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AICAR, GW1516 Are An Exercise In A Pill

Armen Hareyan's picture

AICAR and GW1516 experiments suggest that these two drugs, also called exercise in a pill, might protect against gaining weight on a high-fat diet, which might make it useful for treating obesity.

Researchers have identified two drugs, AICAR and GW1516, that mimic many of the physiological effects of exercise. The drugs increase the ability of cells to burn fat and are the first compounds that have been shown to enhance exercise endurance.

Both AICAR and GW1516 can be given orally and work by genetically reprogramming muscle fibers so they use energy better and contract repeatedly without fatigue. In laboratory experiments, mice taking the drugs ran faster and longer than normal mice on treadmill tests. Animals that were given AICAR, one of the two drugs, ran 44 percent longer than untreated animals. The second compound, GW1516, had a more dramatic impact on endurance, but only when combined with exercise.

Ronald M. Evans, the Howard Hughes Medical Institute investigator who led the study, said drugs that mimic exercise could offer potent protection against obesity and related metabolic disorders. They could also help counter the effects of devastating muscle-wasting diseases like muscular dystrophy. Evans and his colleagues, who are at the Salk Institute for Biological Studies, published their findings on July 31, 2008, in an advance online publication in the journal Cell.

Concerned about the potential for abuse of the two performance-enhancing drugs AICAR and GW1516, Evans has also developed a test to detect the substances in the blood and urine of athletes who may be looking for way to gain an edge on the competition.

In 2004, Evans and his colleagues genetically engineered mice that had altered muscle composition and enough physical endurance to run twice as far as normal mice. These “marathon mice” had an innate resistance to weight gain, even when fed a high-fat diet. “We made these mice and they had low blood sugar, they resisted weight gain, they had low fats in their blood. They were much healthier animals,” Evans said. “And when we put them on a treadmill, the engineered mice ran twice as far than normal mice - they transformed into remarkable runners.”

The scientists achieved these effects by modifying a gene called PPAR-delta, a master regulator of numerous genes. Evans and his colleagues showed that by enhancing PPAR-delta's activity, they had shifted the genetic network in muscle cells to favor burning fat over sugar as their energy source. But the effects seen in the marathon mice were caused by a genetic manipulation that was present in their bodies as their muscles were developing. Evans's group began to wonder whether they could duplicate these effects by turning on PPAR-delta in adult mice.

“We had shown that we could pre-program muscle using genetic engineering. If you express this gene while the muscle is being formed, you can increase the amount of non-fatiguing muscle fibers,” Evans says. “But what about reprogramming in an adult? When all the muscles are in place, can you give a drug that washes over the muscle for a few hours at a time and reprograms existing muscle fibers? That's a very different question.”

PPAR-delta has long been an attractive drug target because of its central role in metabolism, so Evans and his colleagues had no shortage of chemical compounds available to test. They began by testing a compound called GW1516. They treated young adult mice with the drug for five weeks. “We measured gene changes and the muscles looked like they were responding, so we knew the drug was working.”

Thus, while fully expecting the drug to dramatically increase endurance - Evans says, “There was no change at all in running performance. Nothing — not even a percent.”

Surprised by this spectacular failure, Evans and his colleagues decided to try a different approach, based on real-life experience. “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 muscle in adults is by training.”

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So the scientists subjected two groups of mice — one that received the drug and one that did not — to interval training. The mice ran for 30 minutes on a slow treadmill five days a week for a total of four weeks. At the end of the training period, all of the mice - regardless of whether they had received GW1516 - had improved their performance. Those that had received GW1516, however, ran 68 percent longer than those that had only done the exercise training. “The dramatic effect of the drug was stunning,” Evans said.

