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 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.
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Nicholas M
NM
Morton
Biotechnical Faculty, Animal Science Department, University of Ljubljana, Ljubljana, Slovenia.
Jasmina
J
Beltram
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Roderick N
RN
Carter
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Zoi
Z
Michailidou
Biotechnical Faculty, Animal Science Department, University of Ljubljana, Ljubljana, Slovenia.
Gregor
G
Gorjanc
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Clare
C
McFadden
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Martin E
ME
Barrios-Llerena
Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, UK.
Sergio
S
Rodriguez-Cuenca
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Matthew T G
MT
Gibbins
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Rhona E
RE
Aird
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, Girona, Spain.|Department of Medicine, University of Girona, Girona, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Girona, Spain.
José Maria
JM
Moreno-Navarrete
The Jackson Laboratory, Bar Harbor, Maine, USA.
Steven C
0000-0002-8458-1871
SC
Munger
The Jackson Laboratory, Bar Harbor, Maine, USA.
Karen L
KL
Svenson
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Annalisa
A
Gastaldello
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Lynne
L
Ramage
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Gregorio
G
Naredo
Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Maximilian
M
Zeyda
Department of Internal Medicine, Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Zhao V
ZV
Wang
The Medical Research Council (MRC) Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Alexander F
AF
Howie
Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
Aila
A
Saari
Central Animal Laboratory, University of Turku, Turku, Finland.
Petra
P
Sipilä
Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Thomas M
TM
Stulnig
Icelandic Heart Association, Kopavogur, Iceland.
Vilmundur
V
Gudnason
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Christopher J
CJ
Kenyon
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Jonathan R
JR
Seckl
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Brian R
BR
Walker
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Scott P
SP
Webster
University-British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Donald R
DR
Dunbar
The Jackson Laboratory, Bar Harbor, Maine, USA.
Gary A
GA
Churchill
Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, UK.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Antonio
A
Vidal-Puig
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, Girona, Spain.|Department of Medicine, University of Girona, Girona, Spain.|Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Girona, Spain.
José Manuel
JM
Fernandez-Real
Icelandic Heart Association, Kopavogur, Iceland.|Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland.
Valur
V
Emilsson
Biotechnical Faculty, Animal Science Department, University of Ljubljana, Ljubljana, Slovenia.|National Institute of Chemistry, Ljubljana, Slovenia.
Simon
S
Horvat
D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat; D055879:Gene Knock-In Techniques; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D023421:Models, Animal; D058990:Molecular Targeted Therapy; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013884:Thiosulfate Sulfurtransferase / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D013884:Thiosulfate Sulfurtransferase