The whimsical dream of getting exercise in a pill has just become more realistic.

In a Salk Institute-led study released Tuesday, researchers were able to provide some of the fat-burning effects of exercise to sedentary mice, And they did it with an orally given drug, a benefit for use in people.

A more advanced version of the drug is being readied for development, said Ron Evans, a study leader. It has been licensed by Mitobridge, a Cambridge, Mass. biotech company.

Frail or infirm patients who can’t easily exercise, such as those with COPD, would benefit from such a drug, Evans said.


When given to the mice for eight weeks, the drug shifted the mouse muscles from burning glucose to burning fat. This preserved more glucose for the brain, enabling the inactive mice to run about 70 to 80 percent longer in a treadmill test of endurance than a control group of their untreated peers.

This endurance boost mimics the effects of exercise, which also shifts muscle metabolism away from glucose toward fat. That shift delays what is known as “hitting the wall,” when the body can’t endure any more fatigue.

By enabling muscles to more easily burn fat, it could also help with weight reduction. Increased insulin sensitivity is also a benefit, he said. Type 2 diabetes is characterized by a loss of insulin sensitivity.

Unlike compounds studied in previous research, this drug provides a no-exercise benefit.


“In previous studies, we’ve needed to exercise the mice,” Evans said. “In this study, we show that no exercise is needed.”

There’s also a danger that athletes could illicitly use the drug as a performance-enhancer, but that’s already being done with a drug made from a crude and less safe early version of the fat-burning technology, Evans said.

The study was published in Cell Metabolism. It can be found at j.mp/salkexer. Evans and Michael Downes were co-senior authors. Weiwei Fan was first author.

Saving it for the brain


Brains preferentially use glucose over fat, but intense exercise forces the body to compete with muscles for glucose, Evans said.

Both the treated and control groups of mice became exhausted when their blood glucose levels dropped to about 70 milligrams per deciliter, implying that hypoglycemia was the cause. However, the mice given the drug took longer to reach that hypoglycemic state, Evans said.

When the scientists examined muscle tissue in mice given the drug, they found changes in activity of 975 genes. Those involved in metabolizing carbohydrates for energy were suppressed; those used to burn fat were turned up. This metabolism-shifting effect didn’t occur in the brain, so it was able to use glucose as needed, Evans said.

Like muscle, much of the brain can metabolize fatty acid byproducts called ketone bodies, The brain uses ketone bodies during fasting or during a ketogenic diet, which is very high in fat and very low in carbohydrates. However, some parts of the brain absolutely require glucose to function.


Fan discovered that glucose was the limiting factor by injecting more of it into exhausted mice that have “hit the wall”, Evans said.

“They can get back on the treadmill and keep running,” Evans said. “The point of (exercise) is to progressively train the muscles to not use sugar and replace it by taking in more fat. It’s a very complicated process because it involves altering your genetic programs. Training is a slow way of changing gene usage. The same thing happens with our drug.”

The drug-induced metabolic shifting is caused by altering a molecular pathway called PPAR delta that Evans and colleagues have been examining for many years.

A 2008 study led by Evans found that activating PPAR delta and a related pathway called AMPK enhanced running endurance in mice by 44 percent. Others have researched this pathway as well. A 2005 study found that activating the pathway helped obese animals lose fat.


Help to patients

Amy Firth, a University of Southern California stem cell researcher who specializes in lung diseases, said she was excited about the discovery, because a loss of lung capacity makes exercise difficult or impractical. If the research can be translated from animals to human use, chronic lung disease patients could get some of the health benefits of exercise.

“An extended period of aerobic exercise is going to benefit the heart and lungs, and that’s incredibly beneficial for those who have chronic lung disease,” said Firth, who was a Salk Institute postdoctoral researcher in the lab of Inder Verma. These include those with cystic fibrosis and COPD, or chronic obstructive pulmonary disease.

COPD was the third leading cause of death in the United States in 2014, according to the Centers for Disease Control and Prevention.


“These patients have a reduced ability to exercise due to a limited lung capacity and ability to get oxygen into the blood to fuel muscle activity,” Firth said. A drug to improve endurance could fundamentally improve their lives.

Lack of exercise by these patients causes their muscles to waste away, Firth said. By giving these patients more endurance, they might be able to exercise enough to reduce or prevent muscle wasting. In addition, exercise has been shown to help lung function.

Rolling back diabetes

Type 2 diabetes should also respond to the drug, Evans said. Because normal levels of insulin doesn’t work as well, patients may need to take drugs, including insulin, to compensate.


“Diabetes tend to have hyperlipidemia or high fat (in the blood)”, Evans said. “High fat in your blood tends to make you insulin-resistant. And so you have not only high fat, but high insulin. By burning fat, you naturally are also going to reduce the insulin resistance progressively and trend toward becoming insulin-sensitive. When that happens, you actually take less and less insulin, because you become more sensitive.”

In addition, burning fat will help reduce the stores of fat that high levels of insulin stashes away.

“Any weight loss in a diabetic is going to improve health dramatically,” Evans said. “For diabetes, even though it’s a complicated disease, this hits the right genetic pressure points to have overall improvement in body health.”

This is also true of metabolic syndrome, a related group of dysfunctions that are closely associated with Type 2 diabetes, Evans said. These dysfunctions include hyperlipidemia, hyperglycemia and hypertension. Heart function is impaired and weight increases.


“So all those parameters move together, including inflammation,” Evans said. “With the drug, they’re shifted back to the equivalent of an exercised body.”

That exercise is what humans have been used to until very recent times, Evans said, and the body is adapted for it.

“Humans are designed to move. We were not designed to have computers.”

Basic science pays off


Evans said the knowledge to create the drug came from years of basic research understanding the genetics and physiology that comes with exercise, and with diseases helped by exercise.

PPAR-delta was discovered in 1995, and a lot of research since then has elucidated how this metabolic switch operates. Evans said that solid understanding of the biology makes the process of translating the research to a therapy much easier.

“By understanding that process, we can find that exercise switch and flip it with a chemical,” he said.

Preparation for a clinical trial could take as little as a year, Evans said. That will use a more advanced version of the prototype used in the animal study.


That prototype has actually been made by the government of Russia and given to athletes, but it is not a good drug, Evans said. The advanced version is safer and more effective.

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UPDATES:

11:15 a.m.: This article was updated with additional details.


This article was originally published at 9 a.m.