© 2007 The Authors 440 Journal compilation © 2007 Blackwell Publishing Ltd ORIGINAL ARTICLE Clinical Endocrinology (2007) 66, 440–446 doi: 10.1111/j.1365-2265.2007.02755.x Blackwell Publishing Ltd Intra-adipose sex steroid metabolism and body fat distribution in idiopathic human obesity Deborah J. Wake*, Magnus Strand†, Eva Rask†, Jukka Westerbacka‡, Dawn E. W. Livingstone*, Stefan Soderberg†, Ruth Andrew*, Hannele Yki-Jarvinen‡, Tommy Olsson† and Brian R. Walker* *Endocrinology Unit, Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Scotland, UK, †Department of Medicine, Umeå University Hospital, Umeå, Sweden, and ‡Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland Summary Objective Causes of visceral fat accumulation include gluco- corticoid excess or decreased oestrogen/androgen ratio either in plasma or within adipose tissue. In obese subjects, the intra-adipose cortisol-generating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is increased, but information on sex steroid signalling is sparse. We aimed to test associations between body fat or fat distribution and mRNA transcript levels for androgen and oestrogen receptors and for enzymes metabolizing sex steroids in adipose tissue. Design A cross-sectional study. Patients Forty-five healthy men and women with body mass index (BMI) 21– 36 kg/m 2 . Measurements In subcutaneous adipose biopsies we measured mRNAs for enzymes metabolizing local oestrogens (aromatase) and androgens [5α-reductase type 1; AKR1C2 (3α-HSD3); AKR1C3 (17β-HSD5, 3α-HSD2)] and for sex steroid receptors [oestrogen receptor (ER)-α and androgen receptor (AR)]. We related these to body fat mass and distribution. Results Generalized obesity (BMI) was associated with increased aromatase mRNA (r = 0·35, P < 0·05). Central obesity (waist : hip ratio) was associated with mRNA for AKR1C2 (r = 0·28, P < 0·05) and AKR1C3 (r = 0·38, P < 0·01) but not aromatase (r = 0·06). 5α- Reductase type 1, ER and AR mRNA levels did not predict fat amount or its distribution. Conclusion These data on transcript levels suggest that, in idiopathic obesity, increased intra-adipose oestrogen generation by aromatase predicts peripheral fat distribution, while androgen metabolism by AKR1C isoforms predicts central fat distribution, supporting the hypothesis that intra-adipose sex steroid metabolism is a determinant of gynoid vs. android patterns of body fat. (Received 11 September 2006; returned for revision 25 October 2006; finally revised 31 October 2006; accepted 1 November 2006) Introduction Sex steroids (androgens and oestrogens) play important roles in determining body fat mass and its distribution, as is evident from predisposition to ‘central’ (‘abdominal’ or ‘android’) obesity in men and ‘peripheral’ (‘gynoid’) obesity in women. In both sexes central obesity is associated with adverse metabolic effects and increased cardiovascular risk 1 and it has been suggested that it reflects a pre- dominance of androgen action over that of oestrogen. 2 Circulating androgen levels are higher in women 3 but are lower in men 4–6 with central obesity. Circulating oestrogen levels are positively associated with body mass index (BMI) in post-menopausal women, 7 in men 8,9 and children. 10,11 However, circulating levels of steroid may not accur- ately measure tissue sex steroid action, which is also controlled by receptor density and by local steroid-metabolizing enzymes. Oestrogen receptors (ER-α and ER-β) 12,13 and androgen receptors (ARs) are present in human adipose tissue, and regional variations in AR expression 14 may explain preferential central fat accumulation. Obesity occurs in ER-α knockout mice, 15,16 and in humans obesity is associated with polymorphisms in AR and ER genes. 17,18 However, whether variations in sex steroid receptor expression in adipose tissue are important in determining variations in body fat and its distribution in the normal population is largely unexplored. Steroid-metabolizing enzymes control tissue steroid concentrations and hence ligand availability for intracellular receptors (sum- marized in Fig. 1). It is now widely recognized that increased 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1) expression in subcutaneous adipose tissue in obesity, which predicts increased local regeneration of cortisol from inert cortisone, may amplify glucocorticoid receptor (GR) activation and hence the metabolic complications of obesity. 19–21 Sex steroid metabolism is similarly modulated within target tissues by enzymes. 22 Intra-adipose aromatase modulates the conversion of androgens to oestrogens (androstenedione to oestrone, and testosterone to oestradiol). Aromatase deficiency in humans 23 and in mice 24,25 results in Correspondence: Professor Brian R. Walker, Endocrinology Unit, Centre for Cardiovascular Science, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK. Tel.: + 44 (0)131 242 6770; Fax: + 44 (0)131 242 6779; E-mail: b.walker@ed.ac.uk