Endocrine Abstracts

Patients with glucocorticoid excess develop a phenotype characterized by central obesity, however, the impact of glucocorticoids upon the processes that regulate lipid accumulation has not been fully explored. We hypothesize that intracellular generation of cortisol from cortisone by 11b-hydroxysteroid dehydrogenase type 1 (11bHSD1) is an important regulator of lipid metabolism.

In adipocytes, acetyl-CoA carboxylase 1 and 2 (ACC1/2) convert acetyl-CoA to malonyl-CoA. ACC1 predominates and is the rate-limiting step in lipogenesis. ACC2 is localized to the mitochondrial membrane, and the malonyl-CoA generated inhibits β-oxidation. Using a human subcutaneous cell line, Chub-s7, we characterized the expression of ACC1/2 and the regulation of lipogenesis (1-[14C]acetate incorporation) and β-oxidation ([3H]-palmitate oxidation) across differentiation and determined the influence of glucocorticoids and insulin.

Across differentiation ACC1 and ACC2 mRNA expression increased (ACC1, 2.3-fold, P<0.05; ACC2, 42.2-fold, P<0.05), as did total ACC protein (3.2-fold, P<0.05). Basal and insulin stimulated ACC1 activity also increased (Undifferentiated (d.p.m.) 412±44 vs 662±93 (5 nM ins), P<0.05, Differentiated 5351±304 vs 11250±880 (5 nM ins), P<0.05) whereas β-oxidation decreased (13.6-fold, P<0.05). In differentiated cells Dexamethasone (Dex) (0.5 uM) increased ACC2 mRNA expression (2.8-fold, P<0.01) but not ACC1, total ACC protein increased (3.0-fold, P<0.05). Dex decreased basal ACC activity in a dose dependent manner (76.8±7.8% (5 nM), 60.3±3.2% (500 nM), P<0.05). However, low dose Dex enhanced insulin stimulated lipid accumulation (33.9±10.1% (5 nM ins) vs 106±25.5% (5 nM ins, Dex 5 nM), P<0.05). Dex treatment had no effect upon β-oxidation. Cortisone decreased basal ACC activity and this was recovered with the selective 11bHSD1 inhibitor PF877423 (77.4±1.6% (cortisone 500 nM), 144.2±18.6% (PF877423+ cortisone), vs PF877423).

We have described a novel interaction between insulin and glucocorticoids in the regulation of lipid accumulation within human adipocytes. These data also demonstrate the importance of pre-receptor glucocorticoid metabolism in the regulation of adipocyte lipid metabolism.