Exercise pill switches on master regulator that controls the ability of cells to burn fat

By giving ordinary adult mice a drug - a synthetic designed to mimic fat - Salk Institute scientist Dr. Ronald M. Evans is now able to chemically switch on PPAR-d, the master regulator that controls the ability of cells to burn fat.

Even when the mice are not active, turning on the chemical switch activates the same fat-burning process that occurs during exercise. The resulting shift in energy balance (calories in, calories burned) makes the mice resistant to weight gain on a high fat diet.

The hope, Dr. Evans told scientists attending Experimental Biology 2007 in Washington, DC, is that such metabolic trickery will lead to a new approach to new treatment and prevention of human metabolic syndrome. Sometimes called syndrome X, this consists of obesity and the often dire health consequences of obesity: high blood pressure, high levels of fat in the blood, heart disease, and resistance to insulin and diabetes.

Dr. Evan's Experimental Biology presentation on April 30 is part of the scientific program of the American Society for Biochemistry and Molecular Biology.

This chemical switch is not the first success Dr. Evan's laboratory has had in being able to turn on the PPAR-d switch in adipose or fat cells, activating local metabolism and increasing the amount of calories burned. As a Howard Hughes Medical Investigator at The Salk Institute's Gene Expression Laboratory, Dr. Evans discovered the role of the gene for PPAR-d, the master regulator of fat metabolism. By permanently turning on this delta switch in mice through genetic engineering, he was able to create a mouse with an innate resistance to weight gain and twice the physical endurance of normal mice. Because they were able to run an hour longer than a normal mouse, they were dubbed "marathon mice."

Subsequent work in the Evans laboratory found that activation of PPAR-d in these mice also suppresses the inflammatory response associated with arthrosclerosis.

But the genetic metabolic engineering that created the marathon mouse is permanent, turned on before birth. While a dramatic proof of concept that metabolic engineering is a potentially viable approach, it offers no help to an adult whose muscles are already formed and who now would benefit greatly from having more active, fat-burning muscles.

That is why the potential of chemical metabolic engineering - possibly a one-a-day pill as opposed to permanent genetic metabolic engineering - is so exciting, says Dr. Evans. In today's society, too few people get an ideal amount of exercise, some because of medical problems or excess weight that makes exercise difficult. Having access to an "exercise pill" would improve the quality of muscles, since muscles like to be exercised, and increase the burning of energy or excess fat in the body. And that would result in less fatty tissue, lower amounts of fat circulating in the blood, lower blood glucose levels and less resistance to insulin, lowering the risks of heart disease and diabetes.

The ability to chemically engineer changes in metabolism also has given the researchers more insight into how the PPAR-d switch works, says Dr. Evans. Genetically engineering changes in metabolism in the marathon mice triggers both increased fat burning and increased endurance. Adult normal mice that receive the drug to switch on PPAR-d show increased fat burning and resistance to weight gain, but they do not show increased endurance. Dr. Evans says this suggests the delta switch can operate in different modes, and the laboratory is in the process of figuring out exactly how. He hopes his strategy will make it possible.

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