Obesity, particularly visceral and upper body subcutaneous obesity, is associated with higher risk for obesity-related co-morbidities, including type 2 diabetes and cardiovascular disease. Glucocorticoids (GC) are powerful regulators of fat deposition and fat distribution. Obesity is associated with an increase in local cortisol production within both subcutaneous and visceral adipose tissues. In addition, visceral (omental) adipose tissue is more responsive to GC in vitro, suggesting depot differences in GC action contribute to depot differences in fat cell metabolism and endocrine function. Our preliminary gene array studies show that chronic treatment of human adipose tissue with GCs regulates numerous genes related to metabolism and inflammation in vitro, and identified several potentially important GC targets that could contribute to the depot-specific activation of different gene networks. The relevance of these changes to in vivo physiology and the underlying mechanisms by which GC coordinate the activity of different gene networks that regulate the metabolic and endocrine functions of the adipocyte remain unclear. Thus, Specific Aim 1 of the current proposal will focus on identifying the genes in abdominal subcutaneous adipose tissue that are regulated by glucocorticoids in vivo. Because GC effects depend on nutritional state/insulin, we will compare the effects of hydrocortisone administered in the fasted state or in combination with meals, on global gene expression (Affymatrix gene arrays). Adipose tissue will be sampled 3.5h after hydrocortisone administration (with or without a meal) to determine primary GC target genes. To elucidate the mechanisms underlying the differential effects of GC in visceral fat, Specific Aim 2 will compare GC-regulated gene expression in organ cultures of Abd sc and omental adipose tissue and primary adipocytes in vitro using a candidate gene approach.
Specific Aim 3 will test the functional importance of apparent primary GC targets at the level of the adipocyte with analysis of alterations in the expression of downstream targets using analysis of candidate genes and gene arrays, and functional changes in adipocyte metabolism and adipokine secretion. Collectively, these data will enhance understanding of the mechanisms by which GC promote obesity, particularly visceral fat deposition, by pointing to novel targets for therapeutic intervention for visceral obesity and its metabolic complications.

Public Health Relevance

The `diabesity'epidemic and its metabolic complications detract from the quality of life of the majority of Americans. Our proposed work addresses the mechanisms by which glucocorticoids, hormones secreted during stress, regulate the amount of fat deposited in human adipose tissues, and whether the fat is mainly deposited in central (abdominal) or peripheral depots and hence contribute to risk for developing diabetes and cardiovascular disease. These data will provide a critical first step to unraveling the complex, pleiotropic effects of GC in human adipose tissues. Furthermore, identifying the key targets of GC action in fat may provide novel insights into the effects of GC in orchestrating the integration of the endocrine, immune and metabolic functions of the adipocyte.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080448-02
Application #
7841944
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Haft, Carol R
Project Start
2009-06-01
Project End
2014-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
2
Fiscal Year
2010
Total Cost
$401,544
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
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

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