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

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 mitoc...

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Detalles Bibliográficos
Autores: Morton, Nicholas M., Beltram, Jasmina, Carter, Roderick N., Michailidou, Zoi, Gorjanc, Gregor, McFadden, Clare, Barrios Llerena, Martin E., Rodriguez Cuenca, Sergio, Gibbins, Matthew T.G., Aird, Rhona E., Moreno Navarrete, José María, 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, Fernández-Real Lemos, José Manuel, Emilsson, Valur, Horvat, Simon
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2016
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10256/16968
Acceso en línea:http://hdl.handle.net/10256/16968
Access Level:acceso abierto
Palabra clave:Obesitat
Diabetis no-insulinodependent
Non-insulin-dependent diabetes
Obesity
Descripción
Sumario: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

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