In 2004, Evans and his colleagues genetically manipulated a gene in mice called PPAR-delta, a master regulator of different genes. The genetically engineered mice could reportedly run twice as far as normal mice and stayed lean even when fed a high-fat diet.

While the results were a breakthrough, the next step was to find a drug that could mimic these effects. Evans then tested a compound called GW1516, which researchers are currently considering as potential obesity and diabetes drugs. Yet even though it affected the genes of the mice, it did not affect their metabolism.

The researchers then went back to the drawing board and brain-stormed what happens naturally in real life. “If you’re out of shape – and most of us are – and you want to change, you have to do some exercise. The way we reprogram muscles in adults is by training,” said Evans.

With this in mind, the researchers trained the rodents, while administering the GW1516 drug to a few – not all – of the mice. Tests then showed that while all the mice became more athletic, those given the pill ran 68% longer than those that had only done the exercise training. “The dramatic effect was stunning,” said Evans, but he added that the pill would not help people who might have muscle-wasting diseases, fatigue or who were too overweight to exercise.

This realization caused the Californian researchers to seek a different way to affect PPAR-delta. One compound that is well understood is AMP – activate protein kinase or AMPK, which is “a master regulator of cellular and organismal metabolism,” according to Evans.

With this new compound, the researchers were sure the activity caused by AMPK would be the secret to allowing the PPAR-delta drugs to work. The team then administered AICAR, a pill which mimics AMPK to the mice which makes the muscles think they are burning fat and the results showed that 44% of the mice ran for longer periods than the animals which hadn't received the pill.

“This is a drug that is like pharmacological exercise,” Evans said. “After four weeks of receiving the drug, the mice were behaving as if they’d been exercising,” and could outrun the mice given the traditional exercise training.

While the pills are only available experimentally now, Evans is not working with any drug companies, but he stated that GW1516 had a relatively simple chemical structure and could be easily synthesized.

“One of the pills may someday help people enhance their exercise or training, while the other might be more suited for couch potatoes who need to kick-start themselves,” Evans and his colleagues reported in the journal Cell.

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