by Thomas Incledon, PhD(c), RD, LD/LN, RPT, NSCA-CPT, CSCS, CFT
We all have those trouble spots. You know, the places that seem to fight fat loss no matter what we do. Fortunately science has revealed numerous agents that seem to magically accelerate the fat loss process, often times sparing muscle even better than dieting alone. Unfortunately some of these agents can be down right dangerous. In this article we will take a look at a variety of agents that have potential to impact fat loss.
Oxidative Phosphorylation and Oxidative Uncouplers
In order to understand how these agents work, we need to have a common starting ground. Some simple definitions are in order here. Oxidative phosphorylation is simply the formation of adenosine triphosphate (ATP) as a result of transferring electrons to oxygen. ATP is the chemical form of energy that we need to drive a number of reactions. These reactions can be used to digest food, transport nutrients, walk, lift weights, talk, read, and think. If we uncouple the oxidative process, we can inhibit our ability to make ATP. The energy that is produced is released as heat. Since oxidative uncouplers increase heat production, they are sometimes referred to as thermogenic agents. Some uncoupling may be useful in weight-loss, but if taken too an extreme, thermogenic activity can get out of control and then uncontrollable fevers can result. For this reason and because other side effects are possible, it is important to understand how an agent works before you use it.
DNP (2,4-Dinitrophenol)
I first read about DNP from an article by Dan Duchaine. He made it seem like it was no big deal to take it and that problems could be avoided with a little common sense. Out of curiosity I did some literature reviews and found out everything I could about DNP. You have to go way back to the 1930s to find the research on DNP, and this is before Old-Medline starts (1960 or so). The history of this agent dates back to the 1800s when French munition workers were using it to make explosives. They didn’t have to worry about OSHA compliance or anything like that back then. These guys were working with chemicals without any type of protective suits, masks, etc. They absorbed the DNP though their lungs, from the air around them and through their skin from handling it. Case reports appeared describing how profuse sweating, fever, agitation, death and an early rigor mortis [1]. Since these results were do to an uncontrolled exposure to DNP, some doctors thought that maybe controlled exposure could be useful for weight loss [2-7]. This seemed to work and DNP prescriptions were being handed out like candy. Then the problems started. Case reports of cataracts, peripheral neuritis, allergic reactions, jaundice, hepatic dysfunction, hematologic problems, cardiac arrhythmias, and death started cropping up [8]. This occurred even at therapeutic dosages (around 3.5 mg per kilogram of body mass). I have heard of people trying as much as 8 mg/kg over the last few years. Since toxic dosages appear to be at 10 mg/kg, this doesn’t seem too smart. DNP use under a competent physician’s care can be used safely, but what is scary is that even at safe dosages some people developed cataracts and other problems after they stopped taking DNP. The risks make this one drug to stay away from.
2,2’-methylenebis (4-ethyl-6-tert-butylphenol) or MBEBP
MBEBP is a synthetic antioxidant that is also an oxidative uncoupler. Some guys have managed to get their hands on it for use as a weight loss agent. There is very limited information available on this substance. I could find just four studies and only two of them were in English. Both studies dealt with rats [9, 10]. Similar to DNP, 10 mg/kg and above can be lethal. Weight gain was significantly depressed by MBEBP. Hemoglobin and triglycerides levels were decreased. You might be able to live with that, but how about testicular atrophy and a decrease in sperm production? Bottom line is that this is another agent with two many side effects to make it worth considering and there hasn’t been any human research.
Sodium usniate
Recently a chemical isolated from the Kombucha plant has been marketed as a weight-loss agent. Sodium usniate disassociates into sodium and usnic acid. In one study using mouse liver mitochondria, only 1 micromole of usnic acid completely abolished oxidative phosphorylation, while 50 times more DNP was needed to do the same thing [11]. Because of it’s strong effects, there is no doubt that this agent can increase weight loss, even though no human studies have validated this notion. However, numerous side effects are associated with Kombucha used as a tea and usnic acid itself. Medline is filled with reports of unexplained illnesses, liver problems, and allergic reactions associated with Kombucha tea consumption [12-15]. In addition, usnic acid is toxic to a variety of cells lines from different species [16-19]. It’s possible that other agents from Kombucha are causing the problems reported and not the usnic acid. However, given the toxicity of usnic acid to cells and the fact that it is a much stronger inhibitor of oxidative phosphorylation than DNP, it would be wise to hold off on using this agent until more research is known. If it turns out to be safe for use, than it will still help you to lose body fat. If it turns out to have some complications associated with it, then you saved yourself a load of hassles.
