No longer do rats have to run their little tails off to lose a few ounces. Brigham Young University scientists have discovered a way to chemically force the critters' muscles to begin burning fat - without exercising.
Actually, the rats aren't any better off for the experience. It's not a weight-loss program for them but an experiment that uncovered fundamental facts about cell physiology.Even worse for the rats, the laboratory animals are anesthetized and killed painlessly with overdoses while the experiment continues. Then the chemistry of their muscle cells is examined in detail.
But what's bad luck for rodents may be a great discovery that leads to new hope for people who are overweight or suffering from Type II diabetes.
What zoology professor Will Winder and his team found is that the injection of a drug called AICA forces muscle cells to take up glucose, or sugar, and burn fat. And this happens without exercise or fasting.
As the team wrote in a paper published last December by the Journal of American Physiology:
"To our knowledge, this is the first report of an increase in fatty acid oxidation by skeletal muscle in response to a decrease in malonyl-CoA." The last-named chemical is a "gatekeeper" in the muscle cell, determining whether fat can enter.
When a cell has a lot of malonyl-CoA, the molecular gate closes and fat can't get in. In order to burn fat for energy, the cell has to lose malonyl-CoA.
"Back in 1989 we did a study where we ran rats on the treadmill, then measured the malonyl-CoA after they ran for different amounts of time," Winder said during a visit at his office and adjacent lab.
In those investigations, the scientists found that the level of this chemical drops during exercise. The decrease is signaled to the muscle cell, which decides it must let more fat in to be burned, replacing energy lost during exercise.
The signal that triggers this cell activity is an enzyme called AMPK, which is brought into play by muscle contractions during exercise. But the team speculated that maybe a muscle cell can be duped into thinking the signal was there through an entirely different way.
If that happened, it could be induced to burn fat without exercising.
The method was to dose the muscle with a drug called AICA.
From work carried out elsewhere, Winder knew that AICA can activate the signaling enzyme in liver and fat cells. He wondered if it could do the same for muscle cells.
During last year, the team worked to find out, he said. They included Winder; student Emily J. Kurth; Gary F. Merrill, a cardiovascular physiologist who was on sabbatical at BYU; and Grahame Hardie of the University of Dundee, Scotland. "It took us the full year."
They tested muscles of rats' hind limbs, using both those that were and were not treated with the drug. They controlled blood going into the muscle, knowing exactly what its components were. Then they tested the blood coming from the limbs to see how much glucose and fat the muscles were taking up.
For more detail about what was going on, they also froze the muscles with liquid nitrogen, then ground them and determined their components.
Obviously, the deceased rats weren't exercising at all. Yet the team found that with the drug, the muscle cells still increased their fatty acid oxidation markedly. But nothing happened without the drug.
Also, the levels of the gatekeeper chemical, malonyl-CoA, were similar to those produced by fasting or exercise. Somehow, the drug had turned on the chemical signal artificially.
"If a drug could be found which would be suitable for administration to human subjects, patients, which would artificially activate AMP-kinase (AMPK), it'll probably be useful in treating both obesity and Type II diabetes," Winder said.
He stressed that the drug has been tried on rats only. "It's not approved for human use," he said. Even if it were, at $500 a pop it would be far too expensive.
An injection that expensive probably would not help a person any more than would running for one hour.
Chad Hancock, a senior in exercise physiology from Pocatello, Idaho, explained that the discovery is one step toward the goal of improved treatment. It helps scientists understand the chemistry by which fat is burned and sugar is taken up.
"If we understand the mechanism of glucose uptake, then we can prescribe better treatment," he said. Eventually, building on these experiments, "more effective treatments can be prescribed."
Kurth added that the work may be most significant for Type II diabetes, the type that afflicts the vast majority of diabetics. "It doesn't give us a cure for diabetes, but it tells us where to look for a cure," she said.