Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Primary accessions

ArrayExpress

Gene Expression Omnibus

Referenced accessions

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.

References

  1. Flegal, K.M., Carroll, M.D., Ogden, C.L. & Curtin, L.R. Prevalence and trends in obesity among US adults, 1999–2008. J. Am. Med. Assoc. 303, 235–241 (2010).

    Article  CAS  Google Scholar 

  2. Yanovski, S.Z. & Yanovski, J.A. Obesity prevalence in the United States—up, down or sideways? N. Engl. J. Med. 364, 987–989 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ljungvall, A. & Zimmerman, F.J. Bigger bodies: long-term trends and disparities in obesity and body-mass index among U.S. adults, 1960–2008. Soc. Sci. Med. 75, 109–119 (2012).

    Article  PubMed  Google Scholar 

  4. Morton, N.M. et al. A polygenic model of the metabolic syndrome with reduced circulating and intra-adipose glucocorticoid action. Diabetes 54, 3371–3378 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Horvat, S. et al. Mapping of obesity QTLs in a cross between mouse lines divergently selected on fat content. Mamm. Genome 11, 2–7 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Prevorsek, Z., Gorjanc, G., Paigen, B. & Horvat, S. Congenic and bioinformatics analyses resolved a major-effect Fob3b QTL on mouse chr 15 into two closely linked loci. Mamm. Genome 21, 172–185 (2010).

    Article  PubMed  Google Scholar 

  7. Bünger, L. et al. Long-term divergent selection on fatness in mice indicates a regulation system independent of leptin production and reception. FASEB J. 17, 85–87 (2003).

    Article  PubMed  CAS  Google Scholar 

  8. Morton, N.M. et al. A stratified transcriptomics analysis of polygenic fat and lean mouse adipose tissues identifies novel candidate obesity genes. PLoS One 6, e23944 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Westley, J. Rhodanese. Adv. Enzymol. 39, 327–368 (1973).

    CAS  PubMed  Google Scholar 

  10. Hall, A.H., Saiers, J. & Baud, F. Which cyanide antidote? Crit. Rev. Toxicol. 39, 541–552 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Bonomi, F., Pagani, S., Cerletti, P. & Cannella, C. Rhodanese-mediated sulfur transfer to succinate dehydrogenase. Eur. J. Biochem. 72, 17–24 (1977).

    Article  CAS  PubMed  Google Scholar 

  12. Pagani, S. & Galante, Y.M. Interaction of rhodanese with mitochondrial NADH dehydrogenase. Biochim. Biophys. Acta 742, 278–284 (1983).

    Article  CAS  PubMed  Google Scholar 

  13. Nandi, D.L., Horowitz, P.M. & Westley, J. Rhodanese as a thioredoxin oxidase. Int. J. Biochem. Cell Biol. 32, 465–473 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Wang, R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol. Rev. 92, 791–896 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Tiranti, V. et al. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat. Med. 15, 200–205 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Smirnov, A. et al. Mitochondrial enzyme rhodanese is essential for 5 S ribosomal RNA import into human mitochondria. J. Biol. Chem. 285, 30792–30803 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Vernochet, C. et al. Adipose-specific deletion of Tfam increases mitochondrial oxidation and protects mice against obesity and insulin resistance. Cell Metab. 16, 765–776 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tormos, K.V. et al. Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab. 14, 537–544 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kusminski, C.M. et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat. Med. 18, 1539–1549 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Geng, B. et al. Increase or decrease hydrogen sulfide exert opposite lipolysis but reduce global insulin resistance in high-fat-diet-induced obese mice. PLoS One 8, e73892 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Feng, X. et al. Hydrogen sulfide from adipose tissue is a novel insulin resistance regulator. Biochem. Biophys. Res. Commun. 380, 153–159 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Simoncic, M. et al. Divergent physical activity and novel alternative responses to high-fat feeding in polygenic fat and lean mice. Behav. Genet. 38, 292–300 (2008).

    Article  PubMed  Google Scholar 

  23. Svenson, K.L. et al. High-resolution genetic mapping using the Mouse Diversity outbred population. Genetics 190, 437–447 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang, Z.V., Deng, Y., Wang, Q.A., Sun, K. & Scherer, P.E. Identification and characterization of a promoter cassette conferring adipocyte-specific gene expression. Endocrinology 151, 2933–2939 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Xu, A. et al. The fat-derived hormone adiponectin alleviates alcoholic and non-alcoholic fatty liver diseases in mice. J. Clin. Invest. 112, 91–100 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Herman, M.A. et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 484, 333–338 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sen, U. et al. Cardioprotective role of sodium thiosulfate on chronic heart failure by modulating endogenous H2S generation. Pharmacology 82, 201–213 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Sabelli, R. et al. Rhodanese–thioredoxin system and allyl sulfur compounds. FEBS J. 275, 3884–3899 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Koh, E.H. et al. Essential role of mitochondrial function in adiponectin synthesis in adipocytes. Diabetes 56, 2973–2981 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Moreno-Navarrete, J.M. et al. Decreased RB1 mRNA, protein and activity reflect obesity-induced altered adipogenic capacity in human adipose tissue. Diabetes 62, 1923–1931 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wabitsch, M. et al. Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation. Int. J. Obes. Relat. Metab. Disord. 25, 8–15 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Loos, R.J. The genetic epidemiology of melanocortin 4 receptor variants. Eur. J. Pharmacol. 660, 156–164 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Smemo, S. et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 507, 371–375 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kilpeläinen, T.O. et al. Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nat. Genet. 43, 753–760 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Heid, I.M. et al. Meta-analysis identifies 13 new loci associated with waist–hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat. Genet. 42, 949–960 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rung, J. et al. Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat. Genet. 41, 1110–1115 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Vigouroux, C., Caron-Debarle, M., Le Dour, C., Magré, J. & Capeau, J. Molecular mechanisms of human lipodystrophies: from adipocyte lipid droplet to oxidative stress and lipotoxicity. Int. J. Biochem. Cell Biol. 43, 862–876 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Jacquemont, S. et al. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature 478, 97–102 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homolog. Nature 372, 425–432 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. Mathes, W.F., Kelly, S.A. & Pomp, D. Advances in comparative genetics: influence of genetics on obesity. Br. J. Nutr. 106 (suppl. 1), S1–S10 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Soloveva, V., Graves, R.A., Rasenick, M.M., Spiegelman, B.M. & Ross, S.R. Transgenic mice overexpressing the β1-adrenergic receptor in adipose tissue are resistant to obesity. Mol. Endocrinol. 11, 27–38 (1997).

    CAS  PubMed  Google Scholar 

  43. Harms, M. & Seale, P. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19, 1252–1263 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Hawley, S.A. et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336, 918–922 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hawley, S.A. et al. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 11, 554–565 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Munger, S.C. et al. RNA-seq alignment to individualized genomes improves transcript abundance estimates in multiparent populations. Genetics 198, 59–73 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Steele, R., Wall, J.S., De Bodo, R.C. & Altszuler, N. Measurement of size and turnover rate of body glucose pool by the isotope-dilution method. Am. J. Physiol. 187, 15–24 (1956).

    Article  CAS  PubMed  Google Scholar 

  48. Hildebrandt, T.M. & Grieshaber, M.K. Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria. FEBS J. 275, 3352–3361 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

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

Authors and Affiliations

Authors

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.

Corresponding authors

Correspondence to Nicholas M Morton or Simon Horvat.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 1–4 (PDF 1475 kb)

Source data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing