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

PHILADELPHIA Getting from point A to B may sound simple, but not so in the formation of fat cells.

In a finding with potential drug-development implications, Mitchell A. Lazar, M.D., Ph.D., director of the Institute for Diabetes, Obesity, and Metabolism at the University of Pennsylvania School of Medicine, and colleagues report in the current issue of Genes & Development the discovery of an intermediate state between early-stage fat cells and fully mature ones that is only present transiently during the fat-cell formation process. This intermediate state is induced by hormones related to cortisol, which are known to contribute to obesity and metabolic disturbances in people.

New therapies for obesity or metabolic diseases such as diabetes could potentially target this transition state toward a maturing fat cell.

The transition state present within 24 hours of the start of the fat-cell differentiation process is defined by chemical changes to genetic material called chromatin, which package a cell's DNA. These changes kick start the expression of regulatory proteins and provide a cellular memory that allows the cell to continue developing even after the signal to undergo this transition has waned.

Probing the Genome

Like all cells in the body, fat cells arise from stem cells. Embryonic stem cells give rise to another type of stem cell, which in turn gives rise to early-stage fat cells. Upon stimulation, those early cells complete their differentiation to become fully mature fat cells. Lazar and his team asked: What are the molecular players required to induce the final transformation?

Using a cell culture system, the team, led by postdoctoral researcher David Steger, PhD, probed genes involved in fat-cell development and function for chromatin changes that were associated with the start of mature fat-cell formation. They found chromatin changes near a gene encoding the master regulator of differentiation, 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, both proteins also induce the expression of fat-cell genes, thereby committing the cell to its ultimate fate.

"The idea that a transient hormone signal coordinates many locations throughout the genome in the process of making a fat cell is surprising and informative," Lazar says.

And that state or rather, the molecular players that comprise it -- could provide a useful target for anti-obesity drug development, he adds.


'/>"/>

Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert  

Related medicine news :

1. Texas Childrens Cancer Center first in Texas to magnetically lengthen 9-year-olds leg as she grows
2. NJHA: Charity Care Must Be a Priority as Uninsured Burden Grows
3. As girth grows, risk of sudden cardiac death shrinks
4. SciAnswers.com Grows and Adds a Technical and Healthcare Professionals Job Board.
5. Service Foods Reduces its Carbon Footprint and Grows Sales
6. Pet Health Insurance Grows as Pets Live Longer and Healthier Lives
7. Transplanted Trachea Grows Own Blood Supply in Patients Arm
8. Urinary Incontinence Rates Increase Worldwide As Awareness Grows About Treatment Options: Urethral Slings Are Popular Alternatives When Medications Fail
9. The Flag Company, Inc.'s Recently Released “Feel Good” Light Lenses Grows Into Its Own Website
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
A fat cell grows up
(Date:2/23/2017)... ... February 23, 2017 , ... ERT, a global ... announced that Premier Research, a leading clinical development service provider, has selected ERT’s ... increasingly complex, due in part to an array of circumstances including the use ...
(Date:2/23/2017)... ... (PRWEB) February 23, 2017 ... nation to come together to combine its favorite springtime pastime ... favorite fruit – apples! To celebrate National Nutrition Month, the ... “Apple Madness” bracket tournament – a five-week, five-round online competition ...
(Date:2/23/2017)... , ... February 23, 2017 , ... HealthPostures, the desk ... an expert sit stand solutions representative to the Minneapolis Home and Garden Show which ... the event that is garnering national attention is the Minneapolis Convention Center. , ...
(Date:2/22/2017)... York, NY (PRWEB) , ... February 22, 2017 ... ... professional life and athletics. It’s enough to overwork even the sharpest brain. , ... that offer peak healthy activity without over clocking the brain. Each capsule contains ...
(Date:2/22/2017)... ... February 22, 2017 , ... Secure Exchange Solutions, ... largest network of hospitals, health information exchanges, physicians and patients, announced today that ... (ONC-HIT) 2015 Edition Health IT Module Certification via Drummond Group LLC, an Authorized ...
Breaking Medicine News(10 mins):
(Date:2/23/2017)... Research and Markets has announced the addition of the "Global ... 2025" report to their offering. ... The Global Cardiac Prosthetic Devices Market is ... next decade to reach approximately $8.9 billion by 2025. ... the given segments on global as well as regional levels presented ...
(Date:2/23/2017)... , Feb. 23, 2017  Spheryx, ... one poster presentation at PittCon 2017 Conference ... Pittcon is the world,s largest annual premier ... serves a wide array of industry, academic ... discovery and QA, food safety, environmental, bioterrorism ...
(Date:2/23/2017)... 23, 2017 Provectus Biopharmaceuticals, Inc. (OTCQB: PVCT) ... oncology and dermatology biopharmaceutical company, today announced that it ... Rodrigues as special advisers to the Company,s Board ... the board on financial and corporate strategy. ... commitment of up to $2.5 million from Eric ...
Breaking Medicine Technology: