11-Dehydrocorticosterone Causes Metabolic Syndrome, Which Is Prevented when 11β-HSD1 Is Knocked Out in Livers of Male Mice

Metabolic syndrome is growing in importance with the rising levels of obesity, type 2 diabetes, and insulin resistance. Metabolic syndrome shares many characteristics with Cushing's syndrome, which has led to investigation of the link between excess glucocorticoids and metabolic syndrome. Indeed, increased glucocorticoids from intracellular regeneration by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) drives insulin resistance and increases adiposity, but these metabolic changes are assumed to be due to increased circulating glucocorticoids. We hypothesized that increasing the substrate for 11β-HSD1 (11-dehydrocorticosterone, 11-DHC) would adversely affect metabolic parameters. We found that chronic administration of 11-DHC to male C57BL/6J mice resulted in increased circulating glucocorticoids, and down-regulation of the hypothalamic-pituitary-adrenal axis. This elevated 11β-HSD1-derived corticosterone led to increased body weight gain and adiposity and produced marked insulin resistance. Surprising...