelis, Susanne Neschen: Phenotypic comparison of common mouse strains developing high-fat diet-induced hepatosteatosis. MOLECULAR METABOLISM (2013) 2(4): 435–446.

Elisabeth Kemter, Petra Prückl, Birgit Rathkolb, Kateryna Micklich, Thure Adler, Lore Becker, Johannes Beckers, Dirk H. Busch, Alexander A. Götz, Wolfgang Hans, Marion Horsch, Boris Ivandic, Martin Klingenspor, Thomas Klopstock, Jan Rozman, Anja Schrewe, Holger Schulz, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabé de Angelis, Eckhard Wolf, Bernhard Aigner: Standardized, Systemic Phenotypic Analysis of UmodC93F and UmodA227T Mutant Mice. PLoS ONE (2013) 8(10): e78337.

Farnaz Keyhani-Nejad & Martin Irmler & Frank Isken & Eva K.Wirth & Johannes Beckers & Andreas L. Birkenfeld & Andreas F. H. Pfeiffer: Nutritional strategy to prevent fatty liver and insulin resistance independent of obesity by reducing glucose-dependent insulinotropic polypeptide responses in mice. Diabetologia (2015) 58(2):374–383.

Susanne Neschen, Markus Scheerer, Anett Seelig, Peter Huypens, Jürgen Schultheiss, Moya Wu, Wolfgang Wurst, Birgit Rathkolb, Karsten Suhre, Eckhard Wolf, Johannes Beckers, and Martin Hrabé de Angelis: Metformin Supports the Antidiabetic Effect of a Sodium Glucose Cotransporter 2 Inhibitor by Suppressing Endogenous Glucose Production in Diabetic Mice. Diabetes (2015) 64(1):284–290.

Mika Scheler, Martin Irmler, Stefan Lehr, Sonja Hartwig, Harald Staiger, Hadi Al-Hasani, Johannes Beckers, Martin Hrabé de Angelis, Hans-Ulrich Häring, and Cora Weigert: Cytokine response of primary human myotubes in an in vitro exercise model. Am J Physiol Cell Physiol (2013) 305(8):C877–C886.

Swetlana Sirko, Martin Irmler, Sergio Gascon, Sarah Bek, Sarah Schneider, Leda Dimou, Jara Obermann, Daisylea De Souza Paiva, Francoise Poirier, Johannes Beckers, Stefanie M. Hauck, Yves-Alain Barde, and Magdalena Götz: Astrocyte Reactivity After Brain Injury — The Role of Galectins 1 and 3. GLIA (2015) Seite 1–22.

Magnus Wolf, Shili Chen, Xinjie Zhao, Mika Scheler, Martin Irmler, Harald Staiger, Johannes Beckers, Martin Hrabe de Angelis, Andreas Fritsche, Hans-Ulrich Häring, Erwin D. Schleicher, Guowang Xu, Rainer Lehmann, and Cora Weigert: Production and Release of Acylcarnitines by Primary Myotubes Reflect the Differences in Fasting Fat Oxidation of the Donors. J Clin Endocrinol Metab. (2013) 98(6):E1137–E1142.

Vogt MC, Paeger L, Hess S, Steculorum SM, Awazawa M, Hampel B, Neupert S, Nicholls HT, Mauer J, Hausen AC, Predel R, Kloppenburg P, Horvath TL, Brüning JC. Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding. Cell. 2014 Jan 30;156(3):495-509. doi: 10.1016/j.cell.2014.01.008. Epub 2014 Jan 23.

WP 6: Application of integrative bioinformatics for identification of novel CNS targets relevant for the control of systems metabolism, obesity, and T2DM; Leader: Hans-Werner Mewes

Desislava Boyanova-Koetschan, Carolin Prexler, Gabi Kastenmüller, Hans-Werner Mewes: Analysis of genetic variants in nuclear receptor targets and their influence on human metabolism. PLOS Genetics Journal to be submitted.