A1 Refereed original research article in a scientific journal
Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness
Authors: 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
Publisher: NATURE PUBLISHING GROUP
Publication year: 2016
Journal: Nature Medicine
Journal name in source: NATURE MEDICINE
Journal acronym: NAT MED
Volume: 22
Issue: 7
First page : 771
Last page: 779
Number of pages: 9
ISSN: 1078-8956
eISSN: 1546-170X
DOI: https://doi.org/10.1038/nm.4115
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 pharmgcological 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.
