Depot Dependent Effects of Dexamethasone on Gene Expression in Human Omental and Abdominal Subcutaneous Adipose Tissues from Obese Women

Abstract

Glucocorticoids promote fat accumulation in visceral compared to subcutaneous depots, but the molecular mechanisms involved remain poorly understood. To identify long-term changes in gene expression that are differentially sensitive or responsive to glucocorticoids in these depots, paired samples of human omental (Om) and abdominal subcutaneous (Abdsc) adipose tissues obtained from obese women during elective surgery were cultured with the glucocorticoid receptor agonist dexamethasone (Dex, 0, 1, 10, 25 and 1000 nM) for 7 days. Dex regulated 32% of the 19,741 genes on the array, while 53% differed by Depot and 2.5% exhibited a Depot*Dex concentration interaction. Gene set enrichment analysis showed Dex regulation of the expected metabolic and inflammatory pathways in both depots. Cluster analysis of the 460 transcripts that exhibited an interaction of Depot and Dex concentration revealed sets of mRNAs for which the responses to Dex differed in magnitude, sensitivity or direction between the two depots as well as mRNAs that responded to Dex only in one depot. These transcripts were also clearly depot different in fresh adipose tissue and are implicated in processes that could affect adipose tissue distribution or functions (e.g. adipogenesis, triacylglycerol synthesis and storage, insulin action). Elucidation of the mechanisms underlying the depot differences in the effect of Dex on the expression of specific genes and pathways that regulate adipose function may offer novel insights into understanding the biology of visceral adipose tissues and their links to metabolic health.

Impaired Glucocorticoid Suppression of TGFβ Signaling in Human Omental Adipose Tissues Limits Adipogenesis and May Promote Fibrosis

“…Hormonal factors such as glucocorticoids also regulate adipogenesis ( 11 , 12 ). We and others have observed depot differences in glucocorticoid actions between human Om and Abdsc adipose tissues ( 13 – 15 ). Therefore, we tested whether differential sensitivity to a glucocorticoid receptor agonist, dexamethasone (Dex), contributes to depot differences in adipogenesis.…”

Differential Regulation of circRNA, miRNA, and piRNA during Early Osteogenic and Chondrogenic Differentiation of Human Mesenchymal Stromal Cells

“…The protein encoded by FADS2, ∆-6 desaturase, is the rate-limiting enzyme for the synthesis of arachidonic acid from linoleic acid [55,56]. Only a few data have been published correlating glucocorticoids and FADS2 gene expression or protein activity; however, the effect of dexamethasone on FADS2 transcription may be tissue-and context-dependent, while it was suggested to have an inhibitory effect on enzyme activity [55,[57][58][59]. ZEB1 is a transcriptional repressor: it inhibits IL2 gene expression [60] and it is reported as a central component in adipocytic differentiation [61] and for the repression of stemness-inhibiting miRNAs [62].…”

An inhibitor of 11-β hydroxysteroid dehydrogenase type 1 (PF915275) alleviates nonylphenol-induced hyperadrenalism and adiposity in rat and human cells

“…5c ). The commercial PADM used in this study contains dexamethasone 1 μM with insulin 7.5 μg/ml, and dexamethasone combined with insulin dose-dependently upregulated adipogenesis and fat accumulation in cultured adipocytes [ 55 ]; therefore, the NP effect on adipogenic activity was masked by the optimized differentiation medium. PF decreased while NP increased PF-inhibited (PF at 1.5 or 2 μM) lipid accumulation (Fig.…”