Endocrine Abstracts

The global epidemic of obesity has heightened the need to understand the mechanisms that underpin its pathogenesis. Clinical observations in patients with Cushing's syndrome have highlighted the link between cortisol and central obesity. However, whilst circulating cortisol levels are normal or reduced in obesity, local regeneration of cortisol, from inactive cortisone, by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been postulated as a pathogenic mechanism. Whilst adipose tissue over expression in human obesity has not been clearly demonstrated, global inhibition of 11beta-HSD1 using carbenoxolone improves insulin sensitivity.
12 obese patients (6 male, BMI 35.9+/-0.9kg/m², mean+/-SE) were commenced on a very low calorie diet (Lipotrim, 425 (female), 559 (male) kcal/day). Detailed characterization of cortisol metabolism and a fat tissue biopsy were performed before and after weight loss.
All patients achieved significant weight loss (14.1+/-1.3% of initial body weight). Total fat mass fell from 41.8+/-1.9 to 32.0+/-1.7kg, p<0.0001. In addition, fat free mass decreased (64.4+/-3.4 to 58.9+/-2.9kg, p<0.0001) and systolic blood pressure and total cholesterol also fell (systolic BP: 135+/-5 to 121+/- 5mmHg, p=0.002: total cholesterol: 5.4+/-0.2 to 4.8+/-0.2mmol/l, p=0.01). Proliferation rate in cultured pre-adipocytes did not change (cell divisions over 7 days, 3.7+/-0.3 vs 3.4+/-0.4, p=0.5). Whilst whole adipose tissue 11beta-HSD1 expression as measured using real-time PCR did not alter with weight loss (p=0.11), 11beta-HSD1 in isolated adipocytes increased 3.4 fold (p=0.05). Furthermore, cortisol generation following oral cortisone acetate increased, consistent with increased hepatic 11beta-HSD1 activity (eg. serum cortisol at 240mins; 330+/-63 vs. 488+/-79nmol/l, p=0.008)
Decreased 11beta-HSD1 activity and expression in obesity may act as a compensatory mechanism to enhance insulin sensitivity through a reduction in tissue specific cortisol concentrations. With weight loss, this mechanism is no longer required, resulting in increased adipocyte 11beta-HSD1 expression, and increased cortisol generation. Inhibition of 11beta-HSD1 may therefore be a novel, therapeutic strategy for insulin sensitization.