SKIP THE TREADMILL? Compared with the leg muscle tissue of normal mice (left), that of mice genetically modified to produce excess PPAR-delta (right) consists of more slow-twitch fibers (dark blue)--a change similar to that induced by sustained exercise. Image: YONG-XU WANG ET. AL. IN PLoS BIOLOGY, VOL. 2, NO.10, E294, OCTOBER 2004
In the battle against flab, who wouldn't love an "exercise" pill? Such a quick fix might be possible: biomedical researchers have found a way to rev up the metabolic machinery and thereby keep excess weight off--using genetics instead of the gym.
The key appears to be a protein called PPAR-delta. A decade ago Ronald M. Evans of the Salk Institute for Biological Studies in La Jolla, Calif., discovered that it regulates other genes involved in the breakdown of fat. He showed that activating PPAR-delta raised metabolism and helped animals burn more fat. For his latest study, Evans and his colleagues from Seoul National University wanted to know if PPAR-delta had measurable effects in terms of weight change.
So they genetically engineered mice to produce extra PPAR-delta in their muscle. When put on a high-fat, high-calorie diet for 13 weeks, the transgenic mice gained only a third of the weight that their unmodified brethren did. What is more, mice on this diet remained resistant to obesity even when they were kept inactive.
To accomplish its remarkable metabolic and antiobesity tasks, PPAR-delta evidently modifies the composition of skeletal muscle in the mice. Muscle consists of fast-twitch fibers, which rely on sugar for fuel and are used primarily for rapid movements, and slow-twitch fibers, which convert fat into energy and are responsible for sustained activity. The transgenics had double the amount of the fat-burning, slow-twitch muscle compared with normal littermates.
The increase in slow-twitch fibers, usually associated with long-lasting, vigorous exercise, also translated into greater endurance. On the mouse treadmill, the transgenics could run 1,800 meters, twice the distance a mouse normally runs before exhaustion, and for an hour longer than the usual 90 minutes. "We nicknamed them ¿marathon mice' because they behave like conditioned athletes," says Evans, whose study appears in the October PLoS Biology. He suspects that changes have also occurred in the cardiovascular and nervous systems, both of which are intimately linked to the muscles. He has not yet seen any serious side effects from the extra PPAR-delta.
Although Evans recognizes the potential for abuse by athletes, he believes that his work has more practical implications in treating metabolic ailments, including obesity and heart disease. Patients with such conditions often cannot exercise because of their weight or other complicating problems. "This work could lead to an exercise pill that gives many of the benefits of training without the need to sweat," Evans predicts. Indeed, in a separate experiment he gave normal mice a drug called GW501516, which activates PPAR-delta directly. The drug caused many of the same changes in muscle and metabolism as those in the transgenic mice, including protection against weight gain.
Whether such a pill also works in humans may be answered sooner than expected. Pharmaceutical giant GlaxoSmithKline is currently testing GW501516 in obese and diabetic patients as a way of improving their good cholesterol, or HDL, levels. The company says that it has not looked to see how the drug affects endurance or weight but that it plans to do further tests.
Although the alteration of other genes has produced animals with more slow-twitch fibers, none of the changes have influenced metabolism like PPAR-delta. "This is major step forward in understanding how muscles and metabolism are linked," says Nadia Rosenthal, head of the Mouse Biology Program at the European Molecular Biology Laboratory in Rome. The creation of the marathon mice is reminiscent of Rosenthal's earlier work that led to "Schwarzenegger mice," rodents that bulked up after receiving gene therapy with the muscle-building gene IGF-1. In that case, however, taking IGF-1 in pill form did not produce the same effects.
It is too soon to label PPAR-delta as an obesity cure, warns Paul Root Wolpe, a bioethicist at the University of Pennsylvania. In the early days of functional genomics, many genes and proteins have been touted as panaceas. "The desire to find a drug, protein or gene that will solve all ills is ancient," Wolpe notes. "That desire hasn't changed much over thousands of years, only the technology has."