Article

Dinitrophenol in the treatment of obesity

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Abstract

Since our first report on the metabolic stimulant action of 2-4 dinitrophenol (alpha)¹ in animals and men, and a preliminary paper indicating clinical possibilities for this compound,² its use has been continued in the outpatient department of the Stanford Clinics and in private practice. Some of the early clinical results in obesity were summarized in a progress report.³ Various clinical reports have detailed the actions of the drug under different dietary conditions,⁴ its circulatory effects,⁵ changes in blood cholesterol,⁶ and effects on the icteric index and van den Bergh test.⁷ The evidences for changes in blood cholesterol, liver damage and certain red blood cell characteristics were negative. Our experimental work and clinical experience with the drug has now extended over a period of four years, during which time it has been given to hundreds of patients. Therefore it is felt that there may

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... The use of drugs that uncouple oxidative phosphorylation, causing a major increase in oxidation of nutrients without an increase in ATP generation, could be used as tools for addressing this last issue. Dinitrophenol administration in humans was found to have a linear relationship with metabolic rate and weight loss, so that at a dose of 0.5 g/day it increased metabolic rate by about 50% and decreased body weight by almost 1 kg/week (Tainter et al., 1935;Harper et al., 2001). The use of dinitrophenol to treat obesity in the United States in the 1930s (Tainter et al., 1935;Harper et al., 2001) made some subjects very hungry during treatment. ...
... Dinitrophenol administration in humans was found to have a linear relationship with metabolic rate and weight loss, so that at a dose of 0.5 g/day it increased metabolic rate by about 50% and decreased body weight by almost 1 kg/week (Tainter et al., 1935;Harper et al., 2001). The use of dinitrophenol to treat obesity in the United States in the 1930s (Tainter et al., 1935;Harper et al., 2001) made some subjects very hungry during treatment. If this were a general effect, it would suggest that oxidation of fuels per se, was not responsible for providing feedback on energy intake, and that oxidative phosphorylation was more likely to be the cause. ...
... However, the information on the effects of dinitrophenol in humans is far from clear, since some subjects became less hungry during treatment, so that in reality there was no consistent overall effect on appetite. It is difficult to assess the significance of these briefly reported observations, partly because no measurements of dietary intake were made, and partly because dinitrophenol can cause a range of side effects which suppress appetite (for example, nausea, gastrointestinal symptoms, loss of taste (especially for salt and sweet), skin rashes and a variety of other symptoms) (Rabinowitch and Fowler, 1934;Tainter et al., 1935;Harper et al., 2001). In addition, uncoupling oxidative phosphorylation would not distinguish between carbohydrates and fat because both are uncoupled by dinotrophenol. ...
Article
The energy values of carbohydrates continue to be debated. This is because of the use of different energy systems, for example, combustible, digestible, metabolizable, and so on. Furthermore, ingested macronutrients may not be fully available to tissues, and the tissues themselves may not be able fully to oxidize substrates made available to them. Therefore, for certain carbohydrates, the discrepancies between combustible energy (cEI), digestible energy (DE), metabolizable energy (ME) and net metabolizable energy (NME) may be considerable. Three food energy systems are in use in food tables and for food labelling in different world regions based on selective interpretation of the digestive physiology and metabolism of food carbohydrates. This is clearly unsatisfactory and confusing to the consumer. While it has been suggested that an enormous amount of work would have to be undertaken to change the current ME system into an NME system, the additional changes may not be as great as anticipated. In experimental work, carbohydrate is high in the macronutrient hierarchy of satiation. However, studies of eating behaviour indicate that it does not unconditionally depend on the oxidation of one nutrient, and argue against the operation of a simple carbohydrate oxidation or storage model of feeding behaviour to the exclusion of other macronutrients. The site, rate and extent of carbohydrate digestion in, and absorption from the gut are key to understanding the many roles of carbohydrate, although the concept of digestibility has different meanings. Within the nutrition community, the characteristic patterns of digestion that occur in the small (upper) vs large (lower) bowel are known to impact in contrasting ways on metabolism, while in the discussion of the energy value of foods, digestibility is defined as the proportion of combustible energy that is absorbed over the entire length of the gastrointestinal tract. Carbohydrates that reach the large bowel are fermented to short-chain fatty acids. The exact amounts and types of carbohydrate that reach the caecum are unknown, but are probably between 20 and 40 g/day in countries with 'westernized' diets, whereas they may reach 50 g/day where traditional staples are largely cereal or diets are high in fruit and vegetables. Non-starch polysaccharides clearly affect bowel habit and so, to a lesser extent, does resistant starch. However, the short-chain carbohydrates, which are also found in breast milk, have little if any laxative role, although do effect the balance of the flora. This latter property has led to the term 'prebiotic', which is defined as the capacity to increase selectively the numbers of bifidobacteria and lactobacilli without growth of other genera. This now well-established physiological property has not so far led through to clear health benefits, but current studies are focused on their potential to prevent diarrhoeal illnesses, improve well-being and immunomodulation, particularly in atopic children and on increased calcium absorption.
