Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

In search of a lean gene

02.08.2004


Independent research groups have discovered novel therapeutic targets in the battle of the bulge



Independent research groups have discovered novel therapeutic targets in the battle of the bulge. By altering the expression of a single -- albeit different – gene, Drs. Roger Davis (UMASS Medical School, USA) and Ying-Hue Lee (Academia Sinica, Taiwan) have succeeded in creating two different strains of transgenic mice that don’t gain weight, even when fed fat-laden, high calorie diets.
Their reports will be published in the August 15th edition of Genes & Development.

Living longer, weighing less



Dr. Ying-Hue Lee and colleagues at Academia Sinica took a different approach towards the obesity epidemic, analyzing the effects of C/EBP gene replacement in mice. The C/EBP protein family consists of 5 members, 3 of which (alpha, beta, and delta) have established roles in promoting adipogenesis (fat cell differentiation). The researchers were specifically interested in determining the physiological impact of replacing the C/EBPalpha gene with the C/EBPbeta gene.

"No doubt, C/EBPalpha is very important for life as indicated by many excellent studies related to its physiological function. Still, we wondered that its cousin, C/EBPbeta, might do the job well as well if given a chance," explains Dr. Lee.

Dr. Lee and colleagues utilized an existing strain of mice that contains the alpha-to-beta gene substitution, referred to in the paper as "beta/beta mice." They found that beta/beta mice not only live an average of 5 months longer than wild-type mice, but are markably leaner, apparently burning fat at a much higher rate than normal mice.

Dr. Lee and colleagues observed that despite their svelte appearance, beta/beta mice actually eat more food and are no more active than their genetically normal littermates. In search of the cause of this revved-up metabolism, Dr. Lee’s team found that the white adipose tissue, which is normally reserved for fat storage, had actually been converted into fat burning cells in beta/beta mice. The researchers believe that this remarkable conversion in tissue function (from fat storage to fat burning) may be due to the increased expression of yet another gene, Galphas, in the white adipose tissue of beta/beta mice.

To further investigate the effectiveness of C/EBP gene replacement in preventing obesity, Dr. Lee and colleagues introduced the beta/beta alleles into two different mouse models of obesity: Cpefat/fat mice, which are obese due to a suppressed metabolism, and Lepob/ob mice, which are obese due to overeating. Amazingly, this gene modification was able to dramatically decrease weight gain in both strains of mice, illustrating that C/EBP gene replacement can overcome both hereditary and dietary forms of obesity.

Dr. Lee is hopeful that the activation of Galphas may prove useful as a potential therapeutic target in the fight against human obesity, helping to jump-start metabolism in fat storage cells and thereby prevent fat accumulation."It would be wonderful, if fat cells can be programmed to be more wary of their own size and take good care of it themselves," he says.

Targeting obesity and diabetes

As the rate of obesity continues to rise, so does the number of people developing Type 2 diabetes (formerly known as adult-onset or insulin-independent diabetes). In fact, obesity is believed to be one of the most important risk factors for Type 2 diabetes, in which muscle, liver and fat cells become resistant to insulin, causing blood glucose levels to rise and eventually damage nerves and blood vessels.

Dr. Roger Davis and colleagues in the Howard Hughes Medical Institute at UMASS Medical School focused their research effort on the JNK (pronounced "junk") family of kinase enzymes. JNK acts as an intracellular signaling molecule, and is known to contribute to insulin insensitivity during obesity. However, rather than concentrate on JNK, itself, which is involved in a number of physiological processes (and thereby constitutes a more complicated therapeutic target), Dr. Davis’ team centered upon JIP1, a scaffolding protein that interacts with components of the JNK signaling module and facilitates its activation in adipose (fat) tissue.

"The JIP1 scaffold protein is implicated in the effects of stroke to cause brain damage, but whether JIP1 plays a more general role in the response of the body to stress is unclear. One form of stress that may be relevant to JIP1 is obesity. The goal of this study was to test whether JIP1 contributes to the effects of obesity on the body," explains Dr. Davis.

To investigate the role of JIP1 in obesity and insulin resistance, the researchers used a strain of mice in which both copies of the gene encoding JIP1 (Jip1) had been mutated. These Jip1-deficient mice (or knock-out mice as they are known) fail to activate JNK in adipose cells. As a result, they gained 40% less weight than their genetically normal (wild-type) counterparts when fed a high fat, high calorie diet, and displayed increased sensitivity to insulin. Thus, Jip1 inactivation effectively protects against obesity and the development of insulin resistance.

This finding posits Jip1 as a novel target for the rational design of drugs to combat obesity and Type 2 diabetes. Dr. Davis emphasizes that "Our study demonstrates that JIP1 plays a critical role in the response of the body to the stress caused by obesity. Drugs that target the function of JIP1 to regulate JNK activity may therefore be useful for the treatment of obesity and insulin resistance. Our study provides a proof-of-concept that validates this approach using a model organism. An exciting future possibility is the application of this strategy to the treatment of human obesity."

Heather Cosel-Pieper | EurekAlert!
Further information:
http://www.cshl.edu

More articles from Life Sciences:

nachricht Rochester scientists discover gene controlling genetic recombination rates
23.04.2018 | University of Rochester

nachricht One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Molecules Brilliantly Illuminated

Physicists at the Laboratory for Attosecond Physics, which is jointly run by Ludwig-Maximilians-Universität and the Max Planck Institute of Quantum Optics, have developed a high-power laser system that generates ultrashort pulses of light covering a large share of the mid-infrared spectrum. The researchers envisage a wide range of applications for the technology – in the early diagnosis of cancer, for instance.

Molecules are the building blocks of life. Like all other organisms, we are made of them. They control our biorhythm, and they can also reflect our state of...

Im Focus: Spider silk key to new bone-fixing composite

University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

Im Focus: Basel researchers succeed in cultivating cartilage from stem cells

Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.

Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

Structured light and nanomaterials open new ways to tailor light at the nanoscale

23.04.2018 | Physics and Astronomy

On the shape of the 'petal' for the dissipation curve

23.04.2018 | Physics and Astronomy

Clean and Efficient – Fraunhofer ISE Presents Hydrogen Technologies at the HANNOVER MESSE 2018

23.04.2018 | Trade Fair News

VideoLinks
Science & Research
Overview of more VideoLinks >>>