The concept of creating exercise in a pill, which in theory would allow for loss of body fat without a diet or exercise intervention, has been the Holy Grail of the weight loss supplement and metabolic drug industry for decades. The current consumer demand for a product that will allow one to lose weight while accommodating our increasingly sedentary lifestyles cannot be overstated. However, despite this clear demand, there are no effective and safe exercise-in-a-pill type products. It’s confounding that, after all, we store data in clouds, make proteins that do not exist in nature and, edit genetic material — how have we not invented exercise-in-a-pill? The problem, at least in part, is that there is little collaboration between the parties with different lines of work but with the shared ambition of making exercise-in-a-pill. A case in point is the story of 2,4-dinitrophenol (DNP) — illustrative of how living and working in the respective echo chambers of science, industry and policy, where knowledge is self-reinforcing but is not shared outside of the respective communities. Predictably, this lack of communication results in loss of time, money and, most egregiously, a tragic loss of life.
Buzzwords No Substitute for Scientific Expertise
In 1916, the first fatality attributable to DNP was recorded. The victim experienced occupational exposure to DNP while working in a munitions processing plant. His death was rapid, occurring 14 hours after onset of hyperthermia symptoms. The official cause of death was listed as “acute pulmonary oedema due to the absorption by the lung of dinitrophenol.”1 More than 100 years later, DNP is sold over the internet as a weight loss/slimming aid despite persistently leaving a trail of dead users.2 The appeal of DNP stems from its overwhelming efficacy at promoting weight loss without additional dietary or exercise interventions. Despite the FDA issuing a stern warning that DNP is unsafe for human consumption in 1938 and reiterating this over the years,3 there is an illusion of safety because the term “thermogenic” is poorly understood and is widely misappropriated. Thus, when most people hear that DNP is a thermogenic diet-pill they assume this means it is equivalent to products containing relatively benign stimulants, like caffeine, that are erroneously marketed as thermogenic. The term thermogenic, though, when applied to DNP is a very literal descriptor.
Thermogenesis is the process of the body increasing core body temperature. For example, thermogenesis naturally occurs when one shivers. In all adult humans, the muscle contraction characteristic of shivering requires turnover (i.e., expenditure and reconstitution) of the intracellular energy currency, adenosine tri-phosphate (ATP). The processes that participate in the turnover of ATP all produce heat as a by-product.4 The key here is that there must be ATP turnover for heat generation to continue, in normal physiological thermogenesis. The cell has built-in negative feedback loops that tightly regulate the expenditure and reconstitution of ATP.
There are chemicals, though, that can bypass the normal physiological negative feedback loop. DNP is one of these chemicals. In the presence of DNP, the cellular assembly lines that burn fuel will continue unchecked and consequently create an abnormal amount of body heat. Thus, DNP is truly thermogenic. Ingestion of DNP will cause body heat to increase, and death occurs due to hyperthermia. Stimulants on the other hand do not bypass the ATP turnover negative feedback loop, and as such their ability to create heat is maintained within normal physiological confines. This is not only theoretically the case, but experiments with rigorous controls accounting for activity rates found caffeine did not significantly alter internal body temperature.5 This is not to say that stimulants are not potentially dangerous, but stimulants are not truly thermogenic substances. Misbranding stimulants as thermogenics has consequently afforded a perception of safety for true thermogenics, like DNP.
Efficacy & Safety Key Components of Developing Practical Products
Ironically, the metabolic research community fully appreciates the literal definition of thermogenic but has failed to notice or otherwise realize the safety concerns associated with using thermogenic substances for weight loss. Instead, research for pharmacological interventions for obesity has singularly been focused on efficacy with little to no regard for safety. Examining the public database of projects that are funded by grants awarded by the National Institutes of Health (NIH) makes this fact abundantly clear. In currently funded projects, the NIH is providing more than $35 million dollars to research induction of thermogenesis as a proposed treatment option for obesity. The following quotes are from some of the abstracts in these grants:
“Therefore, I propose that… brown adipocytes increases thermogenesis, reduces body fat by dissipating energy as heat and effectively treats obesity.”6
“Completion of these Aims…may suggest novel therapeutic strategies to unleash the thermogenic potential of fat cells.”7
“Moreover, these studies will identify… a potential treatment option to evoke weight loss and… reverse obesity in humans by stimulating…thermogenesis.”8
The fallacy of misdirected metabolic research stems directly from the nature of funding this research. When a grant is submitted to the NIH, the judges of the proposal are peer-reviewers all of whom operate under the same funding mechanism. It stands to reason then that the parties receiving the $35 million dollars in funding for thermogenic solutions to obesity are not going to find fault with their own hypothesis, questioning the impetus for one’s own research is admitting self-defeat. This allows for amplification in the research community of impractical ideas like heating up an individual’s core body temperature for weight loss.
Fusing Science & Compliance: Not Just a Slogan
Commercial entities expedite products to market by checking the boxes for requisite safety parameters but failing to invest in basic science to correctly market their products. Conversely, basic research of weight loss treatments is heavily incentivized to pursue the most efficacious route to the end goal without much thought given to the downstream consumer’s safety. Both the weight-loss supplement industry and metabolic research community have a vested interest in producing exercise-in-a-pill, but neither group has a short-term incentive strong enough to create a true collaboration. Successful product development requires both understanding the basic science that dictates efficacy and knowledge of compliance that dictates safety for the consumer. Here at Burdock Group, we have a strong scientific background coupled with expertise in regulatory affairs that allows for companies and research firms to develop a safe and effective product.
References:
Warthin, AS. 2018. A fatal case of toxic jaundice caused by dinitrophenol. Bulletin of the International Association of Medical Museums.
The Killer Weight Loss Drug DNP Is Still Claiming Young Lives. Vice, Aug. 6, 2018.
80 Years of the Federal Food, Drug and Cosmetic Act. FDA. Site last visited Sept. 26, 2018.
Rowland, LA, Bal, NC, Periasamy, M. (2015) The role of skeletal-muscle-based thermogenic mechanisms in vertebrate endothermy. Biological Reviews of the Cambridge Philosophical Society.
Nancy Dunagan, J.E. Greenleaf, and C.J. Cisar. Thermoregulatory effects of caffeine ingestion during rest and exercise in men. NASA technical memoranda #108783. 1994.
Project Number: 1DP2DK105565-01, Total funding $2,277,000 (over five years). Site last visited Sept. 25, 2018.
Project Number: 1R01DK115875-01A1. Total funding $405,000 (over one year). Site last visited Sept. 25, 2018.
Project Number: 1R01DK115976-01, Total funding $398,150 (over one year). Site last visited Sept. 25, 2018.