Genetic identification of an adipocyte expressed anti-diabetic target in mice selected for resistance to diet-induced obesity. Mus musculus

Discovery of genetic mechanisms of resistance to obesity and diabetes may illuminate new therapeutic strategies to tackle this escalating global health burden. We used the polygenic Lean mouse model, selected for low adiposity over 60 generations, to identify thiosulfate sulfur transferase (Tst, rhodanese) as a candidate obesity-resistance gene with selectively increased adipocyte expression. 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. 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. Overall design: Illumina 100bp paired-end RNA-seq was profiled from subcutaneous inguinal fat from 24 female 26-week old mice from four inbred strains (C57BL/6J, NZO/HiLtJ, CAST/EiJ, WSB/EiJ) raised on standard chow or high fat diet (3 biological replicates per strain*diet group).