... However, there was a clear dependence of metabolic rate on DNP dose (Fig. 2). There was an average 11% increase in metabolic rate for each dosage increment of 0.1 g of DNP (44,48). Doses up to 0.5 g (about 5 mg kg -1 ) were generally well-tolerated apart from patients almost always reporting a feeling of warmth together with increased perspiration (45,46,48). ...
... Therapeutic doses of DNP had no effects on blood pressure or heart rate in normal patients. Interestingly, a subset of 30 hypertensive patients exhibited average falls of 9.4% in systolic and 12.6% in diastolic blood pressure (44). These improvements in hypertension were also noted at doses of DNP insufficient to cause weight loss (48). ...
... The authors did, however, note a 7% incidence of severe skin rashes, necessitating discontinuation of treatment. There was no overt liver or kidney damage, but the same authors voiced some concerns about the incidence of agranulocytosis though they saw no cases in their own long-term studies (44). Of more concern, a number of cases of cataracts were reported in women in 1935 (49,50). ...
Article
Mitochondrial proton cycling is responsible for a significant proportion of basal or standard metabolic rate, so further uncoupling of mitochondria may be a good way to increase energy expenditure and represents a good pharmacological target for the treatment of obesity. Uncoupling by 2,4-dinitrophenol has been used in this way in the past with notable success, and some of the effects of thyroid hormone treatment to induce weight loss may also be due to uncoupling. Diet can alter the pattern of phospholipid fatty acyl groups in the mitochondrial membrane, and this may be a route to uncoupling in vivo. Energy expenditure can be increased by stimulating the activity of uncoupling protein 1 (UCP1) in brown adipocytes either directly or through beta 3-adrenoceptor agonists. UCP2 in a number of tissues, UCP3 in skeletal muscle and the adenine nucleotide translocase have also been proposed as possible drug targets. Specific uncoupling of muscle or brown adipocyte mitochondria remains an attractive target for the development of antiobesity drugs.
... The use of drugs that uncouple oxidative phosphorylation, causing a major increase in oxidation of nutrients without an increase in ATP generation, could be used as tools for addressing this last issue. Dinitrophenol administration in humans was found to have a linear relationship with metabolic rate and weight loss, so that at a dose of 0.5 g/day it increased metabolic rate by about 50% and decreased body weight by almost 1 kg/week (Tainter et al., 1935;Harper et al., 2001). The use of dinitrophenol to treat obesity in the United States in the 1930s (Tainter et al., 1935;Harper et al., 2001) made some subjects very hungry during treatment. ...
... Dinitrophenol administration in humans was found to have a linear relationship with metabolic rate and weight loss, so that at a dose of 0.5 g/day it increased metabolic rate by about 50% and decreased body weight by almost 1 kg/week (Tainter et al., 1935;Harper et al., 2001). The use of dinitrophenol to treat obesity in the United States in the 1930s (Tainter et al., 1935;Harper et al., 2001) made some subjects very hungry during treatment. If this were a general effect, it would suggest that oxidation of fuels per se, was not responsible for providing feedback on energy intake, and that oxidative phosphorylation was more likely to be the cause. ...
... However, the information on the effects of dinitrophenol in humans is far from clear, since some subjects became less hungry during treatment, so that in reality there was no consistent overall effect on appetite. It is difficult to assess the significance of these briefly reported observations, partly because no measurements of dietary intake were made, and partly because dinitrophenol can cause a range of side effects which suppress appetite (for example, nausea, gastrointestinal symptoms, loss of taste (especially for salt and sweet), skin rashes and a variety of other symptoms) (Rabinowitch and Fowler, 1934;Tainter et al., 1935;Harper et al., 2001). In addition, uncoupling oxidative phosphorylation would not distinguish between carbohydrates and fat because both are uncoupled by dinotrophenol. ...
