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.
How the Screen Works
Some screens can be conducted in cell culture by taking living cells grown in the laboratory and exposing them to various drugs. The ability to rapidly test large libraries of compounds in the last few decades through such screens has revolutionized biomedical science.