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A fat cell grows up
Date:5/17/2010

ifferentiation, PPAR-gamma, which is also a target of anti-diabetic drugs.

"That gave us confidence to interrogate the whole genome," Lazar says.

The team scanned the genome for regions that were modified within 24 hours of the onset of fat-cell differentiation and analyzed those regions for potential binding sites for proteins that induce the expression of other genes. These proteins activate the genes whose proteins cause changes in cellular behavior and function.

Complex Control System

The researchers found that many of the chromatin-modified regions contained binding sites for two proteins, CEBP-beta and the glucocorticoid receptor (GR). In turn, these proteins recruit additional proteins to their locations along chromosomes. The result is a protein complex that nudges the precursor fat cell to become a mature fat cell.

That the glucocorticoid receptor is part of this transition state is remarkable, Lazar says, in that the growth factor complex required to induce fat-cell formation includes dexamethasone, one type of gluococorticoid hormone. No one had ever considered why dexamethasone was required to make this transition happen, Lazar says. "The dexamethasone is stimulating the hormone receptor to bind transiently at this site and create the transition state." This happens at dozens of sites in the cell genome, and the hormone is the coordinating signal.

On the basis of their findings, Lazar and his colleagues propose a model in which, upon stimulation of pre-fat cells, CEBP-beta, GR, and other proteins assemble near the PPAR-gamma gene and activate it. Once that happens, the circuit is on, even if the fat-cell-forming stimulus should disappear. In what the investigators call a "feedforward loop," the PPAR-gamma protein induces its own expression, as well as that of another master regulatory gene, CEBP-alpha. CEBP-alpha, in turn, activates its expression as well as that of PPAR-gamma. More importantly,
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert  

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