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Weight Loss Increases 11ß-Hydroxysteroid Dehydrogenase Type 1 Expression in Human Adipose Tissue

Division of Medical Sciences, Queen Elizabeth Hospital, University of Birmingham (J.W.T., J.S.M., P.M.S.), Birmingham, United Kingdom B15 2TH; and Regional Endocrine Laboratory, Department of Clinical Biochemistry, University Hospital Birmingham National Health Service Trust (P.M.S.C., G.H., L.S.), Birmingham, United Kingdom B29 6JD

Address all correspondence and requests for reprints to: Dr. Paul M. Stewart, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom B15 2TH. E-mail: p.m.stewart{at}bham.ac.uk.

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 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) has been postulated as a pathogenic mechanism. Although levels of expression of 11ßHSD1 in adipose tissue in human obesity are debated in the literature, global inhibition of 11ßHSD1 improves insulin sensitivity. We have determined the effects of significant weight loss on cortisol metabolism and adipose tissue 11ßHSD1 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). 11ßHSD1 mRNA expression in isolated adipocytes increased 3.4-fold (P < 0.05). Decreased 11ßHSD1 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 11ßHSD1 may therefore be a novel, therapeutic strategy for insulin sensitization.

Abbreviations: BMI, Body mass index; CBG, cortisol-binding globulin; HOMA, homeostasis model assessment; 11ßHSD1, 11ß-hydroxysteroid dehydrogenase type 1; THE, tetrahydrocortisone; THF, tetrahydrocortisol.

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