Studies by Ronald Evans at the Salk Institute (left), Bruce Spiegelman at Harvard University (middle), and Gerald Shulman at Yale University (right) shed light on how muscle and metabolism contribute to fitness.

Just as the government stockpiles and releases gasoline reserves according to demand, our bodies store and mobilize energy to meet our needs—making it available to muscles when we're active and hoarding it when food is scarce. Normally, we control metabolism exquisitely, maintaining a constant body weight even as our pace of life ebbs and flows. But when we eat far more than we burn, obesity results.

Weight-loss strategies typically focus on reducing the number of calories a person consumes. But this strategy doesn't work for most people, says Ronald M. Evans, an HHMI investigator at the Salk Institute for Biological Studies in La Jolla, California. "Few people can make a lifestyle change and eat less," he says.

In 2004, Evans announced he had engineered, by genetically altering the animal's muscle, a "marathon mouse" that, with no prior training, could run longer than the average mouse. Now, he is trying to create superfit mice by using drugs rather than genetic manipulation—a more practical real-world treatment. One such promising drug is already being tested in the hopes it might speed people's efforts to get in shape and help steady a fluctuating metabolism that can lead to diabetes.

While genetic engineering "preprograms" the young muscle of his marathon mouse, Evans says, a drug faces the more daunting challenge of "reprogramming" normal adult muscle. To begin to tackle this problem, he decided to work with exploratory drugs under development by the pharmaceutical industry. Previously, Evans showed that a new class of experimental drugs can improve the ability of mice to burn fat. He reasoned that one way to improve athletic performance might be by redirecting a similar set of molecular circuits to maximize fuel consumption in muscle.

For years, Evans and his colleagues have focused on a team of proteins, known as PPARs, that call the shots in metabolism; they direct groups of genes involved in burning and storing energy. PPARgamma, for instance, prods fat cells to grab and store fat from the blood, whereas PPARdelta stokes muscles to burn fat. "One is like charging a battery and the other is like freeing up all that stored energy," says Evans.

Could toying with these molecules, he wondered, tip the balance of metabolism in favor of burning fat and help people lose weight? Some results produced intriguing hints of success: mice without PPARdelta grew portly when they ate a high-fat diet, whereas mice with boosted PPARdelta activity stayed slim even when they chowed down on fat.

PPARdelta is more prevalent in so-called slow-twitch muscles (the ones that power marathoners) than in fast-twitch muscles (which provide explosive power for sprinters). Slow-twitch muscles devour oxygen—an efficient way to fuel muscles without fatigue—because they are replete with mitochondria, the cellular power plants that burn fat to produce a steady stream of energy for cells. Not surprisingly, obese people tend to carry fewer slow-twitch muscle fibers than normal and are known to fatigue easily.

Photos: Evans: Courtesy of The Salk Institute for Biological Studies; Spiegelman: Jason Grow; Shulman: Gale Zucker

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