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AICAR, GW1516 Are An Exercise In A Pill

AICAR, GW1516 Are An Exercise In A Pill

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.”

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

Submitted by Armen Hareyan

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T3 cytomel for weight loss

T3 (cytomel)

It has been over 100 years since the discovery by Magnus-Levy that thyroid hormones play a central role in energy homeostasis, and 75 years since the hormones were first used for weight loss. Despite this great length of time, the precise mechanisms by which thyroid hormones exert their calorigenic effect are not completely characterized, and still actively debated. Despite numerous clinical studies having shown that the administration of thyroid hormone induces weight loss, it is not currently indicated as a weight loss agent. This is probably due to the number of side effects observed during thyroid hormone use at the relatively high doses used in the majority of obesity treatment studies. These deleterious effects include cardiac problems such as tachycardia and atrial arrhythmias, loss of muscle mass as well as fat, increased bone resorption and muscle weakness. Nevertheless, thyroid hormones, particularly triiodothyronine (T3) are a mainstay in the arsenal of drugs used by bodybuilders for fat loss. The widespread underground use of T3 warrants an understanding of its mechanism of action, as well as a knowledge of how it is most effectively and safely used, with an eye to minimizing side effects.

Thyroid Function and Physiology

Before jumping right into a discussion of the use of thyroid hormone for fat loss, a little review of thyroid function and physiology might be in order. The thyroid gland secretes two hormones of interest to us, thyroxine (T4) and triiodothyronine (T3). T3 is considered the physiologically active hormone, and T4 is converted peripherally into T3 by the action of the enzyme deiodinase. The bulk of the body’s T3 (about 80%) comes from this conversion. The secretion of T4 is under the control of Thyroid Stimulating Hormone (TSH) which is produced by the pituitary gland. TSH secretion is in turn controlled through release of Thyrotropin Releasing Hormone which is produced in the hypothalamus. This is analogous to testosterone production, where GnRH from the hypothalamus causes the pituitary to release LH, which in turn stimulates the testes to produce testosterone.

In addition to T3, it has recently been recognized that there exist two additional active metabolites of T3: 3,5 and 3,3′ diiodothyronines, which we will collectively call T2. Studies have shown that 3,3′-T2 may be more effective in raising resting metabolic rate when hypothyroid subjects are treated with T3, than when normal (euthyroid) subjects are given T3. Therefore in normal subjects 3,5-T2 may be the principal active metabolite of T3 (1)

Like the hypothalamic-pituitary-gonadal axis, the thyroid gland is under negative feedback control. When T3 levels go up, TSH secretion is suppressed. This is the mechanism whereby exogenous thyroid hormone suppresses natural thyroid hormone production. There is a difference though between the way anabolic steroids suppress natural testosterone production and the way T3 suppresses the thyroid. With steroids, the longer and heavier the cycle is, the longer your natural testosterone is suppressed. This is not the case with exogenous thyroid hormone.

An early study that looked at thyroid function and recovery under the influence of exogenous thyroid hormone was undertaken by Greer (2). He looked at patients who were misdiagnosed as being hypothyroid and put on thyroid hormone replacement for as long as 30 years. When the medication was withdrawn, their thyroids quickly returned to normal.

Here is a remark about Greer’s classic paper from a later author:

“In 1951, Greer reported the pattern of recovery of thyroid function after stopping suppressive treatment with thyroid hormone in euthyroid [normal] subjects based on sequential measurements of their thyroidal uptake of radioiodine. He observed that after withdrawal of exogenous thyroid therapy, thyroid function, in terms of radioiodine uptake, returned to normal in most subjects within two weeks. He further observed that thyroid function returned as rapidly in those subjects whose glands had been depressed by several years of thyroid medication as it did in those whose gland had been depressed for only a few days” (3)

These results have been subsequently verified in several studies.(3)(4) So contrary to what has been stated in the bodybuilding literature, there is no evidence that long term thyroid supplementation will somehow damage your thyroid gland. Nevertheless, most bodybuilders will choose to cycle their T3 (or T4 which in most cases works just as well) as part of a cutting strategy, since T3 is catabolic with respect to muscle just as it is with fat. As previously mentioned, long term T3 induced hyperthyroidism is also catabolic to bone as well as muscle.

The proviso about T4 vs T3 for weight loss alluded to above needs some elaboration. There have been a number of studies that have shown that during starvation, or when carbohydrate intake is reduced to approximately 25 to 50 grams per day, levels of deiodinase decline, hindering the conversion of T4 to the physiologically active T3.(5) From an evolutionary standpoint this makes sense: during periods of starvation the body, teleologically speaking, would like to reduce its basal metabolic rate to preserve fat and especially muscle stores. However, a recent study demonstrating the effectiveness and safety of the ketogenic diet for weight loss recorded no change in circulating T3 levels.(6) So this issue not completely settled. Nevertheless, persons contemplating thyroid supplementation during ketogenic dieting might prefer T3 over T4 since the bulk of the research does suggest a decline in the peripheral conversion of T4 to T3 during low carb dieting.

Now that we have reviewed a little about thyroid function, let’s consider just how it is that thyroid hormone exerts its fat burning effects.

