• A Corrigendum to this article was published on 01 April 2018

This article has been updated

Abstract

The discovery of genetic mechanisms for resistance to obesity and diabetes may illuminate new therapeutic strategies for the treatment of this global health challenge. We used the polygenic 'lean' mouse model, which has been selected for low adiposity over 60 generations, to identify mitochondrial thiosulfate sulfurtransferase (Tst; also known as rhodanese) as a candidate obesity-resistance gene with selectively increased expression in adipocytes. Elevated adipose Tst expression correlated with indices of metabolic health across diverse mouse strains. Transgenic overexpression of Tst in adipocytes protected mice from diet-induced obesity and insulin-resistant diabetes. Tst-deficient mice showed markedly exacerbated diabetes, whereas pharmacological activation of TST ameliorated diabetes in mice. Mechanistically, TST selectively augmented mitochondrial function combined with degradation of reactive oxygen species and sulfide. In humans, TST mRNA expression in adipose tissue correlated positively with insulin sensitivity in adipose tissue and negatively with fat mass. Thus, the genetic identification of Tst as a beneficial regulator of adipocyte mitochondrial function may have therapeutic significance for individuals with type 2 diabetes.

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Change history

  • 07 March 2018

    In the version of this article initially published, the colors of the lines were switched in the graph that shows the glucose infusion rates for wild-type mice and Adipoq-Tst transgenic mice in Figure 3b. The top line should be purple, and the bottom line should be black. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

N.M.M. was supported by a Career Development Fellowship, an Institutional Strategic Support Fund award and a New Investigator Award from the Wellcome Trust (100981/Z/13/Z), a Research Councils UK Fellowship and a British Heart Foundation Centre of Research Excellence exchange award. We thank the Slovenian Research Agency for support (core funding P4-0220; project N5-0003 Syntol and J4-6804; all to S.H.) and for a Young Scientist Fellowship (J.B.). We acknowledge support of the British Heart Foundation Research Excellence Award in support of the contribution by the Bioinformatics Core (D.R.D.). T.M.S. received funding from the Federal Ministry of Economy, Family and Youth and from the Austrian National Foundation for Research, Technology and Development. G.A.C. was supported by the US National Institutes of Health grant R01GM 070683. J.M.F.-R. acknowledges funding from FIS PI11/00214. A.V.-P. was funded by the UK Medical Research Council (MRC) MDU, an MRC Programme grant, MRC DMC Core and MITIN (HEALTH-F4-2008-223450). We thank M. Wabitsch (University of Ulm) for the gift of the SGBS human preadipocyte cell line.

Author information

Affiliations

  1. University–British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.

    • Nicholas M Morton
    • , Roderick N Carter
    • , Zoi Michailidou
    • , Clare McFadden
    • , Martin E Barrios-Llerena
    • , Matthew T G Gibbins
    • , Rhona E Aird
    • , Annalisa Gastaldello
    • , Lynne Ramage
    • , Gregorio Naredo
    • , Christopher J Kenyon
    • , Jonathan R Seckl
    • , Brian R Walker
    • , Scott P Webster
    •  & Donald R Dunbar
  2. Biotechnical Faculty, Animal Science Department, University of Ljubljana, Ljubljana, Slovenia.

    • Jasmina Beltram
    • , Gregor Gorjanc
    •  & Simon Horvat
  3. Metabolic Research Laboratories, Level 4, Wellcome Trust–MRC Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, UK.

    • Sergio Rodriguez-Cuenca
    •  & Antonio Vidal-Puig
  4. Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, Girona, Spain.

    • José Maria Moreno-Navarrete
    •  & José Manuel Fernandez-Real
  5. Department of Medicine, University of Girona, Girona, Spain.

    • José Maria Moreno-Navarrete
    •  & José Manuel Fernandez-Real
  6. Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Girona, Spain.

    • José Maria Moreno-Navarrete
    •  & José Manuel Fernandez-Real
  7. The Jackson Laboratory, Bar Harbor, Maine, USA.

    • Steven C Munger
    • , Karen L Svenson
    •  & Gary A Churchill
  8. Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.

    • Maximilian Zeyda
    •  & Thomas M Stulnig
  9. Department of Internal Medicine, Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Zhao V Wang
  10. The Medical Research Council (MRC) Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.

    • Alexander F Howie
  11. Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.

    • Aila Saari
  12. Central Animal Laboratory, University of Turku, Turku, Finland.

    • Petra Sipilä
  13. Icelandic Heart Association, Kopavogur, Iceland.

    • Vilmundur Gudnason
    •  & Valur Emilsson
  14. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Antonio Vidal-Puig
  15. Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland.

    • Valur Emilsson
  16. National Institute of Chemistry, Ljubljana, Slovenia.

    • Simon Horvat

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Contributions

N.M.M. and S.H. conceived the experiments; N.M.M., J.B., R.N.C., Z.M., G.G., S.C.M., S.R.-C., C.M., M.E.B.-L., R.E.A., L.R., A.F.H. and S.H. performed experiments on in vivo models or samples; N.M.M., R.N.C., J.M.M.-N., M.T.G.G., C.M. and A.G. performed experiments on in vitro models; J.M.M.-N., V.G., J.M.F.-R. and V.E. provided and analyzed gene expression data from human adipose tissue; M.Z. and T.M.S. provided human adipose tissues; G.N. generated the TST inhibitor; A.S. and P.S. generated the Adipoq-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., A.V.-P., J.M.F.-R., V.E. and S.H. discussed results and commented on the manuscript; and N.M.M. and S.H. wrote the paper.

Competing interests

N.M.M. and S.P.W. hold a target patent (WO2012/104589) for TST in weight-related disorders.

Corresponding authors

Correspondence to Nicholas M Morton or Simon Horvat.

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https://doi.org/10.1038/nm.4115

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