Pulsatile Delivery of Cortisol Regulates Lipid Storage in Adipocytes in Vitro and Human Adipose Gene Expression in Vivo

Abstract

Glucocorticoids (GC) regulate the distribution and function of human adipose tissue, and their pathophysiological effects are attributed to changes in their concentration. We hypothesized that the diurnal cortisol rhythm contributes to its effects.Microarray analysis and qPCR were used to identify genes with expression changes as circulating cortisol declines between 9:00 and 15:00, in human abdominal subcutaneous adipose tissue of healthy volunteers (n=5). Placebo or a single, physiological dose of cortisol were administered out of phase (11:30) to identify genes with expression changes dependent on the cortisol rhythm. A novel in vitro model was established to study the long‐term effects of pulsatile versus constant GC in human adipocytes.We identified 280 genes significantly upregulated and 292 downregulated from 9:00 to 15:00. Cortisol changed the expression pattern of 191 (33.4%) genes. We verified changes in the clock gene PER1, the GC receptor co‐chaperone FKBP5, and KLF15, a regulator of circadian nitrogen homeostasis. In vitro, pulsatile GC established rhythmic clock gene expression in human adipocytes, led to enlarged lipid droplets and lower basal lipolysis and de novo fatty acid synthesis compared to constant GC.These findings suggest that higher turnover of triglycerides may occur in patients with disrupted glucocorticoid rhythm and contribute to increased cardiometabolic risk.Research support: NIH DK080448, P30 DK046200 and UL1‐TR000157.