Exercise Pill Will Rev up Metabolism & Protect Against Obesity

Altering a single gene can give your body the benefits of training without the need to sweat, allowing your body to eat large amounts of food without getting fat. The discovery could lead to treatments for obesity and disorders associated with it, such as heart disease and type 2 diabetes.

"PPAR-delta [peroxisome proliferator-activated receptor-delta] and its ligands comprise a key molecular switch to regulate muscle fiber specification, obesity resistance, insulin sensitivity, and most surprisingly, physical endurance," Dr. Ronald M. Evans and his team report in the October issue of the journal Public Library of Science Biology.

They said their study could lead to an "exercise pill" — a PPAR-delta agonist — that gives many of the benefits of training without the need to sweat. "It is a pill that, in part, mimics the metabolic activity associated with exercise," says Dr. Evans of The Salk Institute in La Jolla, California.

Revving up PPAR-delta has been shown to help increase metabolism, Dr. Evans said. "Part of our goal is the development of treatments for metabolic disease, diabetes and obesity," he added.

The researchers developed transgenic mice in which the PPAR-delta gene in skeletal muscle is permanently activated. The mice grew more type I slow-twitch muscle fibers, which are rich in mitochondria and are used for endurance-type exercise, as opposed to the fast-twitch muscles used for sprinting.

The researchers expected to see changes in metabolism but were surprised at how extensive they were. The genetically engineered mice could run for an hour longer than normal mice, "which translates to nearly a kilometer further," they write. And when fed a high-fat diet, the transgenic animals gained only one-third the amount of weight that wild-type mice gained on the same diet after 97 days. Tests showed they were burning off the fat even when they did not exercise, Dr. Evans said.

"One of the questions for the future is studying the impact this has on longevity," he said. "So far, there are no side effects other than that they are resistant to weight gain. They are fertile and they are able to give rise to the next generation of long-distance runners."

While Dr. Evans and colleagues used genetic manipulation, they said using a pill to create a similar effect is already possible.

They gave normal mice an experimental drug called GW501516 that also activates PPAR-delta. The drug is being developed by GlaxoSmithKline to treat people with fat metabolism disorders. Normal mice given the drug could eat a high-fat diet without gaining weight, Evans said. 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.
PloS Biology 2004;2:e294.
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