Adipocytes are highly specialized cells that play a major role in energy homeostasis in vertebrates. Obesity is the primary disease of fat cells and the most common metabolic disorder in the industrial world. Obesity affects >30% of the adult population in the United States and is a major risk factor for the development of non-insulin dependent diabetes mellitus (NIDDM), cardiovascular disease, and hypertension. Recent studies suggest that obesity and its related disorders may be linked to a breakdown in the regulatory mechanisms which control the expression of a variety of genes in adipocytes. Significant advances towards an understanding of these regulatory processes have been made by studying the function of transcription factors which regulate the differentiation of fat cells and are involved in the modulation of adipocyte gene expression. It is well recognized that several transcription factors are induced during adipocyte differentiation, play a critical role in the regulation of adipocyte gene expression, and are altered in conditions of obesity and/or insulin resistance. We have focused on STATs (Signal Transducers and Activators of Transcription), a family of transcription factors whose activity is largely controlled by hormone induced tyrosine phosphorylation. Our efforts have focused on two STAT proteins, STAT5A and STAT 5B, whose expression is induced during adipogenesis. Studies from our laboratory and several others have demonstrated the adipogenic capabilities of STAT 5A. Although STAT5A promotes lipid deposition in preadipocytes, there is a variety of observations to indicate that STAT 5A has anti-lipogenic actions in mature adipocytes. Growth hormone, a potent inducer of STAT 5 proteins is well known to have effects that are lipolytic, anti-lipogenic and diabetogenic. It is known that STATs can have cell specific functions, and we hypothesize that STAT5 proteins play a vital role in the regulation of genes involved in lipid metabolism and insulin resistance in adipocytes. Our preliminary studies demonstrate that STAT5 tyrosine phosphorylation in white adipose tissue is altered in rodent models of obesity. In addition, we have evidence to suggest that STAT 5 proteins may affect the endocrine properties of adipocytes by regulating the expression of several adipokines. The studies outlined in the specific aims focus on understanding the function of STAT 5 proteins in mature adipocytes and how these transcription factors affect lipogenesis, insulin sensitivity, and the production of endocrine factors from fat cells.

Public Health Relevance

Significant advances towards understanding obesity and diabetes have been made by studying the function of transcription factors which are involved in controlling adipocyte gene expression. Our studies focus on understanding the function of STAT 5 proteins in fat cells and how these transcription factors affect lipogenesis, insulin sensitivity, and the production of endocrine factors in adipocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052968-14
Application #
8212526
Study Section
Special Emphasis Panel (ZRG1-EMNR-G (04))
Program Officer
Haft, Carol R
Project Start
1999-09-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
14
Fiscal Year
2012
Total Cost
$326,374
Indirect Cost
$105,851
Name
Lsu Pennington Biomedical Research Center
Department
None
Type
Organized Research Units
DUNS #
611012324
City
Baton Rouge
State
LA
Country
United States
Zip Code
70808
Richard, Allison J; Stephens, Jacqueline M (2014) The role of JAK-STAT signaling in adipose tissue function. Biochim Biophys Acta 1842:431-9
Zhao, Peng; Elks, Carrie M; Stephens, Jacqueline M (2014) The induction of lipocalin-2 protein expression in vivo and in vitro. J Biol Chem 289:5960-9
Sanchez-Infantes, David; White, Ursula A; Elks, Carrie M et al. (2014) Oncostatin m is produced in adipose tissue and is regulated in conditions of obesity and type 2 diabetes. J Clin Endocrinol Metab 99:E217-25
Nam, Heesun; Ferguson, Bradley S; Stephens, Jacqueline M et al. (2013) Impact of obesity on IL-12 family gene expression in insulin responsive tissues. Biochim Biophys Acta 1832:11-9
White, Ursula A; Stephens, Jacqueline M (2011) The gp130 receptor cytokine family: regulators of adipocyte development and function. Curr Pharm Des 17:340-6
Richard, Allison J; Stephens, Jacqueline M (2011) Emerging roles of JAK-STAT signaling pathways in adipocytes. Trends Endocrinol Metab 22:325-32
Stewart, William C; Pearcy, Lisa A; Floyd, Z Elizabeth et al. (2011) STAT5A expression in Swiss 3T3 cells promotes adipogenesis in vivo in an athymic mice model system. Obesity (Silver Spring) 19:1731-4
White, Ursula A; Stewart, William C; Stephens, Jacqueline M (2011) Gp130 cytokines exert differential patterns of crosstalk in adipocytes both in vitro and in vivo. Obesity (Silver Spring) 19:903-10
White, Ursula A; Stephens, Jacqueline M (2010) Neuropoietin activates STAT3 independent of LIFR activation in adipocytes. Biochem Biophys Res Commun 395:48-50
Amini, Zhaleh; Boyd, Bryant; Doucet, Julie et al. (2009) St. John's Wort inhibits adipocyte differentiation and induces insulin resistance in adipocytes. Biochem Biophys Res Commun 388:146-9

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