ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 25 OC2.7

Depot specific differences in the sensitivity to glucocorticoid and insulin action in human adipose tissue

Laura Gathercole, David Hauton, Stuart Morgan, Iwona Bujalska, Paul Stewart & Jeremy Tomlinson

University of Birmingham, Birmingham, UK.

Intra-abdominal adiposity is associated with insulin resistance and increased cardiovascular morbidity and mortality. Differences in gene expression between omental (om) and subcutaneous (sc) adipose have been described, but molecular mechanisms underpinning differences in adipose biology are not known. Patients with glucocorticoid excess, Cushing’s syndrome, develop a phenotype characterized by central obesity. We have characterized the regulation of lipogenesis by glucocorticoids and insulin in paired om and sc differentiated pre-adipocytes measuring lipogenic gene expression by real-time PCR and 1-[14C]-acetate incorporation into lipid.

Differentiated sc pre-adipocytes had more lipid droplets, increased mRNA expression of lipogenic genes (ACC1 3.2 fold, FAS 10.9 fold, ACC2 17.8 fold, LPL 44.7 fold) and higher 1-[14C]-acetate incorporation than om cells (8.9 fold). However, lipogenesis in om cells was more responsive to insulin stimulation (control (100%): sc 149±22.14%, om 209±1.86%, P<0.05). In the absence of insulin, Dexamethasone (Dex) had no effect on lipogenic gene expression in sc or om cells. However, in the presence of insulin, in both sc and om cells, Dex increased FAS expression, (sc 2.4 fold; om 3 fold) and in om cells only, increased ACC1 expression (1.6 fold). Dex decreased lipogenesis in sc (100% (control), 81.9±3.9% (5 nM), 67.3±4.8% (500 nM)) and om (72.0±5.4% (5 nM), 46.9±5.7% (500 nM)) cells in a dose dependent manner. In sc cells, in the presence of insulin (5 nM), Dex no longer inhibited lipogenesis and did not impair insulin-stimulated lipogenesis (100% (control), 149.0±22.1% (No Dex), 145.5±29.4% (5 nM), 128.2±39.3% (500 nM)). In contrast, Dex deceased lipogenesis in om cells in the presence of insulin, reflecting either a persistence of the direct action of Dex, or its ability to induce insulin resistance and limit insulin-stimulated lipogenesis (100% (control), 208.9±1.86 (No Dex), 181.45±11.8% (5 nM), 125.1±12.0% (500 nM)).

Om adipose tissue sensitivity to both glucocorticoids and insulin may drive lipid flux, contributing to the Cushing’s phenotype and may also help to explain the detrimental impact of om fat accumulation.

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