Endocrine Abstracts

The central obese phenotype characteristic of Cushing's syndrome emphasises the role of glucocorticoids (GC) in regulating adipose tissue mass and distribution. We have shown that GCs stimulate adipocyte differentiation, but equally inhibit adipose stromal cell (ASC) proliferation. These effects are regulated at a pre-receptor level through 11beta-hydroxysteroid dehydrogenase type 1, but the 'post-receptor' signalling pathways remain unclear. To define novel GC targets in human obesity, high density oligonucleotide Affymetrix HG U133 microarrays were used to profile gene expression in human adipose tissue from subcutaneous (sc) and omental (om) sites, and separately from primary cultures of human sc and om ASC before and after 24 hours culture with 100nM cortisol. The expression level of over 33,000 transcripts was analysed using Affymetrix Data Mining Tool software and NetAffx Analysis Centre. 163 gene products showed a >2-fold increase in om tissue compared to sc whole adipose tissue (p<0.001). These comprised mediators of apoptosis (e.g. tumour necrosis factor, member 14, death-associated protein kinase 1), cellular proliferation and differentiation (retinoic acid receptor responder 3, tissue inhibitor of metalloproteinase), cytoskeletal (laminin, beta 1) and steroid and prostaglandin metabolising enzymes. 32 transcripts showed a 2-fold reduction in om vs sc adipose tissue including leptin, apolipoprotein C-I, the alpha2 adrenergic receptor and 3alpha-HSD type II.
32 gene products were up-regulated and 38 down-regulated by GC in om ASC but not in sc ASC. Induced gene products included HSD11B1 (encoding 11beta-HSD1), TGF-betaII receptor and PI-3-kinase regulatory subunit. LIF, a MAP kinase regulator (RGS4) and G-protein-coupled receptor 48 (GPR48) were down-regulated gene products. GPR48 is expressed in human pancreas, kidney, ovary and heart and is an orphan G-protein-cAMP coupled receptor.
We have identified several novel gene products that may underpin omental versus subcutaneous adiposity. Studies of the regulation of expression of these putative GC target genes in both depots will further our understanding of GC induced obesity.