In the pathogenesis of obesity, dysregulated tissue cortisol metabolism (controlled by 11β-HSD1), is postulated to be involved. Fifteen patients (seven mens, mean BMI 50.8±7 kg/m2) awaiting Roux En Y gastric Bypass (RYGB) surgery underwent assessment of 11β-HSD1 activity using cortisol generation profile. Corticosteroids in serum and subcutaneous adipose tissue microdialysis fluid and urinary corticosteroid metabolites were analysed by liquid and gas chromatography mass spectrometry. Results were compared to six post op patients and non-obese controls. Mean area under the curve (AUC) for serum cortisol (F) to cortisone (E) ratio (marker of 11β-HSD1 activity) was significantly reduced in pre-op patients compared to post-op patients: 1037±448.9 vs 1656±505.1 units/min (P=0.0045). Subcutaneous adipose tissue Microdialysis fluid showed a threefold reduction in F/E AUC ratio following RYGB surgery: 303.2 vs 103.2 units/min. Total urinary cortisol metabolites (Fm) were significantly raised in severely obese patients compared to non-obese controls; 6602±742 vs 4396±2362 μg/24 h (P=0.026). The ratios of (THF+5αTHF)/THE (marker of 11β-HSD1 activity) and Fm/Em were not significantly different. The ratios of androsterone/etiocholanolone and 5′ tetrahydrocortisol/5α tetrahydrocortisol (markers of 5α reductase activity) were not significantly different. In this obese cohort, there is evidence of hypothalamicpituitaryadrenal axis activation as reflected by increased total cortisol metabolites, driven by decreased hepatic 11β-HSD1 generation of cortisol. Global urine metabolites are not different reflecting possible up regulation of 11β-HSD1 in adipose tissue and muscle, and down regulation in liver. This may reflect a protective mechanism to reduce hepatic cortisol exposure.
Declaration of funding: Newman fellowship, UCD, Dublin.