... It would need to be demonstrated that all vital functions are uncompromised with chemical uncoupling, in particular the heart in a setting of increased BMR. Another potential risk of chemical uncoupling is increases in core body temperature at high doses, although at lower doses the heat is usually dissipated with no change in temperature [44, 45]. Cataracts have been reported in some patients treated with 2,4-dinitrophenol, but this was not replicated in more recent animal models [46] and may be a property of 2,4-dinitrophenol vs general uncouplers. ...
... A key question is to what degree does energy expenditure have to be increased to achieve meaningful weight loss? According to calculations from a study conducted in 1935, a 10% increase in BMR resulted in weight loss of ∼0.3 to 0.45 kg/ week [44]. If the calculations are accurate and a less aggressive approach was taken today, then a 5% increase in BMR should result in half that weight loss, but still provide annual weight reductions of 10% or ∼12 kg (26 lb) for patients with BMI over 30 kg/m 2 . ...
... The cell responds by increasing the rate of oxygen consumption ( Á V O 2 [pink line] or energy expenditure) to generate more NADH and FADH 2 as a source of protons (when oxidised back to NAD + and FAD) as a mechanism to re-establish the electrochemical gradient ðΔe u H þÞ. Since NADH and FADH 2 come from the metabolism of glucose and lipids, the RER (orange line) is primarily unchanged (high doses shift RER towards lipids). In the presence of a chemical uncoupler, energy expenditure is constitutively enhanced since the Δ< m is out of balance to the author's knowledge, no reports of a compensatory increase in food consumption due to the increase in energy expenditure in patients treated with 2,4-dinitrophenol in the 1930s [40, 44, 45]. In a recent study, 2,4-dinitrophenol was provided to mice for their entire adult lifespan and daily food consumption remained unchanged. ...
Article
Since over-nutrition accelerates the development of obesity, progression to type 2 diabetes, and the associated co-morbidity and mortality, there has been a keen interest in therapeutic interventions targeting mechanisms that may curb appetite, increase energy expenditure or at least attenuate insulin resistance. Over the past decade, numerous peri-mitochondrial targets in the de novo lipid synthesis pathway have been linked to an increase in energy expenditure and the drug development industry has pursued the gene products involved as candidates to develop drugs against. The basis of this link, and specifically the premise that lowering tissue and cellular malonyl-CoA can increase energy expenditure, is scrutinised here. The argument presented is that fuel switching as effected by changes in cellular malonyl-CoA concentrations will not trigger the mitochondria to increase energy expenditure because: (1) an increase in beta-oxidation by lowering respiratory exchange ratio (indicative of the metabolic fuel consumed) does not equal an increase in energy expenditure (how rapidly fuel is consumed); (2) the ATP:oxygen ratios (i.e. ATP energy made:oxygen required for the reaction) are similar when metabolising lipids (2.8) vs glucose (3.0); (3) substrate availability (NEFA) does not drive energy expenditure in vivo; and (4) the availability of ADP in the mitochondrial matrix determines the rate of energy expenditure, not the availability of fuel to enter the mitochondrial matrix. To increase mitochondrial energy expenditure, work must be done (exercise) and/or the mitochondrial proton leak must be enhanced, both of which increase availability of ADP. In fact, despite the historic taboo of chemical uncoupling, this mechanism validated in humans is closest on task to increasing whole-body energy expenditure. Chemical uncoupling mimics the naturally occurring phenomenon of proton leak, accelerating the metabolism of glucose and lipids. However, it is completely non-genomic (i.e. the target is a location, not a gene product) and is not associated with addiction or mood alterations common to satiety agents. A significant hurdle for drug development is to discover a safe mitochondrial uncoupler and to formulate it potentially as a pro-drug and/or oral pump, to avoid the issue of overdosing experienced in the 1930s. The potential therapeutic impact of such a compound for an over-nutritioned patient population could be profound. If effective, the mitochondrial uncoupler mechanism could resolve many of the associated diseases such as type 2 diabetes, hypertension, obesity, depression, sleep apnoea, non-alcoholic steatohepatitis, insulin resistance and hyperlipidaemia, therefore becoming a 'disease-modifying therapy'.
