Synergism of Obesity Genes With Hepatic Steroid Sulfotransferases to Mediate Diabetes in Mice

Sulfotransferases controlling the intrahepatic ratio of active androgens to estrogens represent key determinants of whether an obesity mutation will be diabetogenic in C57BL/KsJ female mice. Three unlinked genes (diabetes [db], obese [ob], and fat [fat]) all produced comparable obesity in C57BL/KsJ females, but only the fat mutation was not diabetogenic. The fat gene was incapable of eliciting virilizing changes in hepatic sulfotransferase activity, whereas both db and ob accelerated estrogen and suppressed androgen sulfation. Northern-blot analysis confirmed anomalous suppression of hepatic androgen sulfotransferase transcription in db and ob but not fat females. These findings suggest the utility of obesity genes in analyzing the interaction between hyperandrogenism, hyperinsulinemia, and diabetes.