Mapping Data

Experiment

• Experiment
  TEXT-QTL-Candidate Genes
• Chromosome
  15
• Reference
  J:236030 Morton NM, et al., Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness. Nat Med. 2016 Jul;22(7):771-9
• ID
  MGI:5905060

Genes

Gene
Fob3b2
Tst

Notes

• Experiment
  The discovery of genetic mechanisms for resistance to obesity and diabetes may illuminate new therapeutic strategies for the treatment of this global health challenge.
  
  In the current study the polygenic lean mouse model, L- line, which has been selected for low adiposity over 60 generations, was used to identify mitochondrial thiosulfate sulfurtransferase (Tst; also known as rhodanese) as a candidate obesity-resistance gene with selectively increased expression in adipocytes.
  
  To prioritize positional candidate lean genes from within major adiposity QTLs (Fob3, Fob3, Fob3b1 and Fob3b2) mRNAs whose levels were increased specifically in the adipose tissue WAT depots (3 distinct white adipose tissues depots, subcutaneous, epididymal and mesenteric) of lean mice were selected. The nuclear-encoded Tst gene, which is positioned on chromosome 15 (78,399,556- 78,405,859) within the F-line obesity QTL Fob3b2, fulfilled all of the inclusion criteria. Tst mRNA was ~7-fold higher across the three WAT depots in lean versus fat mice [F-line].
  
  In Fob3b2-M2 heterozygotes, expression of the Tst allele originating from lean mice was higher than expression of the allele originating from fat mice (Supplementary Fig. 1f,g). Given that the Fob3b2-M2 congenic line carries a ~2.8-Mbp lean-line segment around Tst, the allele-dosage studies implicate a cis-mediated mechanism underlying increased levels of Tst mRNA in lean mice.
  
  [M2 congenic developed from congenic M line in J:158707 carrying the Fob3b2 QTL between 75.25-82.93 Mb].
  
  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.