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, although circulating
cortisol levels are normal or reduced in
obesity, local regeneration of
cortisol, from inactive
cortisone, by
11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) has been postulated as a pathogenic mechanism. Although levels of expression of 11betaHSD1 in adipose tissue in human
obesity are debated in the literature, global inhibition of 11betaHSD1 improves
insulin sensitivity. We have determined the effects of significant
weight loss on
cortisol metabolism and adipose tissue 11betaHSD1 expression after 10-wk ingestion of a very
low calorie diet in 12 obese patients (six men and six women; body mass index, 35.9 +/- 0.9 kg/m2; mean +/- SE). 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 +/- 1.7 kg (P < 0.0001). In addition, fat-free mass decreased (64.4 +/- 3.4 to 58.9 +/- 2.9 kg; P < 0.0001) and systolic blood pressure and total
cholesterol also fell [systolic blood pressure, 135 +/- 5 to 121 +/- 5 mm Hg (P < 0.01); total
cholesterol, 5.4 +/- 0.2 to 4.8 +/- 0.2 mmol/liter (P < 0.05)]. The serum
cortisol/
cortisone ratio increased after
weight loss (P < 0.01). 11betaHSD1
mRNA expression in isolated adipocytes increased 3.4-fold (P < 0.05). Decreased 11betaHSD1 activity and expression in
obesity may act as a compensatory mechanism to enhance
insulin sensitivity through a reduction in tissue-specific
cortisol concentrations. Inhibition of 11betaHSD1 may therefore be a novel, therapeutic strategy for
insulin sensitization.