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Nat Med. 2016 Jul;22(7):771-9. doi: 10.1038/nm.4115. Epub 2016 Jun 6.

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

Author information

1
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
2
Biotechnical Faculty, Animal Science Department, University of Ljubljana, Ljubljana, Slovenia.
3
Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, UK.
4
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, Girona, Spain.
5
Department of Medicine, University of Girona, Girona, Spain.
6
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Girona, Spain.
7
The Jackson Laboratory, Bar Harbor, Maine, USA.
8
Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
9
Department of Internal Medicine, Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
10
The Medical Research Council (MRC) Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
11
Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
12
Central Animal Laboratory, University of Turku, Turku, Finland.
13
Icelandic Heart Association, Kopavogur, Iceland.
14
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
15
Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland.
16
National Institute of Chemistry, Ljubljana, Slovenia.

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.

PMID:
27270587
PMCID:
PMC5524189
DOI:
10.1038/nm.4115
[Indexed for MEDLINE]
Free PMC Article

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