August 24, 2004
La Jolla, CA – A molecular switch known to regulate fat metabolism appears to prevent obesity and turns laboratory mice into marathon runners, a Salk Institute study has found.
The discovery of the switch could lead to treatments for obesity and disorders associated with it, such as heart disease and type 2 diabetes. The study, led by professor Ronald Evans and his postdoctoral fellow Yong-Xu Wang, appears in the September issue of the Public Library of Science Biology journal (PLoS Biology). Evans is also an Investigator of the Howard Hughes Medical Institute.
Evans, Wang and team discovered that activation of the switch, a receptor called PPAR-delta, increases the rate at which the body burns fat. This makes PPAR-delta an exciting potential target for drugs that treat diabetes and lipid disorders.
The team produced a genetically engineered mouse endowed with the activated form of PPAR-delta in its skeletal muscles. The result was a dramatic increase in “non-fatiguing” or “slow twitch” muscle cells and a mouse capable of running up to twice the distance of a normal littermate without training.
By expressing genes for an activated form of the receptor PPAR-delta, we created a mouse that could, compared to normal mice, run marathons, said Evans. The activated form of PPAR-delta produced muscle fibers that enhanced endurance exercise.”
By turning on PPAR-delta, the team had produced highly efficient muscle fibers that burned fat more rapidly. As a result, the mice were almost unable to gain weight even in the absence of exercise.
“These muscles also provided resistance to obesity, despite the level of exercise,” said Evans. “By manipulating this receptor, it is possible to design treatments that change our muscle makeup and help resist obesity and associated metabolic disorders.
To test the concept, Evans and his team treated normal mice with an experimental drug called GW501516 that activates PPAR-delta. These mice also expressed genes for slow-twitch muscles and gained less weight when given a high-fat diet. This drug is now in the earliest stages of being tested on people for its effects on obesity and other disorders of fat metabolism such as high blood cholesterol.
This experiment underscores the importance of metabolism in fighting obesity and improving fitness, said Evans. Activating the PPAR switch may prevent physical fatigue and enhance the quality of exercise, which may lead to a new class of drugs to promote weight loss and treat diseases arising from an overweight population.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. Jonas Salk, M.D., founded the institute in 1960 with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.