By: Spook
Introduction
This article is for information purposes only. It is not intended to offer any kind of advice to treat any type of disease. If you have a medical condition or are interested in fibrate drugs please consult your doctor.
In this issue I would like to take some time to discuss a class of drugs known as fibrates. For some reason fibrates are not often discussed in bodybuilding literature; I would like to change that as I feel these compounds have tremendous potential to aid in one's body composition goals.
The fibrates are all pretty much derivatives of fibric acid. They are all ligands for the Peroxisome Proliferater Activated Receptor (PPAR). The PPAR is a nuclear receptor; it exists inside the nucleus protected by the nuclear membrane. For ligands to bind to the PPAR receptor they must first find their way into the nucleus.
The PPAR Receptors
There are three types of PPAR receptors. There is alpha, gamma, and beta/delta. Alpha is the receptor that the fibrates bind to with the greatest efficacy. The gamma receptors are mostly bound by another class of drugs, such as Rosiglitazone. These PPAR-gamma agonists are often given to Type II diabetics as they improve insulin resistance. This is especially so if the subject suffers from high concentrations of fat in his/her blood or has abdominal obesity.
PPAR-gamma helps to produce additional fat cells to better store the elevated fatty acids that are floating around in such a subject's blood stream. As a result, it improves insulin resistance. The downside is that this tends to just make the person gain fat. Not something a bodybuilder would be interested in.
The fibrates on the other hand mostly bind to PPAR-alpha. PPAR-alpha is in most respects the opposite of PPAR-gamma, in that it will help to reduce bodyfat. The PPAR pathway in many ways mimics how androgens work. Androgens enter the cell mostly through passive diffusion, where they form a heterodimer with two androgen receptors and another androgen. Then this heterodimmer can enter the nucleus and induce DNA transcription, which increases protein synthesis.
PPAR is very similar, except that the DNA sequences that get transcribed are different. A ligand for the PPAR must first form a dimmer with a Peroxisome X Receptor (PXR). Of importance is that PPAR is very promiscuous; it's not a single lock and key system like many other receptors and ligands. PPAR will bind to many different ligands. Once a ligand is bound to a PXR it can then enter the nucleus where it binds to the PPAR and activates it.
The PPAR then initiates transcription of many different proteins. The proteins it transcribes differ from one tissue to the next. It also differs significantly between species. The natural ligands for the PPAR are fatty acid derivatives and some metabolites of prostaglandins. Specifically, EPA and DHA (found in fish oil) are particularly potent ligands for PPAR-alpha. Fibrates do this as well, however they are much more effective.
PPAR delta is the last of the PPAR receptors. It is also called beta in some of the literature so we will call it beta/delta for the remainder of this article. It is not yet known exactly what PPAR beta/delta's use is. Some hypothesize that it is simply a backup for PPAR alpha, as PPAR alpha knockout mice show unregulated beta/delta activity that compensates for the loss of alpha.
Fibrates and PPAR Activation
Now that the background information is out of the way, we can talk about why you might actually want to use these compounds. When PPAR-alpha is activated it causes the production of a group of proteins, many of which are directly involved in fatty acid oxidation. Fat loss is really a three-stage process: release, transport, and finally oxidation. Compounds that enhance lipolysis such as ephedrine and caffeine or clenbuterol take care of the first step to fat loss…quot;namely, release.
That still leaves transport and oxidation. Luckily ephedrine and caffeine also enhance transport to some degree. When the beta-adrenoreceptors (B-AR) in your muscle or liver are activated these compounds stimulate a protein called Fatty Acid Transferase (FAT/CD36). Think of this as GLUT but for fat.
So although fats, unlike carbohydrates, can enter cells through passive diffusion they can also be actively transported. This aids fat uptake into muscle tissue and liver tissue where it can be used for fuel. The other half of the transport problem is blood flow. Blood flow around fat tissue is not particularly good. We need to enhance this to move those newly liberated fatty acid molecules away from the fat cells so that they can be oxidized. There are several things that can aid transport, though they are unfortunately beyond the scope of this article. Just know that it is an issue that needs attention.
Fibrates are of benefit because they help take care of the last problem: oxidation. In muscle or liver tissue that is treated with a PPAR-ligand you get enhanced transcriptions of a host of fat burning enzymes, like CPT, FAT/CD 36, etc. So we could think of fibrates as fatty acid partitioning drugs. Fibrates essentially cause more fats to make their way to muscle and liver tissue rather than fat tissue. Sounds pretty good to me.
In fact, these drugs are so well researched I won't bore you with the details. Suffice it to say, rats given fibrates are protected from diet-induced obesity, and show lower fat weight compared to controls. A search on this issue will yield thousands of studies on the subject.