The scientists were intrigued by this synergistic interaction and wanted to know how exercise allowed the drug to work. One possibility was an enzyme called AMP kinase (AMPK). During exercise, cells burn ATP as their primary source of energy. In the process, they create a by-product called AMP. When cells sense the presence of AMP, they activate AMPK. Activation of AMPK creates more ATP for the cell to burn. AMPK also triggers changes that lower blood sugar, sensitize cells to insulin, enable cells to burn more fat, suppress inflammation, and otherwise influence metabolic pathways. This is one reason that exercise is so beneficial.

Evans's team found that in addition to replenishing the cell's energy stores, AMPK also assists PPAR-delta in activating its gene targets. “It hops onto PPAR-delta in the nucleus and turbo-charges its transcriptional activity,” Evans explained. “We think AMPK activity is the secret to allowing PPAR-delta drugs to work.”

The critical question was whether chemical activation of AMPK is sufficient to trick the muscle into thinking it has been exercised. The second drug, called AICAR, enabled them to answer that question. AICAR mimics AMP, Evans said, “so muscle thinks it's burning fat.” The researchers were encouraged when they found that when they gave the drug to mice, they activated many of the genes in muscle that are turned on by exercise.

After four weeks of treatment with AICAR, Evans and his colleagues once again challenged sedentary mice to run on the treadmill. They found that mice that had received AICAR were able to run 44 percent longer than untreated mice. “This is a drug that is like pharmacological exercise,” Evans says. “After four weeks of receiving the drug, the mice were behaving as if they'd been exercised.” In fact, he says, those that got the drug actually ran longer and further than animals that received exercise training.

The animals receiving AICAR improved their running performance and their ability to burn fat. None of these effects, however, were as strong as they were in the animals that received both exercise and activation of PPAR-delta via GW1516.

Evans said this indicates that the benefits are likely due to collaboration between cells' AMPK and PPAR-delta signaling pathways. The team's genetic analyses supported this hypothesis; they found that AICAR and GW1516 alone activated a subset of exercise-induced genes, but activating both pathways (by combining GW1516 with exercise) activated a larger group of genes. Many of those genes regulate metabolism and muscle remodeling. Evans and his colleagues called this the “endurance gene signature.”

Like exercise, AICAR and GW1516 trigger a variety of changes that contribute to muscles cells' improved endurance and ability to burn fat. These changes include an increase in mitochondria, the structures responsible for producing energy; a shift in metabolism that takes advantage of lipids as an energy source; and an increase in blood flow, which enables the steady delivery of fat to burn. While the scientists only examined the drugs' effects on muscle cells in this study, Evans says it is likely that they confer benefits on other systems impacted by exercise, such as the heart and lungs.

Based on his group's findings, Evans is optimistic about using small molecules that mimic exercise to treat and prevent a variety of common conditions. For example, the way in which AICAR and GW1516 transformed the muscle fibers of mice suggests they might help reverse the muscle frailty associated with aging or diseases like muscular dystrophy. “We have now created the potential for a really simple intervention in an area of major health problems for which there is no intervention,” he says.

More broadly, AICAR and GW1516 could offer the benefits of exercise to people who do not get enough. “Almost no one gets the recommended 40 minutes to an hour per day of exercise,” he says. “For this group of people, if there was a way to mimic exercise, it would make the quality of exercise that they do much more efficient. This might be enough to move people out of the `danger zone' toward a lower risk, healthier set point. By intervening early, you may forestall the emergence of more serious problems.”

Evans expects these types of drugs will be attractive to a variety of individuals. “If you like exercise, you like the idea of getting more bang for your buck,” he says of GW1516. “If you don't like exercise, you love the idea of getting the benefits from a pill,” as with AICAR. So, while Evans sees tremendous opportunities for health benefits from drugs that mimic exercise, he also sees serious potential for abuse.

“Drugs that improve health are not only going to be used by people who have medical problems. They may also be used by people who are healthy - or by athletes who want an edge,” said Evans. He noted that the sports world has long been aware of his lab's work demonstrating a link between PPAR-delta and endurance. What's more, GW1516 has a relatively simple chemical structure and can be synthesized easily. Evans anticipates that athletes will seek their own sources of the drug - if they haven't already.

Concerned about the potential for abuse, Evans thought it was important to develop a test that could detect whether the drug was being used as a performance-enhancing substance. With HHMI support, his group has created a highly sensitive test that uses mass spectrometry to detect the two drugs and their metabolic by-products in the blood or urine. While the test is very reliable in mice, Evans says that further analyses are needed to ensure that it is accurate in humans. Evans, HHMI and the World Anti-Doping Agency are now working to certify the detection system and make it available in time to retroactively test athletes who compete in the 2008 Olympics.



...how about testing the Tour De France cyclists.....?
I understand the drugs are both in use already as part of organ replacement process. So they have been tested as safe on humans but the issue remains untested re longer term use on an everyday basis to redirect metabolic targets. The article is detailed, refers to research going back several years, and talks about secondary research targets like the check test on athletes. The glaring omission is about the next stage to test that vital longer term human reaction. Rather than concentrating on the negatives of those who would misuse the treatment, please attend to the positive side of the many many people who desperately need this help to address established obesity, moderate diabetes or manage exercise when weakened by injury etc. So what's the schedule to bring this through to public use?
My heart muscles need help with endurance. Now.
I would like to know where the AICAR and GW 1516 can be obtained. I think it would help my fatigue. Please advise. Thank you. Dan Wirth
If these drugs prove to be the miracle drugs that they're constantly considered to become, then we are about to see a great change in our society. If you can imagine the impact they can have on a society that places such a high standard on personal appearance while having such a high (and increasing) obesity rate. Exercise makes us happy, healthy, and able. Since the implications are appealing to everyone, their use would rival that of asprin. Millions of newly happy, healthy, and able people would now be roaming the earth. We would see a large decrease in welfare covered medical needs. In fact, there would be a large decrease in medical needs overall due to a healthier population, and an increase in life expectancy. Now, imagine giving this drug to law enforcement officers... Our military... Our diabetic parents... Ourselves... Society will change. Oh, yes, society will change. Now, to create an online stock trading account. It's just a matter of time before a company starts mass production and distribution. My money is on them. - Benjamin W. Potter
When will this be avaliable for the Public? Will Insurance cover?
If aicar helps in all the ways discribed I want to invest now!!!
When will this be availanle to the public?
If we make something like this mainstream, i think it could save the world trillions of dollars in obesity related health care. I hardly think of it in terms of misuse if it helps people live healthier happier lives. If someone came out with a pill you could take regularly to avoid cancer, I doubt anyone would cry foul. So why would it be an issue if there is a pill that could prevent obsesity, and help prevent diabetes and heart disease. It's the future alot of people were hoping for a hundred years ago. Of course the republicans might think of it as too scary, but things are changing and so are people's views. How much longer before there is a pill that reverses the effects of aging?
This sounds like a wonderful breakthrough and will benefit a wide variety of people. There will be those who swear that exercise is always more important than taking a pill, but times change, science advances and the quality of our lives improves.
I am a diabetic... thi is great news.
The media assists the drug industry in concealing this fact. They are sold as nutritional supplements and are almost invariably safe and beneficial to almost everybody. Substances like acetyl-l-carnitine (ALCAR) and fish oil have widespread, universal benefits. When you see millions of dollars being spent on research, its often to develop a PATENTABLE version of X. Resveratrol is a good example. You can buy resveratrol now. Its not that expensive. Any patented drug will be expensive. When drugs fall off patent, thet become unavailable. Its BECAUSE they are cheap and effective, not in spite of it. Thats the way our broken system 'works'.
I want it - I need it - it will help the food industry grow, McD & Co need to give it freebies along with fries
reverse aging already exists... it's called HGH. It also is great for fat losss and muscle building, plus skin tightening and complection, etc. And insurance wont touch HGH for anti-aging purposes... they don't want you to live so they have to pay for you longer.
