Tissue-specific dysregulation of cortisol metabolism in human obesity

Cortisol has been implicated as a pathophysiological mediator in idiopathic obesity, but circulating cortisol concentrations are not consistently elev ated. The tissue-specific responses to cortisol may be influenced as much b y local pre-receptor metabolism as by circulating concentrations. For examp le, in liver and adipose tissue cortisol is regenerated from inactive corti sone by 11 beta -hydroxysteroid dehydrogenase type 1 (11 beta -HSD1). In ob ese Zucker rats 11 beta -HSD1 activity is reduced in liver but enhanced in adipose tissue. This study addressed whether the same tissue-specific disru ption of cortisol metabolism occurs in human obesity. 34 men were recruited from the MONICA population study in Northern Sweden to represent a wide ra nge of body composition and insulin sensitivity. Plasma cortisol was measur ed at 0830h and 1230h, after overnight low-dose dexamethasone suppression, after intravenous corticotropin releasing hormone (CRH), and after oral cor tisone administration. Urinary cortisol metabolites were measured in a 24 h sample. A subcutaneous fat biopsy was obtained from le participants to mea sure cortisol metabolism in vitro. Higher body mass index was associated wi th increased total cortisol metabolite excretion (r=0.47, p<0.01), but lowe r plasma cortisol at 1230 h and after dexamethasone, and no difference in r esponse to CRH. Obese men excreted a greater proportion of glucocorticoid a s metabolites of cortisone rather than cortisol (r=0.43, p<0.02), and conve rted less cortisone to cortisol after oral administration (r=-0.49, p<0.01) , suggesting impaired hepatic 11<beta>-HSD1 activity. By contrast, in vitro 11 beta -HSD1 activity in subcutaneous adipose tissue was markedly enhance d in obese men (r=0.66, p<0.01). We conclude that in obesity, reactivation of cortisone to cortisol by 11<beta>-HSD1 in liver is impaired, so that pla sma cortisol levels tend to fall, and there may be a compensatory increase in cortisol secretion mediated by a normally functioning hypothalamic-pitui tary-adrenal axis. However, changes in 11 beta -HSD1 are tissue-specific: s trikingly enhanced reactivation of cortisone to cortisol in subcutaneous ad ipose tissue may exacerbate obesity; and it may be beneficial to inhibit th is enzyme in adipose tissue in obese patients.