OBESITY-INDUCED DIABETES (DIABESITY) IN C57BL KSJ MICE PRODUCES ABERRANT TRANSREGULATION OF SEX STEROID SULFOTRANSFERASE GENES/

The diabetes (db) gene is a recessive obesity mutation in the mouse ca pable of producing diabetes only through interaction with heretofore u ndefined modifiers in the genetic background of certain inbred strains . Here we identify the genetic map locations of androgen and estrogen sulfotransferase genes important in maintaining the balance of active sex steroids in the liver. The Std locus encoding dehydroepiandrostero ne sulfotransferase was mapped to proximal Chromosome 7, and the Ste l ocus encoding estrogen sulfotransferase was mapped to Chromosome 5. Th e db mutation in the diabetes-susceptible C57BL/KsJ strain aberrantly regulated mRNA transcript levels from these two loci. Hepatic Ste mRNA transcripts were increased from undetectable levels in normal males a nd females to high levels in db/db mice of both sexes. An anomalous su ppression of Std transcription was observed in db/db females, but not in normal females. These reciprocal changes in mRNA concentrations in mutant females were reflected by an induction of a high affinity estro gen sulfotransferase activity and a concomitant loss of dehydroepiandr osterone sulfotransferase activity. These db gene-elicited effects wer e specific for the sex steroid sulfotransferases since other potential sex steroid metabolizing enzymes (phenol sulfotransferase, sex steroi d sulfohydrolase, and UDP-glucuronyltransferase) were unaffected. Thes e aberrant changes would virilize hepatic metabolism in females by inc reasing the ratio of active androgens to estrogens. In human females, non-insulin-dependent diabetes mellitus often develops when visceral o besity and hyperinsulinemia are associated with hyperandrogenization. This study demonstrates that background modifier genes interacting del eteriously with an obesity mutation are not necessarily defective alle les. Rather, some are functional genes whose regulation has been alter ed by pleiotropic effects of the obesity gene.