Genetic identification of thiosulfate sulfur-transferase as an anti-diabetic target inadipocytes of mice selected for resistance to diet-induced obesity.

Key words: obesity, diabetes, obesity-resistance, genetics, quantitative trait loci, thiosulfate sulfur-transferase, tbc

Authors: Nicholas M. Morton1*, Jasmina Beltram2, Roderick E. Carter1, Zoi Michailidou1,Gregor Gorjanc2, Clare McFadden1, Martin Barrios-Llerena1, Sergio Rodriguez-Cuenca3,Matthew Gibbins1, Rhona E. Aird1,José Maria Moreno-Navarrete4, Steven C. Munger5, Karen L. Svenson5, Annalisa Gastaldello1, Lynne Ramage1, Gregorio Naredo1, Maximilian Zeyda6, Zhao V. Wang7, Alexander F. Howie8, Aila Saari9, Petra Sipila9, Thomas Stulnig6, Vilmundur Gudnasson10, Christopher J. Kenyon1, Jonathan R. Seckl1, Brian R. Walker1, Scott P. Webster1, Donald R. Dunbar1, Gary A. Churchill5, Antonio Vidal-Puig3, José Manuel Fernandez-Real4, Valur Emilsson10, 11, Simon Horvat2, 12.

Affiliations:1. University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. 2. Biotechnical Faculty, Animal Science Department, University of Ljubljana, Groblje 3, 1230 Domzale, Slovenia.3.Metabolic Research Laboratories, Level 4, Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, CB2 OQQ, UK. 4.Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, CIBERobn Fisiopatología de la Obesidad y Nutrición, Girona, Spain. 5.The Jackson Laboratory, 600 Main St, Bar Harbor, ME 04609 USA.6. Clinical Division of Endocrinology and Metabolism, Medical University of Vienna, A-1090 Vienna, Austria.7.Department of Internal Medicine, Touchstone Diabetes Center University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd. Dallas, TX 75390-8549, USA.8. Centre for Reproductive Health, University of Edinburgh, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. 9. Department of Physiology and Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland. 10.Icelandic Heart Association, Holtasmari 1, IS-201 Kopavogur, Iceland. 11.Faculty of Pharmaceutical Sciences, University of Iceland,Hagi, Hofsvallagata 53
107 Reykjavík,Iceland.12.National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia.

Acknowledgements

N.M.M. was supported by a Career Development Fellowship, Institutional Strategic Support Fund award and an Investigator Award from the Wellcome Trust, a Research Councils UK Fellowship and a British Heart Foundation Centre of Research Excellence exchange award.We thank the Slovenian Research Agency (core funding P4-0220, project N5-0003 Syntol and J4-6804 to S.H.); and a Young Scientist Fellowship to J.B. We acknowledge support of the British Heart Foundation Research Excellence Award in support of the Bioinformatics Core contribution. J.M. F.-R acknowledges funding fromFIS PI11/00214. T.V-P was funded by MRC CORD, an MRC Programme grant and MITIN (HEALTH-F4-2008-223450).We thank Martin Wabitsch (Ulm, Germany) for the gift of the SGBS human preadipocyte cell line.

AUTHOR CONTRIBUTIONS

N.M.M. and S.H. conceived the experiments. N.M.M., J.B., R.C., Z.M., G.G., S.C.M., S.R-C., C. McF., M. B-Ll, R.E.A, L.R., A.F.H. and S.H. performed experiments on in vivo models or samples. N.M.M., R.C., J.M.M.-N., M.G., C. McF., and A.G. performed experiments on in vitro models. J.M.M.-N., V.G., J.M.F.-R. and V.E. provided and analysed human adiposegene expression data. M.Z., T.S. provided human adipose tissues. G.N. generated TST inhibitor. A.S. and P.S. generated the Ad-Tst mice.Z.V.W. generated the adiponectin promoter DNA vector. D.R.D. performed bioinformatics analyses. S.C.M., K.L.S. and G.A.C generated the Diversity Outbred mouse resources and data. S.R.-C., C.J.K., J.R.S., B.R.W, S.P.W., T.V.P., J.M.F.-R, V.E and S.H. discussed results and commented on the manuscript. N.M.M. and S.H. wrote the paper.