Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Obese mice provide clues to a natural system that puts brakes on obesity

16.07.2003


First gene discovered that is switched on only in fat cells of obese mice

A gene that gets switched on only in the fat cells of obese mice may be a key to preventing obesity in humans, according to new research at The Rockefeller University in New York City and the Joslin Diabetes Center in Boston.

The finding, reported in the August 1 issue of the Journal of Clinical Investigation, marks the first time a gene has been identified that is induced, or activated, in the fat cells of obese animals. According to Rockefeller University professor Markus Stoffel, M.D., Ph.D., lead investigator of the study, the gene, called Foxa-2, inhibits young body cells from becoming mature fat-producing cells called adipocytes. In addition, when this gene is switched on in mature adipocytes, it functions as a brake to slow down further fat production and storage.



"We know a lot about the various molecular pathways that stimulate or promote fat production, and the focus has been on trying to block these pathways to fight obesity," says Stoffel. "This pathway is one of only a few that we know of that naturally work to counteract obesity.

"We have shown that Foxa-2 has two beneficial effects in mice: it counterregulates the formation of fat and it increases the activity of genes important for insulin sensitivity," Stoffel continues. "This is the ideal combination for pharmacologically treating obese or type 2 diabetic patients, or people with a risk of developing obesity."

Foxa-2 was originally discovered in the 1980s by Rockefeller scientist James E. Darnell Jr., M.D., as an activator of genes in the liver. Subsequent research by Stoffel and colleagues at Rockefeller showed that Foxa-2 also activates genes in the insulin-producing islet cells in the pancreas and it is expressed in the gut and the lung. However, previous research by scientists could not provide evidence for its expression in fat cells. The reason, says Stoffel, is "that we did not look at fat cells from obese animals."

"We were only able to find Foxa-2 in fat tissues when we extracted fat from a leptin-deficient mouse, which has a mutation in the ’ob’ gene," says Stoffel, referring to studies with mice that are obese due to low levels of the hormone leptin, the protein product of the obese gene, which was identified by Rockefeller professor Jeffrey M. Friedman, M.D., Ph.D., in the mid-1990s.

Leptin is a hormone secreted by adipocytes that acts on an area of the brain called the hypothalamus. Leptin, Stoffel notes, causes mice and people to lose weight by increasing food intake and energy expenditure, while Foxa-2’s effects are solely on the adipocyte at the level of the cell.

"The discovery of Foxa-2 in fat cells of obese mice was unexpected," Stoffel continues. "We were able to replicate this finding in mice that were obese due to mutations in several genes and in diet-induced obese mice."

Stoffel and colleagues found Foxa-2 expression in mature adipocytes and in pre-adipocytes, young cells that have not accumulated lipids. In addition, Foxa-2 expression was higher in visceral fat than in subcutaneous fat, which is stored under the skin. Visceral fat, found around the gut, is a form of fat that predisposes people to complications of obesity, including type 2 diabetes.

To understand Foxa-2’s role in pre-adipocytes, the Stoffel and his colleagues "overexpressed," or activated above normal levels, Foxa-2 in laboratory cultures of these cells. The scientists then added the necessary hormonal and nutritional signals for these cells to turn into mature fat cells. They found that the pre-adipocytes did not accumulate lipids, and Foxa-2 did not induce genes in these cells that typically are active in mature adipocytes.

During the normal course of differentiation of pre-adipocytes into fat, the activity or expression of a gene called Pref-1 decreases. Stoffel found that Foxa-2 activates Pref-1, and that this activation inhibited the transformation of the laboratory cultured pre-adipocytes into mature adipocytes. The researchers also found overexpression of a set of genes that metabolize glucose, suggesting that Foxa-2 also directly activates these genes.

When Foxa-2 was overexpressed in mature adipocytes that normally do not express Foxa-2, Stoffel and his colleagues found increased expression of genes that break down glucose and burn fat.

"We know that adipocytes of obese animal models are insulin-resistant, so levels of glucose metabolism enzymes decrease," says Stoffel. "At the level of the mature adipocyte, Foxa-2 seems to counterregulate obesity by increasing these enzymes in the adipocyte or at least working against further decreases."

The researchers then tested the effects of removing this gene in living mice. Because both copies of Foxa-2 are necessary for survival, the researchers deleted, or "knocked out," only one copy of this gene, which effectively reduced its activity by 50 percent. When fed a high fat diet for six weeks, these knockout mice gained much more weight than genetically normal mice fed the same diet.

Analysis of fat cells from the Foxa-2 knockout mice showed that activity levels of Pref-1 and the glucose metabolism genes decreased.
"It is now apparent that when we overfeed a mouse and it becomes obese, Foxa-2 is induced, which then activates a set of genes that work against obesity," says Stoffel. "Obviously that’s not sufficient to prevent obesity, but it is sufficient to slow it down. Without this force, the mice accumulate more fat.

"It’s an ineffective system, since otherwise people wouldn’t get obese, but it is clear that if you take the system away, there is an increase in obesity."

The next step for the researchers is to identify stimuli that induce Foxa-2 in people.

"We know that Foxa-2 is expressed in human adipocytes, and if we knew the stimuli that are responsible for inducing Foxa-2 we could potentially induce Foxa-2 activity in people at risk for developing obesity and possibly counteract the development of obesity as well as increase insulin sensitivity," says Stoffel. Both obesity and insulin resistance are risk factors for type 2 diabetes.

In their research with mice, Stoffel and his colleagues showed that growth hormone can induce Foxa-2 in cultured cells that normally don’t express the gene.

Stoffel cautions that growth hormone is not the answer for treating obesity in people.

"We do not believe that growth hormone is responsible for the induction of Foxa-2 in obesity because we know that obese patients actually have a relative deficiency of growth hormone," Stoffel says. "And, we can’t give growth hormone to patients because there are too many negative side effects."

Joseph Bonner | EurekAlert!
Further information:
http://www.rockefeller.edu

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Water - as the underlying driver of the Earth’s carbon cycle

17.01.2017 | Earth Sciences

Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

17.01.2017 | Materials Sciences

Smart homes will “LISTEN” to your voice

17.01.2017 | Architecture and Construction

VideoLinks
B2B-VideoLinks
More VideoLinks >>>