Genome-wide orchestration of adipocyte biology by PPARgamma and C/EBP.

Format:

Book

Thesis/Dissertation

Author/Creator:

Lefterova, Martina.

Contributor:

University of Pennsylvania.

Language:

English

Subjects (All):

Genetics.

Molecular biology.

0307.

0369.

Local Subjects:

0307.

0369.

Physical Description:

139 pages

Contained In:

Dissertation Abstracts International 70-01B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

The epidemics of obesity and metabolic disease have increased interest in adipose tissue as a potential therapeutic target. For this reason, understanding the function and development of adipocytes has become critical. A substantial body of research suggests that Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) and CCAAT/enhancer-binding proteins (C/EBPs) are the master regulators of adipocyte biology, although their gene targets have not been characterized extensively. Here, we present evidence that these factors cooperatively regulate adipocyte gene expression by binding at nearby sites across the genome. By taking an unbiased approach, we have identified thousands of novel binding sites for PPARgamma and C/EBPalpha and beta in 3T3-L1 cells, and we have demonstrated that many of the sites are likely to be functional. Furthermore, most genes that are upregulated during differentiation contain binding sites for PPARgamma and C/EBP, and both factors are necessary for the expression of such genes. In addition, we have examined the regulation of one of these genes, resistin, by endoplasmic reticulum (ER) stress, which is a known complication of obesity. Resistin is an adipokine whose dysregulated expression has been implicated in metabolic disease in humans and in mouse models. In mice, resistin mRNA is decreased in obesity, while the levels of circulating protein are paradoxically elevated. Interestingly, we found that ER stress substantially downregulates resistin expression in 3T3-L1 cells, while the levels of secreted protein remain relatively unchanged. In addition, the ER stress-induced effects on resistin mRNA are mediated in part by downregulation of PPARgamma and C/EBPalpha and upregulation of a C/EBP-related repressor, C/EBP homologous protein 10 (CHOP10). Collectively, these findings indicate that PPARgamma and C/EBP factors cooperatively regulate adipocyte gene expression under physiological and pathological conditions.

Notes:

Source: Dissertation Abstracts International, Volume: 70-01, Section: B, page: 0102.

Adviser: Mitchell A. Lazar.

Thesis (Ph.D.)--University of Pennsylvania, 2008.

Local Notes:

School code: 0175.

ISBN:

9781109008241

Access Restriction:

Restricted for use by site license.