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Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness

Nature Medicine volume 22, pages 771–779 (2016)Cite this article

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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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Figure 1: TST is elevated in adipose tissues from lean mice.
Figure 2: Tst overexpression in adipocytes drives obesity resistance.
Figure 3: Adipocyte Tst overexpression drives insulin sensitization and maintained lipolytic capacity.
Figure 4: The effects of Tst gene knockout and TST activation on diabetes in mice.
Figure 5: TST beneficially modulates mitochondrial functions.
Figure 6: TST mRNA levels in human adipose tissue correlate with insulin sensitivity.

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Gene Expression Omnibus

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Expressed Sequence Tag Database

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.

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Authors and 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. Animal Science Department, Biotechnical Faculty, 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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  1. Nicholas M Morton
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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.

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Correspondence to Nicholas M Morton or Simon Horvat.

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Competing interests

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

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Morton, N., Beltram, J., Carter, R. et al. Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness. Nat Med 22, 771–779 (2016). https://doi.org/10.1038/nm.4115

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