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:5/26/2016)... Pittsburgh, PA (PRWEB) , ... May 26, 2016 ... ... transplantation, and one that has a significant negative impact on long-term patient survival, ... to date. The results, published online this week in the Journal of Thoracic ...
(Date:5/26/2016)... ... May 26, 2016 , ... ... solutions for drugs, biologics, consumer health and global clinical supply services, today announced ... to support the company’s continued investment and strategic growth plans in the Asia ...
(Date:5/26/2016)... ... May 26, 2016 , ... In an effort to provide hair restoration information to the ... users and those who do not use the app. Dr. Mohebi, the founder of Parsa ... Dr. Mohebi Live . , Dr. Mohebi says, “The positive response to the Snapchat ...
(Date:5/26/2016)... ... 26, 2016 , ... Eating Recovery Center, Washington ... a brand new child and adolescent residential treatment center on June 1. The ... more specialized eating disorder treatment and access to life-saving care. , To celebrate, ...
(Date:5/26/2016)... ... May 26, 2016 , ... Nike Yoga Camps at ... daily practices, arts & crafts, discussions, and games all geared towards enhancing your ... have combined backgrounds in kids’ yoga, collegiate sport yoga instruction, and global yoga ...
Breaking Medicine News(10 mins):
(Date:5/26/2016)... TARE (Transarterial Radio-embolization) Using ... and Overall Decreased Use of Hospital Resource ... specialist healthcare company, has today announced the publication ... of ISPOR (International Society for Pharmacoeconomics and Outcomes ... using yttrium-90 glass microspheres is associated with cost ...
(Date:5/26/2016)... , May 26, 2016 Since ... matured into an essential life science tool for conducting ... applications. BCC Research reveals in its new report that ... growth phase, one powered by a range of new ...      (Logo: http://photos.prnewswire.com/prnh/20140723/694805 ) , ...
(Date:5/25/2016)... May 25, 2016 According to ... Type (3D, 2D, 4D), by Therapeutic Area (Oncology, Cosmeceutical/Plastic ... User (Medical Device Manufacturers, Hospitals/ Clinics) - Forecast to ... Medical Animation Market for the forecast period of 2016 ... 301.3 Million by 2021 from USD 117.3 Million in ...
Breaking Medicine Technology: