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 #
5R01DK080448-04
Application #
8257185
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
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$359,434
Indirect Cost
$146,751
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
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Ding, Shi-Ying; Lee, Mi-Jeong; Summer, Ross et al. (2014) Pleiotropic effects of cavin-1 deficiency on lipid metabolism. J Biol Chem 289:8473-83
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
Karastergiou, Kalypso; Fried, Susan K (2013) Multiple adipose depots increase cardiovascular risk via local and systemic effects. Curr Atheroscler Rep 15:361
Lee, Mi-Jeong; Wu, Yuanyuan; Fried, Susan K (2013) Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. Mol Aspects Med 34:1-11
Lee, Mi-Jeong; Gong, Da-Wei; Burkey, Bryan F et al. (2011) Pathways regulated by glucocorticoids in omental and subcutaneous human adipose tissues: a microarray study. Am J Physiol Endocrinol Metab 300:E571-80
Lee, Eun Kyung; Lee, Mi Jeong; Abdelmohsen, Kotb et al. (2011) miR-130 suppresses adipogenesis by inhibiting peroxisome proliferator-activated receptor gamma expression. Mol Cell Biol 31:626-38
Lee, Mi-Jeong; Wu, Yuanyuan; Fried, Susan K (2010) Adipose tissue remodeling in pathophysiology of obesity. Curr Opin Clin Nutr Metab Care 13:371-6