Increased Oxidative Energy Metabolism

Thyroid hormone has long been recognized as a major regulator of the oxidative metabolism of energy producing substrates (food or stored substrates like fat, muscle, and glycogen) by the mitochondria. The mitochondria are often called the “cell’s powerhouses” because this is where foodstuffs are turned into useful energy in the form of ATP. T3 and T2 increase the flux of nutrients into the mitochondria as well as the rate at which they are oxidized, by increasing the activities of the enzymes involved in the oxidative metabolic pathway. The increased rate of oxidation is reflected by an increase in oxygen consumption by the body.

T3 and T2 appear to act by different mechanisms to produce different results. T2 is believed to act on the mitochondria directly, increasing the rate of mitochondrial respiration, with a consequent increase in ATP production. T3 on the other hand acts at the nuclear level, inducing the transcription of genes controlling energy metabolism, primarily the genes for so-called uncoupling proteins, or UCP (see below). The time course of these two actions is quite different. T2 begins to increase mitochondrial respiration and metabolic rate immediately. T3 on the other hand requires a day or longer to increase RMR since the synthesis of new proteins, the UCP, is required (1).

There are a number of putative mechanisms whereby T2 is believed to increase mitochondrial energy production rates, resulting in increased ATP levels. These include an increased influx of Ca++ into the mitochondria, with a resulting increase in mitochondrial dehydrogenases. This in turn would lead to an increase in reduced substrates available for oxidation. An increase in cytochrome oxidase activity has also been observed. This would hasten the reduction of O2, speeding up respiration. These and a number of other proposed mechanisms for the action of T2 are reviewed by Lannie et al.(7)

What is the fate of the extra ATP produced during hyperthyroidism? There are a number of ways by which the increased ATP promotes an increase in metabolic activity, including the following:

Increased Na+/K+ATPase. This is the enzyme responsible for controlling the Na/K pump, which regulates the relative intracellular and extracellular concentrations of these ions, maintaining the normal transmembrane ion gradient. Sestoft(7) has estimated this effect may account for up to to 10% of the increased ATP usage.

Increased Ca++-dependent ATPase. The intracellular concentration of calcium must be kept lower than the extracellular concentration to maintain normal cellular function. ATP is required to pump out excess calcium. It has been estimated that 10% of a cell’s energy expenditure is used just to maintain Ca++ homeostasis. (1)

Substrate cycling. Hyperthyroidism induces a futile cycle of lipogenesis/lipolysis in fat cells. The stored triglycerides are broken down into free fatty acids and glycerol, then reformed back into triglycerides again. This is an energy dependent process that utilizes some of the excess ATP produced in the hyperthyroid state (8). Futile cycling has been estimated to use approximately 15% of the excess ATP created during hyperthyroidism (8)

Increased Heart Work. This puts perhaps the greatest single demand on ATP usage, with increased heart rate and force of contraction accounting for up to 30% to 40% of ATP usage in hyperthyroidism (9)

Mitochondrial Uncoupling

As mentioned, the mitochondria are often characterized as the cell’s powerhouse. They convert foodstuffs into ATP, which is used to fuel all the body’s metabolic processes. Much research suggests that T3, like another much more potent agent DNP, has the ability to uncouple oxidation of substrates from ATP production. T3 is believed to increase the production of so called uncoupling proteins. Uncoupling protein (UCP) is a transporter family that is present in the mitochondrial inner membrane, and as its name suggests, it uncouples respiration from ATP synthesis by dissipating the transmembrane proton gradient as heat. Instead of useful ATP being produced from energy substrates, heat is generated instead. There are conflicting studies about the importance of T3 induced uncoupling. Animal studies have demonstrated an actual increase in ATP production commensurate with increased oxygen consumption as we discussed above. Other studies in humans have shown that in fact uncoupling in skeletal muscle does occur. This would contribute to T3 induced thermogenesis, with a resulting increase in basal metabolic rate.(10)

To make up for the deficit in ATP production (as well as provide fuel for the extra ATP production discussed above) more substrates must be burned for fuel, resulting in fat loss. Unfortunately, along with the fat that is burned, some protein from muscle is also catabolized for energy. This is the downside of T3 use, and the reason many people choose to use an anabolic steroid or prohormone during a T3 cycle to help preserve muscle mass. Studies have shown this to be an effective strategy (11). (Muscle glycogen is also more rapidly depleted, and less efficiently stored during hyperthyroidism. This may account for some of the muscle weakness generally associated with T3 use.)

Countering T3 induced muscle loss with anabolic steroids or prohormones makes sense from a physiological viewpoint as well. Thyroid hormone muscle protein breakdown is mainly mediated via the so-called ubiquitin-proteasome pathway. (12). (There are several independent metabolic pathways of protein breakdown in the body. For instance, another pathway, the lysosomal pathway, is responsible for the accelerated rate of muscle protein breakdown during and after exercise.) Testosterone administration has been shown to decrease ubiquitin-proteasome activity. (13) So anabolic steroids specifically target the muscle protein breakdown process stimulated by T3.

What may not be an effective strategy to maintain muscle mass during a T3 cycle is the use of exogenous growth hormone (GH). Studies have shown that when GH and T3 are administered concurrently, the increased nitrogen retention normally associated with GH use is abolished. This has been attributed to the observation that T3 increases levels of insulin like growth factor binding protein, reducing the bioavailability of igf-1 (14). Nevertheless, GH has fat burning properties independent of igf-1, so using GH with T3 would act additively to speed fat burning, but with little if any preservation of lean body mass. So again, if GH is used in conjunction with T3, anabolic steroid/prohormone use would be indicated.

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