Fibrates are generally given to patients who have a problem with fatty acid trafficking; specifically, fibrates are administered to diabetics who have elevated levels of fatty acids in their blood. Fibrates are also used as treatment for those with cholesterol problems, as PPAR-alpha enhances the transcription of many proteins involved in cholesterol metabolism. Today, most patients with cholesterol problems are given one of the statin medications instead as they work better. However, for unresponsive patients the fibrates are generally prescribed in conjunction with statin therapy.
Possible Side Effects
Now lets discuss the possible downsides. All of the side effects of these medications come about because they do their job almost too well. So this is not a "more is better" kind of drug. It's best to think of the fibrates as long term partitioning agents. In other words, they won't help you lose thirty pounds in thirty days. Think of them instead as optimizing what Mother Nature gave you. This should result in better progress over time. Remember bodybuilding…quot;and the permanent alterations in body composition that result…quot;is a marathon, not a race.
Almost all the side effects of these drugs stem from their how they work. Basically, if you enhance fat oxidation excessively, some bad things begin to happen. The most common and well-researched negative side effect seems to be renal deposits of acytel-CoA. Acytel-CoA is a necessary product of fat oxidation.
As I have discussed in previous articles, it is the balance of acytel-CoA that determines nutrient usage. The body needs acytel-CoA to burn fat in the first place, as acytel-CoA must join with a long chain fatty acid to form an acyal-fatty acid complex that can then be actively transported into the mitochondria by CPT. Unfortunately however, extra actyel-CoA is a prime target for ACC.
ACC will transform that excess acytel-CoA into malonyl-CoA, which actually inhibits CPT. To complicate things even further, one of the primary pathways for acytel-CoA metabolism is the lipogenesis pathway. In humans this is not such a problem in terms of fat storage, however when it's activated it can have negative consequences, particularly for our brains. I will discuss the details later.
Formation of Acetyl Coenzyme A.
So, these drugs are producing a substantial amount of acytel-CoA, which means that a significant number of fats are being burned. The problem is that over time all this extra actyel-CoA can build up in one's kidneys, causing health problems. Luckily there is one fibrate called gemefezbrozil that does not seem to generate this problem in comparison to the other fibrates.
Other side effects of fibrate use include muscle tissue wasting or weakness, cardiac cell death, increased appetite, and decreased testosterone synthesis. All of these are directly dose-dependent. Again, with fibrates, we have another example of how too much of a good thing can be bad. When muscle tissue is induced to burn fatty acids at excessive rates, it generally causes muscle weakness, and on the extreme end can cause cell death. However this only seems to occur if the dose is far beyond the realm of therapeutic doses.
The issue with cardiac cell death is similar. Heart tissue is extremely sensitive to its fuel usage. If its fuel usage is high it starts to instigate cell death. Though, this issue is not so cut and dry, and it's questionable whether this even occurs in humans at all. In humans and rats PPAR is both involved in cellular proliferation and apoptosis. However the effects differ greatly. For example rats given excess fibrates develop liver tumors because the fibrates shut off the natural cell death machinery. In humans fibrates do not have this effect. So really, the issue of cardiac cell death in humans is as yet unsettled.
Finally, fibrate-induced increases in appetite can be a problem. If you're using the fibrates as anti-fat gain drugs while bulking this secondary effect is probably welcome. However, if you're utilizing fibrates to enhance a cutting cycle than this is obviously undesirable. Luckily this effect on appetite can be counteracted. The increase in appetite is largely a product of the extra actyel-CoA that is being manufactured.
As mentioned previously, when there is a large amount of acytel-CoA, the excess gets shuttled down the lipogenesis pathway. Along the way this excess increases the activity of fatty acid synthase (FAS). Increased FAS activity is known to increase appetite primarily by lowering production of MSH and POMC in the Arcuate Nucleus and Lateral Hypothalamus. I wrote extensively about these in my past articles on leptin.
Luckily this side effect…quot;the result of excess actyel-CoA production…quot;can be countered by an FAS inhibitor. There are several FAS inhibitors available on the market. High doses of hydroxycitrate (10g per day) or green tea extract are two such options. High quality hydroxycitrate is available in bulk at reasonable prices. I personally have used 3g four times per day with much success when it comes to appetite suppression.
However, individual response and mileage may vary. Green tea extract is also a potent inhibitor of FAS, and there are numerous green tea extracts available on the market. It is mainly the ECG component that seems to be the strong FAS inhibitor, so I would look for an extract that has a large proportion of ECG.
Usage Recommendations
So who would experience the best results with the fibrates? As I said before, low dose use of these drugs can be conceptualized as an effective fatty acid partitioning agent. It should make cutting cycles more productive, and should keep fat gain at bay when bulking. So over time your results should be superior to what you could have accomplished without fibrate use. For those that are significantly overweight, use at full prescription dose is more appropriate, at least until one loses the excess weight, at which point the dose should be lowered.
This article appears courtesy of www.mindandmuscle.net
Spook
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