Uncoupling Proteins
Brown adipose tissue (BAT) is a specialized form of adipose tissue that produces heat. When stimulated by the sympathetic nervous system, it increases the production of an uncoupling protein called thermogenin (UCP1). This leads to heat production or a thermogenic response. How you wonder? Well normally the energy from certain molecules is used to convert adenosine diphosphate (ADP) to ATP. Thermogenin uncouples the energy from these from ATP production. This results in more fuel consumption (ie burning of calories) and less ATPs being made. BAT is very important in rodents, but is thought to have a minimal effect in humans.
Other uncoupling proteins have also been discovered. UCP2 is found in lung, liver, kidney, heart, skeletal muscle, and white adipose tissue [20]. It is upregulated in white fat cells in response to a fat feeding [21]. UCP2 may play a role in the increased energy expenditure and heat production during infection. Another uncoupling protein (UCP3) is found in skeletal muscle and brown fat [22]. As scientists unravel how these UCPs are turned on and off, novel therapeutic approaches will be formulated to maximize fat loss.
Leptin
Back in 1950 a mouse model of obesity called the “ob mouse” was first described. Four decades later, the ob gene was sequenced and the protein product was discovered. The ob gene has a defect and does not produce a protein called leptin in response to obesity. Normally, as body fat increases, the protein amount of leptin increases, signaling the brain to decrease food intake. By giving the ob mouse leptin, food intake decreases and energy expenditure increases [23]. The end result is more fat loss and less lean body mass loss. Since leptin is produced in humans, this would make you wonder about it’s potential role as a fat loss aid. Well the bad news is that leptin deficiency is rare and leptin levels are elevated in obese people compared to their lean counterparts [24]. It appears more likely that human obesity is associated with leptin resistance rather than leptin deficiency. Does leptin have application for non-obese subjects looking to lose weight? There may be some potential, but many other factors can influence leptin levels, including massive overfeeding, hyperinsulinemia, and high fat feeding. Recent evidence of leptin increasing the production of uncoupling proteins opens up new possibilities. Leptin has been reported to increase all three UCPs [25]. Leptin may modulate thermogenesis by increasing the sympathetic nervous stimulation of BAT and the production of UCP1, and by increasing UCP2 and UCP3 by a non-sympathetic mechanism. As the functions and interactions of leptin are made clearer, the appropriate use of this protein may allow weight loss to be accelerated.
The Ideal Uncoupler
DNP, MBEBP, and usnic acid are oxidative uncouplers. They all have side effects directly and/or indirectly associated with their use and can be toxic. The ideal agent would either activate 1 or more UCPs in a controlled fashion or uncouple oxidative phosphorylation with minimal side effects. Leptin holds some promise in this area for normal leaner people. Obese people may need something to increase leptin sensitivity so that it can bind more readily to the leptin receptor. Pharmaceutical companies are racing to be the first to design drugs to activate UCPs, which may have even more potential. In the mean time several Japanese herbal products have already established that they can induce fat loss and spare lean body mass in rodents without any evidence of side effects. We’ll have to wait for now to find out just what special ingredients these herbal extract have that make them so effective. Maybe the next weight loss agent can be grown in your own garden!
References
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2. Cutting, W.C. and M.L. Tainter. Actions of dinitrophenol. Proceedings of the Society for Experimental Biology & Medicine, 1932. 29(Part 2): p. 1268-1269.
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9. Takagi, A., et al. Toxicity studies of a synthetic antioxidant, 2,2’-methylenebis (4-ethyl- 6-tert-butylphenol) in rats. 1. Acute and subchronic toxicity. Journal of Toxicological Sciences, 1992. 17(3): p. 135-153.
10. Takagi, A., et al. Toxicity studies of a synthetic antioxidant, 2,2’-methylenebis (4-ethyl-6-tert-butylphenol) in rats. 2. Uncoupling effect on oxidative phosphorylation of liver mitochondria. Journal of Toxicological Sciences, 1993. 18(1): p. 49-55.
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21. Fleury, C., et al. Uncoupling protein-2: A novel gene linked to obesity and hyperinsulinemia. Nature and Genetics, 1997. 15: p. 269-272.
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