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Pathways regulated by glucocorticoids in omental and subcutaneous human adipose tissues: a microarray study.

ABSTRACT: Glucocorticoids (GC) are powerful regulators of adipocyte differentiation, metabolism, and endocrine function and promote the development of upper body obesity, especially visceral fat stores. To provide a comprehensive understanding of how GC affect adipose tissue and adipocyte function, we analyzed patterns of gene expression (HG U95 Affymetrix arrays) after culture of abdominal subcutaneous (Abd sc) and omental (Om) adipose tissues from severely obese subjects (3 F, 1 M) in the presence of insulin or insulin (7 nM) plus dexamethasone (Dex, 25 nM) for 7 days. About 20% (561 genes in Om and 569 genes in sc) of 2,803 adipose expressed genes were affected by long-term GC. While most of the genes (90%) were commonly regulated by Dex in both depots, 26 in Om and 34 in Abd sc were affected by Dex in only one depot. 60% of the commonly upregulated genes were involved in metabolic pathways and were expressed mainly in adipocytes. Dex suppressed genes in immune/inflammatory (IL-6, IL-8, and MCP-1, expressed in nonadipocytes) and proapoptotic pathways, yet induced genes related to the acute-phase response (SAA, factor D, haptoglobin, and RBP4, expressed in adipocytes) and stress/defense response. Functional classification analysis showed that Dex also induced expression levels of 22 transcription factors related to insulin action and lipogenesis (LXR?, STAT5?, SREBP1, and FoxO1) and immunity/adipogenesis (TSC22D3) while suppressing 17 transcription factors in both depots. Overall, these studies reveal the powerful effects of GC on gene networks that regulate many key functions in human adipose tissue.

SUBMITTER: Lee MJ

PROVIDER: S-EPMC3279304 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Pathways regulated by glucocorticoids in omental and subcutaneous human adipose tissues: a microarray study.

Lee Mi-Jeong MJ Gong Da-Wei DW Burkey Bryan F BF Fried Susan K SK

American journal of physiology. Endocrinology and metabolism 20101228 3

Glucocorticoids (GC) are powerful regulators of adipocyte differentiation, metabolism, and endocrine function and promote the development of upper body obesity, especially visceral fat stores. To provide a comprehensive understanding of how GC affect adipose tissue and adipocyte function, we analyzed patterns of gene expression (HG U95 Affymetrix arrays) after culture of abdominal subcutaneous (Abd sc) and omental (Om) adipose tissues from severely obese subjects (3 F, 1 M) in the presence of in ...[more]

PMID: 21189358

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Project description:Adipose tissue is a dynamic regulatory organ that has profound effects on the overall health of patients. Unfortunately, inconsistencies in human adipose tissues are extensive and multifactorial, including large variability in cellular sizes, lipid content, inflammation, extracellular matrix components, mechanics, and cytokines secreted. Given the high human variability, and since much of what is known about adipose tissue is from animal models, we sought to establish correlations and patterns between biological, mechanical, and epidemiological properties of human adipose tissues. To do this, twenty-six independent variables were cataloged for twenty patients, which included patient demographics and factors that drive health, obesity, and fibrosis. A factorial analysis for mixed data (FAMD) was used to analyze patterns in the dataset (with BMI > 25), and a correlation matrix was used to identify interactions between quantitative variables. Vascular endothelial growth factor A (VEGFA) and actin alpha 2, smooth muscle (ACTA2) gene expression were the highest loadings in the first two dimensions of the FAMD. The number of adipocytes was also a key driver of patient-related differences, where a decrease in the density of adipocytes was associated with aging. Aging was also correlated with a decrease in overall lipid percentage of subcutaneous tissue, with lipid deposition being favored extracellularly, an increase in transforming growth factor-β1 (TGFβ1), and an increase in M1 macrophage polarization. An important finding was that self-identified race contributed to variance between patients in this study, where Black patients had significantly lower gene expression levels of TGFβ1 and ACTA2. This finding supports the urgent need to account for patient ancestry in biomedical research to develop better therapeutic strategies for all patients. Another important finding was that TGFβ induced factor homeobox 1 (TGIF1), an understudied signaling molecule, which is highly correlated with leptin signaling, was correlated with metabolic inflammation. Furthermore, this study draws attention to what we define as "extracellular lipid droplets", which were consistently found in collagen-rich regions of the obese adipose tissues evaluated here. Reduced levels of TGIF1 were correlated with higher numbers of extracellular lipid droplets and an inability to suppress fibrotic changes in adipose tissue. Finally, this study indicated that M1 and M2 macrophage markers were correlated with each other and leptin in patients with a BMI > 25. This finding supports growing evidence that macrophage polarization in obesity involves a complex, interconnecting network system rather than a full switch in activation patterns from M2 to M1 with increasing body mass. Overall, this study reinforces key findings in animal studies and identifies important areas for future research, where human and animal studies are divergent. Understanding key drivers of human patient variability is required to unravel the complex metabolic health of unique patients.

Dataset Information

Pathways regulated by glucocorticoids in omental and subcutaneous human adipose tissues: a microarray study.

Publications

Pathways regulated by glucocorticoids in omental and subcutaneous human adipose tissues: a microarray study.

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