Patients with
glucocorticoid (GC) excess,
Cushing's syndrome, develop a classic phenotype characterized by
central obesity and
insulin resistance. GCs are known to increase the release of
fatty acids from adipose, by stimulating lipolysis, however, the impact of GCs on the processes that regulate
lipid accumulation has not been explored. Intracellular levels of active GC are dependent upon the activity of 11β-Hydroxysteroid
dehydrogenase type 1 (11β-HSD1) and we have hypothesized that 11β-HSD1 activity can regulate
lipid homeostasis in human adipose tissue (Chub-S7 cell line and primary cultures of human subcutaneous (sc) and omental (om) adipocytes. Across adipocyte differentiation, lipogenesis increased whilst β-oxidation decreased. GC treatment decreased lipogenesis but did not alter rates of β-oxidation in Chub-S7 cells, whilst
insulin increased lipogenesis in all adipocyte cell models. Low dose
Dexamethasone pre-treatment (5 nM) of Chub-S7 cells augmented the ability of
insulin to stimulate lipogenesis and there was no evidence of adipose tissue
insulin resistance in primary sc cells. Both
cortisol and
cortisone decreased lipogenesis; selective 11β-HSD1 inhibition completely abolished
cortisone-mediated repression of lipogenesis. GCs have potent actions upon
lipid homeostasis and these effects are dependent upon interactions with
insulin. These in vitro data suggest that manipulation of GC availability through selective 11β-HSD1 inhibition modifies
lipid homeostasis in human adipocytes.