Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2009) 19 OC19

SFEBES2009 Oral Communications Cardiovascular metabolism (8 abstracts)

Glucocorticoid and insulin regulation of lipogenesis in human adipose tissue

L Gathercole , I Buljalska , P Stewart & J Tomlinson


University of Birmingham, Birmingham, UK.


Patients with glucocorticoid (GC) excess, Cushing’s syndrome, develop a classical phenotype characterized by insulin resistance and central obesity. Whilst it is clear that GCs are essential for adipocyte differentiation, their impact upon many of the processes that regulate lipid accumulation has not been explored in detail. De novo lipogenesis involves carboxylation of acetyl CoA to malonyl-CoA by acetyl CoA carboxylase (ACC), which is subsequently converted to palmitate by fatty acid synthase (FAS). In lipogenic tissues the ACC1 isoform predominates and is the key regulatory step of fatty acid synthesis. ACC2 is localized to the mitochondrial membrane, and the malonyl-CoA it produces inhibits β-oxidation. ACC1 and 2 are highly regulated at the level of mRNA expression and protein phosphorylation. We have therefore characterized the regulation of lipogenesis across differentiation and by glucocorticoids and insulin in the subcutaneous cell line Chub-s7, measuring lipogenic gene and protein expression and basal and insulin stimulated 1-[14C]-acetate incorporation into lipid.

ACC expression increased across differentiation, and insulin increased ACC activity in undifferentiated (412±44 vs 662±93 (5 nM), P<0.05) and differentiated adipocytes (5351±304 vs 11250±880 (5 nM), P<0.05). In differentiated cells Dexamethasone (Dex) increased mRNA expression of FAS (2.2 fold, 10.1±0.4 vs 9.18±0.67 P<0.05) and ACC2 (3.4 fold, 14.3±0.52 vs 12.8±0.76 (Dex 0.5 μM), P<0.01) but not ACC1. Endorsing these findings, ACC1/2 protein expression increased (3.2 fold, P<0.05) as did inactivating serine phosphorylation. Dex alone decreased 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 the ability of insulin to promote lipid accumulation (33.9±10.1% (5 nM ins) vs 106±25.5% (5 nM ins+Dex 5 nM), P<0.05).

We have described a novel interaction between insulin and glucocorticoids in the regulation of lipid accumulation within human adipocytes. This may be important in explaining the clinical impact of endogenous and exogenous GC excess.

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