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.
Highlights
The mass of visceral fat, defined as those depots located within the abdominal cavity and associated with digestive organs, is associated with risk for type 2 diabetes and cardiovascular disease in both men and women [1]
Studies of mechanisms that lead to depot differences in human adipose tissue biology are especially important
The analyses presented here clearly demonstrate the depot-dependence of GC action on gene expression in human visceral (Om) compared to abdominal subcutaneous (Abdsc) adipose tissues
Summary
The mass of visceral fat, defined as those depots located within the abdominal cavity and associated with digestive organs (i.e. omental and mesenteric), is associated with risk for type 2 diabetes and cardiovascular disease in both men and women [1]. Depot differences in rates of triacylglycerol (TAG) turnover, inflammation and adipocyte cellularity are well documented in humans and mouse models [5,6,7], but the mechanisms that underlie depot-dependent variations in GC action and mechanisms that link the size of this depot to systemic metabolic dysfunction remain incompletely understood. Adipose tissue includes multiple cell types, including preadipocytes, endothelial cells, immune cells and adipocytes, all of which are targeted by GCs [11]. In addition to direct GC actions in each cell type, paracrine and endocrine interactions likely contribute to depot differences in GC actions on gene expression and thereby tissue function. The advantage of organ culture in this context is that this system provides a physiologically relevant three dimensional context for the analysis of human adipose tissue hormone action and comparison of depot differences
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