... The use of drugs that uncouple oxidative phosphorylation, causing a major increase in oxidation of nutrients without an increase in ATP generation, could be used as tools for addressing this last issue. Dinitrophenol administration in humans was found to have a linear relationship with metabolic rate and weight loss, so that at a dose of 0.5 g/day it increased metabolic rate by about 50% and decreased body weight by almost 1 kg/week (Tainter et al., 1935;Harper et al., 2001). The use of dinitrophenol to treat obesity in the United States in the 1930s (Tainter et al., 1935;Harper et al., 2001) made some subjects very hungry during treatment. ...
... Dinitrophenol administration in humans was found to have a linear relationship with metabolic rate and weight loss, so that at a dose of 0.5 g/day it increased metabolic rate by about 50% and decreased body weight by almost 1 kg/week (Tainter et al., 1935;Harper et al., 2001). The use of dinitrophenol to treat obesity in the United States in the 1930s (Tainter et al., 1935;Harper et al., 2001) made some subjects very hungry during treatment. If this were a general effect, it would suggest that oxidation of fuels per se, was not responsible for providing feedback on energy intake, and that oxidative phosphorylation was more likely to be the cause. ...
... However, the information on the effects of dinitrophenol in humans is far from clear, since some subjects became less hungry during treatment, so that in reality there was no consistent overall effect on appetite. It is difficult to assess the significance of these briefly reported observations, partly because no measurements of dietary intake were made, and partly because dinitrophenol can cause a range of side effects which suppress appetite (for example, nausea, gastrointestinal symptoms, loss of taste (especially for salt and sweet), skin rashes and a variety of other symptoms) (Rabinowitch and Fowler, 1934;Tainter et al., 1935;Harper et al., 2001). In addition, uncoupling oxidative phosphorylation would not distinguish between carbohydrates and fat because both are uncoupled by dinotrophenol. ...
... Clinically, 2,4-dinitrophenol (a dangerously strong pharmacological stimulant of RMR) can be used to cause ϳ2 lbs. weight loss/wk in humans at a dose of 500 mg/day, which results from a roughly 50 -60% increase in RMR (9). This should be seen as an extreme weight loss regimen given the potentially fatal side effects (2,9), and thus a more reasonable target of pharmacological stimulation of RMR would be a 5-10% increase. ...
... weight loss/wk in humans at a dose of 500 mg/day, which results from a roughly 50 -60% increase in RMR (9). This should be seen as an extreme weight loss regimen given the potentially fatal side effects (2,9), and thus a more reasonable target of pharmacological stimulation of RMR would be a 5-10% increase. Here, we demonstrate that the rate of inaccuracy of respirometry is roughly 10 -12% and posit that this magnitude of inaccuracy, given the target range, is unacceptably large. ...
Article
Substantial research efforts are aimed at identifying novel targets to increase resting metabolic rate (RMR) as an adjunct approach to the treatment of obesity. Respirometry (one form of "indirect calorimetry") is unquestionably the dominant technique used in the obesity research field to assess RMR in vivo, though this method relies upon a lengthy list of assumptions that are likely to be violated in pharmacologically- or genetically-manipulated animals. A "total" calorimeter, including a gradient-layer direct calorimeter coupled to a conventional respirometer, was used to test the accuracy of respirometric-based estimations of RMR in laboratory mice (Mus musculus Linnaeus) of the C57Bl/6 and FVB background strains. Using this combined calorimeter we determined that respirometry underestimates RMR of untreated 9-12 week old male mice by ~10-12%. Quantitative and qualitative differences resulted between methods for untreated C57Bl/6 and FVB mice, C57Bl/6 mice treated with ketamine/xylazine anesthesia, and FVB mice with genetic deletion of the angiotensin II type 2 receptor. We conclude that respirometric methods underestimate RMR in mice in a magnitude that is similar to or greater than the desired RMR effects of novel therapeutics. Sole reliance upon respirometry to assess RMR in mice may lead to false quantitative and qualitative conclusions regarding the effects of novel interventions. Increased use of direct calorimetry for the assessment of RMR and confirmation of respirometry results, and the re-examination of previously discarded potential obesity therapeutics, are warranted.
