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

• Published in: Nature medicine Vol. 22; no. 7; pp. 771 - 779
• Main Authors: Morton, Nicholas M., Beltram, Jasmina, Carter, Roderick N., Michailidou, Zoi, Gorjanc, Gregor, Fadden, Clare Mc, Barrios-Llerena, Martin E., Rodriguez-Cuenca, Sergio, Gibbins, Matthew T. G., Aird, Rhona E., Moreno-Navarrete, José Maria, Munger, Steven C., Svenson, Karen L., Gastaldello, Annalisa, Ramage, Lynne, Naredo, Gregorio, Zeyda, Maximilian, Wang, Zhao V., Howie, Alexander F., Saari, Aila, Sipilä, Petra, Stulnig, Thomas M., Gudnason, Vilmundur, Kenyon, Christopher J., Seckl, Jonathan R., Walker, Brian R., Webster, Scott P., Dunbar, Donald R., Churchill, Gary A., Vidal-Puig, Antonio, Fernandez-Real, José Manuel, Emilsson, Valur, Horvat, Simon
• Format: Journal Article
• Language: English
• Published: 06.06.2016
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4115

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, selected for low adiposity over 60 generations, to identify thiosulfate sulfurtransferase ( Tst, Rhodanese ) as a candidate obesity-resistance gene with selectively increased adipocyte expression. 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 gene deficiency markedly exacerbated diabetes whereas pharmacological TST activation ameliorated diabetes in mice in vivo . Mechanistically, TST selectively augmented mitochondrial function combined with degradation of reactive oxygen species and sulfide. In humans, adipose TST mRNA correlated positively with adipose insulin sensitivity and negatively with fat mass. Genetic identification of Tst as a beneficial regulator of adipocyte mitochondrial function may have therapeutic significance for type 2 diabetes.