thease are the magic drugs and need to be presented for general public at the earliest .
We need them in the open market, society today needs it. Not everybody can go to gym
I am a man 65 years old. Muscular distrophy is killing me slowlly.As a matter of fact,i feel that I am alredy dead because there is no life in not beeing able to move.After an active 43 years Navy life,my only hope is for quick development of these two drugs.PLEASE!!!!!!!!!give us a chance.Allow me and people like me,to try AICAR and GW1516 as part of a scientific research protocol as soon as possible!! !!!!!! Hector Alvarez Viceadmiral (RE) Argentina.
This is the problem with America. This is why everyone is so unhealthy. Instead of hoping that this pill becomes available soon, go hit the gym and start exercising the old fashion way. Everyone is too lazy. These drugs should ONLY be available to the people that need them. They should not be used so some fat, lazy person can get the six pack that he always wanted. America is fat, its that simple and it is ridiculous that people are looking at this as a way to continue to be lazy, instead of being a helpful tool to promote a healthier, more active society. We will instead be creating a lazy society of "fit" people who are only "in shape" because of modern medicine.
I have worked in a gym for almost 2 years. I've have seen the same people come in at least 4 times a week. I would not consider some or evan most of these people to be at their ideal weight. This is NOT for a lack of trying. Their bodies simply don't allow the body to burn the fat properly. Your metabolism may work for you, but it isn't the same for everyone.
Recent studies have shown that fat people are no lazier than anyone else. This "fat=lazy" association is an example of a hurtful stereotype not based in fact. Please attempt to surgically remove it from your brain! All-or-nothing thinking that makes invalid proclamations about "everyone" is seldom helpful. I have a particular interest in these potential drugs because I have CFS/ME and CANNOT exercise. (Exercise produces in PWCs a cytokine cascade that mimics influenza; even walking slowly for 30 minutes on a treadmill knocks me out for anywhere from a week to 2 months!) As I am a Type 2 diabetic, obese, at high risk of heart disease, and suffering with arthritic knees, weight loss would clearly be helpful from a medical standpoint. Therefore, these drugs might provide a real health benefit to me that I am unable to achieve through exercise. I can't wait until they are tested properly in humans! FYI, CFS/ME also involves a mitochondrial dysfunction, making it even harder for PWCs to lose weight. Nonetheless, I have managed to lose 54 pounds in the last 26 months in spite of that and not being able to exercise! I'm not looking for a "six pack", only to be in a healthy weight and BMI range.
Don't Spoil it for the rest of us.
When are the human clinical trials going to start - count me in. Insulin resistance was my main problem long before I developed diabetes. If this had been available 5 years ago I might not be diabetic now.
Now, it seems to me that the only people really complaining about these drugs are the people who dont need them. So the jocks and primadonnas might get knocked down a notch. They wont attrract as much attention anymore when they walk down the street flexing everything because they wont be as much as a novelty anymore...well boo friggin hoo to them. Maybe we'll start judging a person by something OTHER than their wrapper.
Good day! It is very informative and has a very good quality in it. I like it... <a href= "http://www.squidoo.com/MPI"> www.Squidoo.com/MPI </a> <a href= "http://mliragana.blogspot.com/"> mliragana.blogspot.com </a> Thank you very much for your time.
Anonymous, your not suggesting that the appearance of these two new drugs and recent rumours of Armstrong coming out of retirement to race the tour again have anything in common....?
Yes I agree with some of the people who write here.who want the drug to loss weight is not good, but for the people with muscular dystrophy is very good because for us is not a treatment yet. i am 23 years old and I have muscular dystrophy and is hard for me but is hard also for my family.I can still walk but i can't climb the stairs and I know that in a few years my situation will be worse. So I think it will be a good think for us the people who have this health problem. Gina Romania
dont stop the development of them i am a 17 year old kid with muscular dystrophy and i honestly have no idea what to do about it
i am definitely on of those healthy people who would abuse this drug to enhance their bodies but just for the good looks not for the sport or something