Glucocorticoids Turn Over Slowly in Human Adipose Tissue in Vivo

摘要

Context: Lipophilic plasma glucocorticoids are thought to gain rapid access to intracellular compartments in adipose tissue. In other organs, transport can be regulated in a steroid- and tissue-specific manner. Moreover, 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) generates additional cortisol within adipose.Aim: The aim was to measure the rate of exchange of cortisol between plasma and adipose for comparison with rates of intracellular cortisol generation by 11βHSD1.Participants and Interventions: With ethical approval, otherwise healthy females (n = 6) undergoing hysterectomy for benign indications were infused with tracer 9,11,12,12-[~(2)H]_(4)cortisol (d4-cortisol). Adipose biopsies and peripheral venous samples were obtained during surgery after 3.9–5.5 h of infusion. Glucocorticoids were quantified using liquid chromatography tandem mass spectrometry.Results: In plasma, d4-cortisol concentrations and appearance rates of cortisol and d3-cortisol (reflecting 11βHSD1 activity) did not change during surgery. In both omental and sc adipose, cortisol concentrations were lower than in plasma, consistent with differences in corticosteroid binding globulin, and enrichment with d4-cortisol was low (sc, 7.2 ± 0.6%; omental, 7.4 ± 0.7%; vs . plasma, 15.5 ± 1.0%). The rate of accumulation of d4-cortisol in adipose depots was 0.5 ± 0.1 (sc) and 0.4 ± 0.1 (omental) nmol/kg · h, and the proportion of intraadipose cortisol replaced each hour only 10.7 ± 1.0 and 10.4 ± 0.7%, respectively. The contribution of 11βHSD1 to this turnover could not be quantified because very little substrate d3-cortisone accumulated in adipose during infusion.Conclusions: Slow turnover of the adipose glucocorticoid pool suggests that rapid acute fluctuations in circulating cortisol are not reflected in adipose, so that 11βHSD1 activity (previously estimated to generate 9 nmol cortisol/kg · h in sc adipose) may play a relatively important role in modulating activation of glucocorticoid receptors.