Endocrine Abstracts

Central obesity is associated with increased morbidity and mortality. Pre-adipocyte proliferation and differentiation contribute to increases in adipose tissue mass, yet the mechanisms that underpin these processes remain unclear. Patients with glucocorticoid excess develop central obesity, but circulating cortisol levels in idiopathic obesity are normal. The enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts inactive cortisone (E) to active cortisol (F), thereby regulating the availability of cortisol to bind to the glucocorticoid receptor (GR).

Paired omental (om) and subcutaneous (sc) fat biopsies were obtained from 32 women (age 44±1.7 years, BMI 28.2±0.8kg/m²,mean±S.E.) undergoing elective abdominal surgery. 11beta-HSD1 activity and expression was assessed in whole tissue and isolated pre-adipocytes using specific enzyme assays and real-time PCR. Pre-adipocyte proliferation was measured using tritiated thymidine incorporation.

Whole tissue expression of 11beta-HSD1 did not differ between om and sc samples (p=0.85), or vary with BMI (om p=0.27, sc p=0.53, obese [n=11] vs non-obese [n=21]). Activity and expression of 11b-HSD1 was significantly higher in cultured omental pre-adipocytes (44.5±7.8 (mean±S.E.) vs 10.7±1.9 pmol F/mg prot/hr, om vs sc p<0.0001, 4.8 fold increase in om 11beta-HSD1 expression, p<0.001). Furthermore, in omental pre-adipocytes 11beta-HSD1 activity inversely correlated with BMI (R=-0.47, p=0.03), activity was lower in obese patients (28.3±4.1 vs 57.7±10.0 pmol F/mg prot/hr, obese vs non-obese p=0.04). Regulation was at a transcriptional level (1.9 fold increase in 11beta-HSD1 mRNA expression in non-obese, p=0.058). In omental pre-adipocytes, cortisol decreased proliferation (68.2±9.2% vs control (100%), n=6, p<0.005). Inhibition of 11beta-HSD1 with glycyrrhetinic acid (GE) reduced cortisone induced inhibition of pre-adipocyte proliferation (61.4±3.3% [E] vs. 77.6±2.1% (E+GE), p<0.05)

Inhibition of 11beta-HSD1 in omental pre-adipocytes in obesity limits the availability of cortisol to bind to GR and enhances pre-adipocyte proliferation. This mechanism is likely to be crucial in the pathogenesis of central obesity.