The effects of
RU 486 (mitepristone), an antagonist of type II
glucocorticoid receptors (GR), on the development of
obesity in young 5-wk-old obese fa/fa rats has been investigated. After 15 days of treatment, body composition of obese RU 486-treated rats was similar to that of lean-vehicle rats. Analysis of body composition changes showed that
RU 486 effectively reversed the
obesity. It stopped fat deposition in obese rats but increased
protein deposition to the level of lean-vehicle rats.
RU 486 prevented the development of
hyperphagia and reduced gross energetic efficiency in the obese rats but had little effect on lean rats. Brown adipose tissue mitochondrial
GDP binding was increased in obese rats but was reduced in lean rats by
RU 486 treatment.
RU 486 also reduced the elevated activity of hippocampal
glycerophosphate dehydrogenase, a
glucocorticoid-responsive
enzyme, of obese rats to the level of lean rats. The evidence suggests that abnormal activity of
glucocorticoid GR receptors or abnormal cellular responsiveness to
corticosterone receptor complexes may be important in the development of
obesity in the fa/fa rat.