Several enzymes are expressed in adipose tissue which catalyse interconversion of steroids, generating oestrogens (aromatase), androgens (5α-reductase 1), and glucocorticoids (11β-HSD1). These steroids may activate local receptors which influence body fat accumulation and distribution, or be secreted to exert endocrine effects. Several mouse models (e.g. aromatase and 11β-HSD1 knockout mice and studies with 11β-HSD1 inhibitors) illustrate the potential importance of these enzymes in obesity and its metabolic complications. However, in human adipose tissue the magnitude of local steroid generation, the role of these enzymes in dynamic regulation of energy balance, and their importance in obesity all remain uncertain.
We have quantified the generation of cortisol from cortisone by 11β-HSD1 in human adipose tissue in vivo using stable isotope tracers and in vivo microdialysis. These studies suggest that extra-adrenal cortisol generation is substantial, with similar contributions from liver and adipose tissue. Moreover, in obesity, increases in 11β-HSD1 transcript levels and activity in biopsied adipose tissue in vitro are accompanied by increased in vivo generation of cortisol. Further, polymorphisms in 11β-HSD1 predict the metabolic consequences of obesity. In addition, evidence is emerging that 11β-HSD1 in human adipose is under dynamic control in vivo, including by acute changes in insulin and fatty acids, and by chronic changes in dietary fat and PPAR activation.
These observations suggest that 11β-HSD1 within adipose tissue plays a pivotal role in adjusting glucocorticoid receptor activation. However, neither the effects of glucocorticoids on body fat nor the regulation of 11β-HSD1 are identical in humans and rodents, and any interplay between steroid metabolising enzymes in vivo remains largely unexplored. The development of tools to quantify steroid interconversion in vivo, and the advent of enzyme inhibitors, is therefore a beginning rather than an end in understanding the intracrinology of adipose tissue in humans.
06 - 07 Nov 2006
Society for Endocrinology