Endocrine Abstracts

Background: Glucocorticoids have pleiotropic metabolic functions and acute glucocorticoid excess causes dramatic disruption of human metabolism. Whether glucocorticoids exert adipose tissue depot-specific effects on the nontargeted metabolome in unknown.

Aim: Assess the nontargeted metabolome in the systemic circulation and in femoral adipose tissue-specific blood samples in response to physiological hyperinsulinaemia and acute hypercortisolaemia.

Methods: Nine healthy male volunteers were studied on two occasions, after a hydrocortisone infusion (0.2 mg/kg per min for 14 h) and a saline infusion, given in randomized double-blind order. The subjects were studied in the fasting state and after a 75-g glucose drink with collection of systemic and femoral adipose tissue-specific plasma samples using the arteriovenous difference technique. Mass spectrometry–based nontargeted plasma metabolome analysis was performed and analysed by applying univariate analysis after normalization to total peak area per sample.

Results: Acute hypercortisolaemia induced significant changes in most classes of metabolites assessed, with similar trends across the systemic and adipose tissue-specific circulation; however, we observed a mean 2.3-fold increase of sphingolipids in the systemic circulation whilst the femoral adipose tissue did not respond to the stimulus. Acute hypercortisolaemia and hyperinsulinaemia had opposite effects on the output of fatty acids, sphingolipids and components of the tyrosine metabolism in the systemic circulation, with a significant increase in the first and a decrease in the second. Acute hypercortisolaemia also promoted increased release of acylcarnitines, fatty acids and oxidised fatty acids from the femoral adipose tissue, with an opposite effect of hyperinsulinaemia following oral glucose load.

Conclusions: We provide first-time evidence that acute hypercortisolaemia induces significant changes in the nontargeted plasma metabolome of the systemic and the femoral adipose tissue circulation. Our observations shed light on the effects of hypercortisolaemia in humans and may point to novel therapeutic targets to counteract the detrimental consequences of cortisol excess.