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Highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV) is associated with a poorly understood lipodystrophic and hypertriglyceridaemic syndrome, which resembles Cushing's syndrome, but in which plasma cortisol is not elevated. We tested the hypothesis that this HAART-associated lipodystrophy is explained by increased local regeneration of cortisol from inactive cortisone within adipose tissue, catalysed by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1).In this cross-sectional study, a previously described cohort of 30 HIV-infected patients with lipodystrophy were compared with 13 HIV-infected patients without lipodystrophy. Intra-abdominal and subcutaneous adipose tissue were quantified using magnetic resonance imaging. Gene expression in subcutaneous fat was measured using real-time PCR. Urine cortisol and its metabolites were analysed by gas chromatography/mass spectrometry.Patients with lipodystrophy had significantly higher 11β-HSD1 mRNA concentrations (relative to β2-microglobulin mRNA) in subcutaneous adipose tissue than non-lipodystrophic patients (0.29±0.20 vs 0.09±0.07, p=0.0004) and higher ratios of urinary cortisol:cortisone metabolites. Adipose tissue 11β-HSD1 mRNA correlated with multiple features of insulin resistance and with mRNA concentrations for glucocorticoid receptor and angiotensinogen.In adipose tissue of patients with HAART-associated lipodystrophy, 11β-HSD1 mRNA is increased and its concentration is correlated with features of insulin resistance. We suggest that increased adipose tissue 11β-HSD1 may explain the pseudo-Cushing's features in patients with HAART-associated lipodystrophy, and is a potential therapeutic target.