Endocrine Abstracts

11HSD1 regenerates cortisol from cortisone and maintains glucocorticoid receptor (GR) activation. Adipose-specific transgenic 11HSD1 overexpression in mice causes obesity, insulin resistance, and hypertension (reflecting increased adipose angiotensinogen); however, the effect depended upon local GR expression. In human obesity, 11HSD1 activity is increased similarly in biopsied adipose, but the impact remains uncertain. We tested whether increased adipose 11HSD1 activity in obesity: is associated with 11HSD1 mRNA, altered GR expression, elevated intra-adipose cortisol, and/or metabolic complications of obesity; and is measured by conventional investigations (urinary cortisol metabolite ratios).
Under ethical approval volunteers (13 male; 14 female) were selected, providing a range of obesity and insulin sensitivity. In vivo measurements included euglycaemic hyperinsulinaemic clamps and 24hr urine cortisol metabolite profile. In subcutaneous abdominal adipose biopsies we analysed mRNAs (real time PCR), in-vitro 11HSD1 activity, and cortisol and cortisone (RIA).
Adipose 11HSD1 activity and mRNA closely correlated with each other (r=0.57, p<0.01) and with obesity and insulin resistance (all p<0.02) but not with blood pressure or urinary cortisol/cortisone metabolites. Intra-adipose cortisol (53-107picamoles per gram) and cortisone (89-195picamoles per gram) did not correlate with 11HSD1 activity or mRNA or with clinical variables. GRalpha was the major GR mRNA isoform; lower levels associated with insulin resistance (p<0.02) but not obesity or blood pressure. Angiotensinogen mRNA levels were higher in females (p<0.03) but not correlated with other parameters.
Thus increased adipose 11HSD1 activity in obesity is attributable to transcriptional up-regulation, not compensated by GR down-regulation, may contribute to insulin resistance, and is inadequately measured by urinary cortisol/cortisone metabolites. Intra-adipose cortisol levels were not measurably affected by 11HSD1, but may reflect stress during biopsy in this study. Unlike mice, increased 11HSD1 in human adipose does not increase angiotensinogen expression or blood pressure. The importance of 11HSD1 in obesity will best be measured by selective inhibition of adipose 11HSD1.