Signal uncovered to help control when stem cells become fat cells

Mar 28, 2011 By Erin Digitale
When the gene Per3 is switched on, it produces a protein (right) that inhibits (as shown by arrow and “X”) another protein, PPAR gamma, from initiating the transformation of this stem cell (at bottom) into a fat cell. (The uninhibited process is shown at left). Credit: Nicole Rager Fuller

(PhysOrg.com) -- A research team at the School of Medicine and UC-San Francisco has uncovered a molecular signal that plays an important role in directing one type of “adult” stem cells to mature into fat cells.

The finding could help scientists design better drugs for type-2 diabetes and other diseases associated with obesity. And it may eventually lead to therapies for disorders of low muscle mass, such as pediatric muscular dystrophies or muscle degeneration in the elderly.

“We think the development of body composition is linked to stem cell fate,” said Brian Feldman, MD, PhD, an assistant professor of pediatrics and the senior author of the new study, which appeared March 18 in the . “The muscle and fat cell fates are pretty closely connected.”

One class of , the mesenchymal stem cells, gives rise to muscle, fat, cartilage and bone. Mesenchymal cells are considered “adult” stem cells; they are more specialized than embryonic stem cells, which are capable of differentiating into any cell in the body.

The new work suggests that blocking mesenchymal stem cells’ ability to advance to the fat cell fate may redirect the cells to form muscle instead.

“People might be willing to give up some of their fat in favor of developing some muscle,” Feldman said. “That would be the utopia — that we may be able to borrow some cells destined for the fat cell fate to try and treat disease.”

Feldman’s team uncovered a previously unknown role in mesenchymal stem cells for a gene called Per3. The gene produces a protein that inhibits the maturation of mesenchymal stem cells into . When the Per3 gene is switched off, a second gene that acts as the “master regulator” of the fat cell fate is dis-inhibited. This master regulator gene, called PPAR gamma, then sets in motion the chain of events that transforms the cell to a mature fat cell.

The researchers identified Per3’s role by delving into the actions of a class of hormones called glucocorticoids. Glucocorticoids include the naturally-occurring stress hormone cortisol and a variety of medications, such as prednisone, that are used to control asthma and autoimmune disease. Long-term use of glucocorticoid drugs has several undesirable side effects, notably increased risk for obesity and type-2 diabetes. And, in cell cultures, glucocorticoids have been shown to promote the transformation of mesenchymal stem cells to fat cells. The team showed that this happens because glucocorticoids switch off Per3, crippling its ability to inhibit the transformation of a stem cell to a fat cell.

The researchers also demonstrated that mice genetically engineered to have a defect in the Per3 gene had more fat and less lean mass than control mice. These Per3 knockout mice also had reduced glucose tolerance, a measurement of sugar metabolism that suggests they would be prone to type-2 diabetes.

Per3 had been previously known to play a minor role in the body’s circadian clock, which regulates daily rhythms. Based on its new work, Feldman’s team thinks Per3 is controlled in part by the main clock mechanism, suggesting that perturbations in the circadian clock might change how many stem cells become fat cells.

“The surprise is that it looks like the clock is sitting upstream of this gene, integrating our biological rhythms into these cascades that regulate stem cell fate,” Feldman said. Previous epidemiological studies have shown that people with perturbed circadian rhythms, such as people who work night shifts, are at elevated risk for obesity, he noted. “The implication of our work is that there is a molecular mechanism that can be used to test whether that’s more than an epidemiologic association.”

Explore further: Video: How did life on Earth begin?

Related Stories

Human virus makes fat stem cells fatter

Oct 25, 2006

U.S. research showing how a human virus targets fat stem cells to produce more, fatter, fat cells is providing insights into the study of obesity.

Fat-regenerating 'stem cells' found in mice

Oct 10, 2008

Researchers have identified stem cells with the capacity to build fat, according to a report in the October 17th issue of the journal Cell, a Cell Press publication. Although they have yet to show that the cells can renew ...

Fat kills cancer

Jul 03, 2007

Researchers in Slovakia have been able to derive mesenchymal stem cells from human adipose, or fat, tissue and engineer them into “suicide genes” that seek out and destroy tumors like tiny homing missiles. This gene ...

Recommended for you

Chemical biologists find new halogenation enzyme

Sep 15, 2014

Molecules containing carbon-halogen bonds are produced naturally across all kingdoms of life and constitute a large family of natural products with a broad range of biological activities. The presence of halogen substituents ...

Protein secrets of Ebola virus

Sep 15, 2014

The current Ebola virus outbreak in West Africa, which has claimed more than 2000 lives, has highlighted the need for a deeper understanding of the molecular biology of the virus that could be critical in ...

Protein courtship revealed through chemist's lens

Sep 15, 2014

Staying clear of diseases requires that the proteins in our cells cooperate with one another. But, it has been a well-guarded secret how tens of thousands of different proteins find the correct dancing partners ...

Decoding 'sweet codes' that determine protein fates

Sep 15, 2014

We often experience difficulties in identifying the accurate shape of dynamic and fluctuating objects. This is especially the case in the nanoscale world of biomolecules. The research group lead by Professor Koichi Kato of ...

User comments : 1

Adjust slider to filter visible comments by rank

Display comments: newest first

bellecraig
not rated yet Mar 29, 2011

Very true that major brands do give out samples on their products, search online for "123 Get Samples" we just got ours today. You wont need CC.