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

Research output: Contribution to journalArticle

23 Scopus citations

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 languageEnglish (US)
Pages (from-to)771-779
Number of pages9
JournalNature medicine
Volume22
Issue number7
DOIs
StatePublished - Jul 1 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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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