Inhibition of 11ß-hydroxysteroid dehydrogenase type 1 as a promising therapeutic target

Chronically elevated glucocorticoid levels cause obesity, diabetes, heart disease, mood disorders and memory impairments. 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyses intracellular regeneration of active glucocorticoids (cortisol, corticosterone) from inert 11-keto forms in liver, adipose and brain, amplifying local action. Obese humans and rodents show increased 11ß-HSD1 in adipose tissue. Transgenic mice overexpressing 11ß-HSD1 selectively in adipose tissue faithfully recapitulate metabolic syndrome. Conversely, 11ß-HSD1 knockout mice have a ‘cardioprotective’ phenotype, whose effects are also seen with 11ß-HSD1 inhibitors in rodents. However, any major metabolic effects of 11ß-HSD1 inhibition in humans are, as yet, unreported. 11ß-HSD1 null mice also resist congitive decline with ageing, and this is seen in humans with a prototypic inhibitor. Thus 11ß-HSD1 inhibition is an emerging pleiotropic therapeutic target.