DNP: That's Not Chicken I Smell Being Cooked...That's Me!!

Dan Duchaine introduced Dinitrophenol (DNP) a powerful stimulator of UCP several years ago as a powerful weight loss drug, but you would have to be crazy to take it.  DNP, a benzene-based chemical, is nothing new and came to the attention of public health officials during World War I.  DNP was used mainly in the manufacture of dynamite.  Something unusual happened; the workers began building up considerable quantities of DNP in their bodies, both through skin contact and by inhaling the compound's vapors. At first the workers' symptoms were mild: sweating, light fever, increased appetite, heart palpitations, and insomnia. Then, as the days passed, the DNP levels in their bodies steadily increased along with more serious side effects as excess increases and body temperature and some people died.  One of the more specific side effects of inhaling the compound was weight loss. After the war, physicians lost no time in prescribing it to dieters. In humans, it speeds up the metabolic rate until eventually the body burns itself up. Amazingly, DNP had the ability to stimulate metabolism by as much as 50% with noticeable increases in body temperature³⁵. The comparisons to the current drugs for increasing thermogenesis are a mere shadow of DNP at least in terms of thermogenesis. While the ephedrine/caffeine/aspirin stack has been shown to provide safe weight loss, it has only been shown to have an approximately a 3% increase in metabolic rate. Unfortunately DNP's therapeutic index was razor thin and it was not until thousands of people suffered irreversible harm (i.e. high dosages can cause blindness) that mainstream physicians realized that DNP risks outweighed its benefits and abandoned its use.  Doctors reported that some patients on autopsy that used high dosages of DNP were literally "cooked to death."  Researchers are still researching safe and effective ways of increasing UCP.  There are several types of UCP's that can be increased safely by diet and thermogenics.

UCP-1: Works Great in Rats...Not so well in Humans

UCP-1 is found predominately in brown adipose tissue and is responsible for thermogenesis (production of heat).  When UCP's are turned on there is an increase in heat production, metabolism, and resting oxygen consumption.  Beta-adrenergic-receptor stimulation, due to pharmacological agents, has both acute and chronic effects on brown adipose tissue. UCP-1 activity increases within seconds of stimulation, while chronic stimulation over hours and days results in increased amounts of UCP-1 protein and increased activation of brown adipose tissue¹⁴.  As exciting as the research was on rats, the research on stimulating UCP-1 seemed to flop in humans.  Rodents have a greater capacity for thermogenesis than humans.  They have more brown adipose tissue than humans; they also have more UCP-1 than humans which makes a specific UCP-1 drug unlikely to be effective for humans.  UCP1 is believed to play an important role in thermogenesis in rodents but not in humans, in whom brown adipose tissue is limited.

UCP-3: The Muscle Uncoupling Protein

UCP-3, which has a 60% similarity to UCP1, is highly expressed in skeletal muscle and, to a lesser extent, in brown adipose tissue and heart¹⁸. UCP-3 is the only expressed in skeletal muscle which makes it of particular interest to increasing metabolism.  It is important to recognize that the level of UCP1

protein is 200- to 700-fold greater than UCP3 protein levels in skeletal muscle or BAT¹⁹.  Although UCP-3 is expressed at much lower levels than UCP-1, increasing UCP-3 may enhance thermogenesis.

Gene Manipulations of UCP-3

It has been demonstrated that certain people whom have defective UCP-3 gene expression have decreased fat oxidation¹³.  Decreased fat oxidation has also been documented in UCP-3 deficient mice³⁶. In recent studies of skeletal muscle of mice that overexpress UCP-3, there was an increased capacity for fat oxidation³⁷. Mice overexpressing UCP-3 have lower body weights than normal mice²⁰. Additionally, mice that overexpress UCP-3 are not only leaner; they eat more than other mice and have less body-fat. Additionally, when obese, otherwise healthy, subjects were placed on a 900 Kcal diet for 6 months lost weight at very different rates. Researchers were curious why there were differences in the amount of weight loss.  Diet-sensitive subjects, who lost weight at a greater rate than diet-resistant subjects, had 25% higher UCP-3 expression levels than diet-resistant subjects²³.  So now that you understand that increasing UCP-3 can enhance weight loss, let's examine how to increase UCP-3.

Tripping Mice have Increased UCP-3 Activity

DNP was the first drug to stimulate UCP activity but others drugs do as well.  MDMA or ecstasy is a drug that acts as both a stimulant and psychedelic, producing an energizing effect. I don't know if you have been to a rave but those people twirling glow sticks are usually sweating their ass off!! Side effects of ecstasy are a noticeable rise in body temperature, faster heartbeat, skin tingles, sudden sweating and dilated pupils.  So why all the sweating and increased body temperature?  A recent in mice examined how ecstasy affected UCP activation.  Mice treated with ecstasy underwent rapid increases in rectal and muscle temperature.  Ecstasy also caused intense sympathetic activation and increased UCP-3 activity in muscle which may partly explain the rapid increases in body temperature.  In the second part of the study, the researchers administered ecstasy to UCP-3 deficient mice, UCP-3 deficient mice did not have any rise in bodycore temperature demonstrating UCP-3 role in stimulating metabolism²⁰.  This demonstrates that large increases in sympathetic activity increase UCP-3 activity.  Don't be a dumbass and start trying ecstasy to increase UCP-3. There are much safer ways!

Catecholamines Increase UCP-3

Drugs that increase the activity of the central nervous system are a potential therapeutic pharmacological treatment for obesity.  Two drugs which stimulate metabolism and have profound effects on increasing UCP-3 are thyroid and sympathetic agents such as beta agonists (drugs that stimulate catecholamines) ¹⁸. Treatment with β2-adrenergic agonists (Salbutamol, Formoterol) has been demonstrated to increase UCP-3 expression in muscle fibers³⁰.  Both thyroid and catecholamines are potent stimulators of metabolism.  A recent study found that having a low resting metabolic rate is predictive of obesity.  Muscle accounts for 20% of the basal metabolic rate so increasing muscle metabolism enhances fat oxidation.  A significant portion of the variation in metabolic rate between humans can be accounted for by differences in the amount of skeletal muscle energy expenditure, and further support for a probable role of skeletal muscle in mediating thermogenesis comes from the demonstration that adrenaline infusion, which causes a 25% increase in whole body energy expenditure in humans^{14, 16}.