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

Nicholas M. Morton; Jasmina Beltram; Roderick N. Carter; Zoi Michailidou; Gregor Gorjanc; Clare McFadden; Martin E. Barrios-Llerena; Sergio Rodriguez-Cuenca; Matthew T G Gibbins; Rhona E. Aird; José Maria Moreno-Navarrete; Steven C. Munger; Karen L. Svenson; Annalisa Gastaldello; Lynne Ramage; Gregorio Naredo; Maximilian Zeyda; Zhao V. Wang; Alexander F. Howie; Aila Saari; Petra Sipilä; Thomas M. Stulnig; Vilmundur Gudnason; Christopher J. Kenyon; Jonathan R. Seckl; Brian R. Walker; Scott P. Webster; Donald R. Dunbar; Gary A. Churchill; Antonio Vidal-Puig; José Manuel Fernandez-Real; Valur Emilsson; Simon Horvat

doi:10.1038/nm.4115

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

Nicholas M. Morton, Jasmina Beltram, Roderick N. Carter, Zoi Michailidou, Gregor Gorjanc, Clare McFadden, Martin E. Barrios-Llerena, Sergio Rodriguez-Cuenca, Matthew T G Gibbins, Rhona E. Aird, José Maria Moreno-Navarrete, Steven C. Munger, Karen L. Svenson, Annalisa Gastaldello, Lynne Ramage, Gregorio Naredo, Maximilian Zeyda, Zhao V. Wang, Alexander F. Howie, Aila SaariPetra Sipilä, Thomas M. Stulnig, Vilmundur Gudnason, Christopher J. Kenyon, Jonathan R. Seckl, Brian R. Walker, Scott P. Webster, Donald R. Dunbar, Gary A. Churchill, Antonio Vidal-Puig, José Manuel Fernandez-Real, Valur Emilsson, Simon Horvat

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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.

Original language	English (US)
Pages (from-to)	771-779
Number of pages	9
Journal	Nature medicine
Volume	22
Issue number	7
DOIs	https://doi.org/10.1038/nm.4115
State	Published - Jul 1 2016

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Morton, N. M., Beltram, J., Carter, R. N., Michailidou, Z., Gorjanc, G., McFadden, C., Barrios-Llerena, M. E., Rodriguez-Cuenca, S., Gibbins, M. T. G., Aird, R. E., Moreno-Navarrete, J. M., Munger, S. C., Svenson, K. L., Gastaldello, A., Ramage, L., Naredo, G., Zeyda, M., Wang, Z. V., Howie, A. F., ... Horvat, S. (2016). Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness. Nature medicine, 22(7), 771-779. https://doi.org/10.1038/nm.4115

Morton, NM, Beltram, J, Carter, RN, Michailidou, Z, Gorjanc, G, McFadden, C, Barrios-Llerena, ME, Rodriguez-Cuenca, S, Gibbins, MTG, Aird, RE, Moreno-Navarrete, JM, Munger, SC, Svenson, KL, Gastaldello, A, Ramage, L, Naredo, G, Zeyda, M, Wang, ZV, Howie, AF, Saari, A, Sipilä, P, Stulnig, TM, Gudnason, V, Kenyon, CJ, Seckl, JR, Walker, BR, Webster, SP, Dunbar, DR, Churchill, GA, Vidal-Puig, A, Fernandez-Real, JM, Emilsson, V & Horvat, S 2016, 'Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness', Nature medicine, vol. 22, no. 7, pp. 771-779. https://doi.org/10.1038/nm.4115

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

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.",

author = "Morton, {Nicholas M.} and Jasmina Beltram and Carter, {Roderick N.} and Zoi Michailidou and Gregor Gorjanc and Clare McFadden and Barrios-Llerena, {Martin E.} and Sergio Rodriguez-Cuenca and Gibbins, {Matthew T G} and Aird, {Rhona E.} and Moreno-Navarrete, {Jos{\'e} Maria} and Munger, {Steven C.} and Svenson, {Karen L.} and Annalisa Gastaldello and Lynne Ramage and Gregorio Naredo and Maximilian Zeyda and Wang, {Zhao V.} and Howie, {Alexander F.} and Aila Saari and Petra Sipil{\"a} and Stulnig, {Thomas M.} and Vilmundur Gudnason and Kenyon, {Christopher J.} and Seckl, {Jonathan R.} and Walker, {Brian R.} and Webster, {Scott P.} and Dunbar, {Donald R.} and Churchill, {Gary A.} and Antonio Vidal-Puig and Fernandez-Real, {Jos{\'e} Manuel} and Valur Emilsson and Simon Horvat",

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AU - Carter, Roderick N.

AU - Michailidou, Zoi

AU - Gorjanc, Gregor

AU - McFadden, Clare

AU - Barrios-Llerena, Martin E.

AU - Rodriguez-Cuenca, Sergio

AU - Gibbins, Matthew T G

AU - Aird, Rhona E.

AU - Moreno-Navarrete, José Maria

AU - Munger, Steven C.

AU - Svenson, Karen L.

AU - Gastaldello, Annalisa

AU - Ramage, Lynne

AU - Naredo, Gregorio

AU - Zeyda, Maximilian

AU - Wang, Zhao V.

AU - Howie, Alexander F.

AU - Saari, Aila

AU - Sipilä, Petra

AU - Stulnig, Thomas M.

AU - Gudnason, Vilmundur

AU - Kenyon, Christopher J.

AU - Seckl, Jonathan R.

AU - Walker, Brian R.

AU - Webster, Scott P.

AU - Dunbar, Donald R.

AU - Churchill, Gary A.

AU - Vidal-Puig, Antonio

AU - Fernandez-Real, José Manuel

AU - Emilsson, Valur

AU - Horvat, Simon

PY - 2016/7/1

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N2 - 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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Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness

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