Central obesity, especially visceral obesity, is associated with higher risk for metabolic disease such as Type 2 diabetes. Glucocorticoids (GCs) are powerful regulators of adipose tissue function that modulate fat storage and release, regulate the production of adipokines, and suppress inflammation. GCs promote the preferential accumulation of visceral (e.g. Omental (Om)) adipose tissue, and also increase abdominal subcutaneous (Abdsc) adipose tissue. To elucidate mechanisms by which GCs regulate fat distribution and function of human adipose tissues, we tested its long-term effects using an organ culture system. The results indicated that GCs regulate ~30% of all genes, and that the dose-dependent and magnitude of the response was highly depot dependent. In addition to genes that regulate metabolic pathways, GCs caused clear changes in the expression of genes in the transforming growth factor beta (TGF) pathway. The TGF superfamily includes many secreted factors, including TGFb1 and 3, activin A (INHBA) that are known to regulate adipogenesis. This pathway was of interest because the ability to recruit new adipocytes from adipose stem cells (ASCs) within the tissues prevents excessive hypertrophy of existing adipocytes, and thereby preserves the normal metabolic and endocrine functions of the adipose tissues that are essential for metabolic health. Paradoxically, compared to Abdsc ASCs, Om ASCs differentiate poorly. New preliminary data show that expression of anti-adipogenic factors including INHBA is higher in Om. GCs shifted the balance to favor adipogenesis, but Om was less sensitive to these effects. Consistent with this model, net TGF pathway signaling (indicated by the activation of SMAD2) was increased in Om ASCs, in proportional to differentiation degree under standard conditions, and conditioned media from Om adipose tissue or ASC inhibited differentiation of Abdsc ASCs. The goal of this proposal is elucidate the molecular and cellular mechanisms that regulate depot-dependent adipose tissue growth and metabolism. We will address three Specific Aims: 1) To determine the importance of TGF pathway in mediating depot differences in adipogenesis, 2) To test the hypothesis that GC-TGF crosstalk modulates depot-dependent gene expression, adipogenesis and adipocyte function, and 3) To elucidate mechanisms by which mild, chronic hypercortisolemia modulates human adipose tissue function in vivo. Collectively, this work may lead to the identification of therapeutic targets downstream o GR to treat or prevent abdominal obesity and its metabolic consequences.

Public Health Relevance

Obesity increases risk for many chronic diseases, including type 2 diabetes, and thus is a major public health problem. People who store more fat inside the abdomen are at greater risk for obesity-related diseases. This proposal will lead to a deeper understanding of how fat distribution is controlled.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080448-10
Application #
9458713
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Haft, Carol R
Project Start
2007-12-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Fried, Susan K (2017) Adipocyte size redux. Obesity (Silver Spring) 25:15
Karastergiou, Kalypso; Bredella, Miriam A; Lee, Mi-Jeong et al. (2016) Growth hormone receptor expression in human gluteal versus abdominal subcutaneous adipose tissue: Association with body shape. Obesity (Silver Spring) 24:1090-1096
Pickering, R Taylor; Lee, Mi-Jeong; Karastergiou, Kalypso et al. (2016) Depot Dependent Effects of Dexamethasone on Gene Expression in Human Omental and Abdominal Subcutaneous Adipose Tissues from Obese Women. PLoS One 11:e0167337
Lee, Mi-Jeong; Yang, Rong-Ze; Karastergiou, Kalypso et al. (2016) Low expression of the GILZ may contribute to adipose inflammation and altered adipokine production in human obesity. J Lipid Res 57:1256-63
Jang, Hyeran; Bhasin, Shalender; Guarneri, Tyler et al. (2015) The Effects of a Single Developmentally Entrained Pulse of Testosterone in Female Neonatal Mice on Reproductive and Metabolic Functions in Adult Life. Endocrinology 156:3737-46
Fried, Susan K; Lee, Mi-Jeong; Karastergiou, Kalypso (2015) Shaping fat distribution: New insights into the molecular determinants of depot- and sex-dependent adipose biology. Obesity (Silver Spring) 23:1345-52
Lee, M-J; Fried, S K (2014) The glucocorticoid receptor, not the mineralocorticoid receptor, plays the dominant role in adipogenesis and adipokine production in human adipocytes. Int J Obes (Lond) 38:1228-33
Lee, Mi-Jeong; Pramyothin, Pornpoj; Karastergiou, Kalypso et al. (2014) Deconstructing the roles of glucocorticoids in adipose tissue biology and the development of central obesity. Biochim Biophys Acta 1842:473-81
Lee, Mi-Jeong; Fried, Susan K (2014) Optimal protocol for the differentiation and metabolic analysis of human adipose stromal cells. Methods Enzymol 538:49-65
Lee, M-J; Fried, S K (2014) Reply to Armani et al. Can cortisol stimulate adipogenesis without the glucocorticoid receptor? Int J Obes (Lond) 38:1578-9

Showing the most recent 10 out of 20 publications