Activation of the hypothalamic-pituitary-adrenal axis in obesity: cause or consequence?

Cortisol secretion rate is increased in obesity, but plasma cortisol levels are not consistently elevated. This suggests that the principal abnormality in obesity may relate to enhanced peripheral metabolism. Recent studies have identified enhanced inactivation of cortisol by 5alpha-reductase, and impaired regeneration of cortisol in the liver by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), as possible mediators of this increased cortisol clearance rate in obesity. Most intriguingly, the changes in 11beta-HSD1 are tissue-specific, and generation of cortisol from inactive cortisone appears to be increased in adipose tissue in obesity. Selective inhibition of 11beta-HSD1 provides a novel therapeutic target for lowering intra-adipose cortisol concentrations and effect, without inducing other adverse effects of cortisol deficiency.