Journal Article

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

Emilsson, Valur, Munger, Steven C, McFadden, Clare, Naredo, Gregorio, Morton, Nicholas M, Moreno-Navarrete, José Maria, Sipilä, Petra, Michailidou, Zoi, Saari, Aila, Beltram, Jasmina, Gudnason, Vilmundur, Kenyon, Christopher J, Stulnig, Thomas M, Aird, Rhona E, Walker, Brian R, Wang, Zhao V, Webster, Scott P, Howie, Alexander F, Barrios-Llerena, Martin E, Gibbins, Matthew T G, Gastaldello, Annalisa, Dunbar, Donald R, Seckl, Jonathan R, Vidal-Puig, Antonio, Gorjanc, Gregor, Churchill, Gary A, Rodriguez-Cuenca, Sergio, Carter, Roderick N, Ramage, Lynne, Svenson, Karen L, Zeyda, Maximilian, Horvat, Simon, Fernandez-Real, José Manuel

2016

Overview

Genetic analysis in mice selected for leanness has identified thiosulfate sulfurtransferase as a target for the treatment of diabetes. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38/77 / 38/91 / 631/208/729 / 64/110 / 692/308/1426 / 692/699/317 / 82/1 / Adipocytes / Adipocytes - metabolism / Adipose tissue / Adipose Tissue - metabolism / Animals / Biomedicine / Body fat / Cancer Research / Cell Differentiation / Development and progression / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Experimental - genetics / Diabetes Mellitus, Experimental - metabolism / Diabetes Mellitus, Type 2 - genetics / Diabetes Mellitus, Type 2 - metabolism / Diet, High-Fat / Drug therapy / Gene expression / Gene Knock-In Techniques / Genetic analysis / Genetic aspects / Genetics / Global health / Glucose Clamp Technique / Glucose Tolerance Test / Health aspects / Humans / Identification and classification / Infectious Diseases / Insulin / Insulin Resistance - genetics / Metabolic Diseases / Mice / Mice, Inbred Strains / Mice, Transgenic / Mitochondria / Mitochondria - metabolism / Models, Animal / Molecular Medicine / Molecular Targeted Therapy / Neurosciences / Obesity / Obesity - genetics / Obesity - metabolism / Public health / Reactive oxygen species / Real-Time Polymerase Chain Reaction / Rhodanese / RNA, Messenger - metabolism / Sulfides / Sulfurtransferase / Thiosulfate Sulfurtransferase - genetics / Thiosulfate Sulfurtransferase - metabolism / Thiosulfates / Transferases / Transgenic mice