A tiny, translucent zebrafish that glows green when its liver makes glucose has helped an international team of researchers identify a compound that regulates whole-body metabolism and appears to protect obese mice from signs of metabolic disorders.
Led by scientists at the University of California, San Francisco (UCSF), the work demonstrates how a fish smaller than a grain of rice can help screen for drugs to help control obesity, type 2 diabetes and other metabolic disorders, which affect a rising 34 percent of American adults and are major risk factors for cardiovascular disease.
Described this week in the journal Nature Chemical Biology, the new compound emerged from a panel of 2,400 medications and drug-like compounds tested in the zebrafish. The test was designed to identify key regulators of "fasting metabolism"— a state most people face every day after the lingering remnants of their long-digested meals pass slowly down their digestive tract.
Fasting metabolism is the body's way of fulfilling its energy needs between meals by turning to fat and other stored sources. It involves a carefully balanced and coordinated cascade of reactions that see numerous genes in various tissues kick into action and do things like burn fat.
In type 2 diabetes and other metabolic diseases, this careful balance is lost.
"The body cannot keep up with the breakdown of energy, and lipids [molecules of fat] can accumulate to toxic levels in the liver," said UCSF postdoctoral fellow Philipp Gut, MD, who led the research with Didier Y.R. Stainier, PhD, a professor in the Department of Biochemistry and Biophysics.
But looking for drugs that regulate biological processes like metabolism, which involves multiple interacting organs in the body, and even more types of cells, cannot be done in cell screens because they lack the same complexity. Mice are often used to test pharmacological compounds, but screens of this magnitude would require thousands of mice, which would be ethically impossible to justify and prohibitively expensive.
Gut and his colleagues set out to develop the zebrafish screen as an ethical and inexpensive solution, and the new paper demonstrates the validity of this approach, he said. Furthermore, this study illustrates the fact that model organisms should be an integral part of the new roadmap defined by the NIH and other medical research organizations around the world to translate the most advanced laboratory science into benefits for patients, Stainier said.
Of the thousands of compounds the team screened, two appeared to turn on a handful of genes that caused the animals to burn fat as a way of producing energy – an end that would be desirable for many people with metabolic disorders.
Further experiments with one of these compounds in mice showed that it could protect obese mice from metabolic problems.
The article, "Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism," by Philipp Gut, Bernat Baeza-Raja, Olov Andersson, Laura Hasenkamp, Joseph Hsiao, Daniel Hesselson, Katerina Akassoglou, Eric Verdin, Matthew D Hirschey and Didier Y R Stainier will be published online by the journal Nature Chemical Biology on Dec. 2, 2012.
This study was supported by the National Institutes of Health through grant #P30 DK026743, #P30 DK063720, #DK59637, #NS051470, #U01 DK089541 and #RO1 DK60322 and by a grant from the American Heart Association. Additional funds were provided by the Gladstone Institutes, the Glenn Foundation for Medical Research and through a postdoctoral fellowship from the German Research Foundation.
In addition to UCSF, authors on this study are associated with the Gladstone Institutes in San Francisco; Duke University Medical Center in Durham, N.C.; Karolinska Institutet in Stockholm, Sweden; the Garvan Institute of Medical Research in New South Wales, Australia; and the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.
Jason Socrates Bardi | EurekAlert!
Further reports about: > Chemical Biology > Didier > Gates Foundation > Glowing Fingerprints > Max Planck Institute > Medical Wellness > Nature Chemical Biology > Nature Immunology > UCSF > biological process > chemical engineering > fasting metabolism > living cell > medical research > metabolic disorder > risk factor > synthetic biology > type 2 diabetes
27.03.2015 | Oak Ridge National Laboratory
How did the chicken cross the sea?
27.03.2015 | Michigan State University
In an experiment at the Department of Energy's SLAC National Accelerator Laboratory, scientists precisely measured the temperature and structure of aluminum as...
The IPH presents a solution at HANNOVER MESSE 2015 to make ship traffic more reliable while decreasing the maintenance costs at the same time. In cooperation with project partners, the research institute from Hannover, Germany, has developed a sensor system which continuously monitors the condition of the marine gearbox, thus preventing breakdowns. Special feature: the monitoring system works wirelessly and energy-autonomously. The required electrical power is generated where it is needed – directly at the sensor.
As well as cars need to be certified regularly (in Germany by the TÜV – Technical Inspection Association), ships need to be inspected – if the powertrain stops...
When an earthquake hits, the faster first responders can get to an impacted area, the more likely infrastructure--and lives--can be saved.
The Atlantic overturning is one of Earth’s most important heat transport systems, pumping warm water northwards and cold water southwards. Also known as the Gulf Stream system, it is responsible for the mild climate in northwestern Europe.
Scientists now found evidence for a slowdown of the overturning – multiple lines of observation suggest that in recent decades, the current system has been...
Because they are regularly subjected to heavy vehicle traffic, emissions, moisture and salt, above- and underground parking garages, as well as bridges, frequently experience large areas of corrosion. Most inspection systems to date have only been capable of inspecting smaller surface areas.
From April 13 to April 17 at the Hannover Messe (hall 2, exhibit booth C16), engineers from the Fraunhofer Institute for Nondestructive Testing IZFP will be...
25.03.2015 | Event News
19.03.2015 | Event News
17.03.2015 | Event News
27.03.2015 | Agricultural and Forestry Science
27.03.2015 | Materials Sciences
27.03.2015 | Ecology, The Environment and Conservation