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

Lookup NU author(s): Professor Brian Walker

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Abstract

© 2016 Nature America, Inc. All rights reserved.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.


Publication metadata

Author(s): 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, Sipila 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

Publication type: Article

Publication status: Published

Journal: Nature Medicine

Year: 2016

Volume: 22

Issue: 7

Pages: 771-779

Online publication date: 06/06/2016

Acceptance date: 29/04/2016

ISSN (print): 1078-8956

ISSN (electronic): 1546-170X

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/nm.4115

DOI: 10.1038/nm.4115

PubMed id: 27270587


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