... Probably the most thoroughly investigated uncoupling agent is 2,4-dinitrophenol (DNP) (Loomis 1948). Initially used in the manufacturing of munitions during World War I, clinical studies in the early 1930s revealed DNP to be a highly effective weight loss agent (Tainter et al. 1935). At least 100 000 persons were estimated to have taken DNP for weight loss. ...
... Unfortunately, chronic ingestion of DNP was associated with a number of untoward effects. Most frequently observed were skin rashes and cataracts (Boardman 1935;Horner et al. 1935;Tainter et al. 1935), however, rare cases of hepatic dysfunction, blood dyscrasias, cardiac arrhythmias and gastroenteritis were also reported (Sidel 1934;Tainter et al. 1934;Simkins 1937). The nascent Food and Drug Administration removed DNP from the market in 1938. ...
Article
Mitochondrial dysfunction, resulting from the disruption of calcium homeostasis and the generation of toxic reactive oxygen species, is a central process leading to neuronal injury and death following acute CNS insults. Interventions aimed at preventing disturbances in mitochondrial function have therefore become targets of intense investigation. Mitochondrial uncoupling is a condition in which electron transport is disconnected from the production of ATP. As a consequence, there is a decrease in the mitochondrial membrane potential, which can temporarily decrease calcium influx and attenuate free radical formation. The potential use of pharmacological agents with uncoupling properties may provide a novel therapeutic approach for the treatment of acute neuronal injury.
... Adverse health consequences associated with exposure to DNP were published (Perkins, 1919) shortly after the war, providing early evidence of a link between weight loss and DNP. This was supported by reports of deaths in the dye industry of the United States (Hamilton, 1921; Tainter, Stockton, & Cutting, 1935) with cases of continued increases in body temperature postmortem. Sporadic reports of fatalities due to the accidental ingestion of DNP have continued (Cann & Verhulst, 1960). ...
... By the mid-1930s " secret remedies " in the United Kingdom and " patent medicines " in the United States were big businesses, with DNP at the forefront of popularity. It was estimated in 1935 that over 100,000 people in the United States had used DNP (Tainter et al., 1935). Large numbers of weight-reducing preparations containing DNP were being sold across America, some products in which DNP was the sole active agent but often as just one constituent of a cocktail of weight loss ingredients (Hecht & Jannssen, 1987). ...
Article
Background: Despite not being licensed for human consumption, the Internet has triggered renewed, widespread interest and availability of 2,4-Dinitrophenol (DNP). DNP, a cellular metabolic poison, causes thermogenesis resulting in fat burning and weight loss. Whilst extensively available for purchase online, research on user experiences of DNP is limited.Methods: A netnographic approach was used to describe user experiences of DNP via online public websites. Public websites discussing DNP were identified and a purposeful sample selected. Discussion threads were downloaded and a textual qualitative analysis conducted. Four themes containing 71 categories were generated.Results: There exists a plethora of communal folk pharmacological advice and recommendations for DNP manufacture and use, together with associated harms and outcomes. The efficacy and untoward effects of DNP were described and discussed alongside the notion that DNP should only be used by experienced bodybuilders. Dosage and regimes for optimal use were also described.Conclusion: This unique study provides a rich examination of the knowledge, attitudes, and motivations of DNP users, illustrating the significant role of online public websites in sharing information. Further understanding of DNP users and the online communities in which they reside is warranted to facilitate engagement and formulate appropriate and effective policy responses.
... They are widely used as uncouplers of oxidative and photosynthetic phosphorylation, reducing the electrochemical proton gradient on mitochondrial and photosynthetic membranes and thereby stimulating the electron transport in respiratory and photosynthetic chains. The ability of uncouplers to increase energy expenditure prompted the initial interest in the therapeutic use of these agents as antiobesity drugs [1,2]. Later, based on the discovery of dramatic suppression of ROS generation as a result of mild uncoupling (a modest reduction in membrane potential) [3][4][5][6][7][8], administration of uncouplers was suggested for treatment of diseases associated with oxidative stress [9][10][11]. ...
Article
The environmentally sensitive fluorescent probe 7-nitrobenz-2-oxa-1,3-diazole (NBD) is generally utilized to monitor dynamic properties of membrane lipids and proteins. Here we studied the behavior of a homologous series of 4-n-alkylamino-substituted NBD derivatives (NBD-Cn; n=4, 6, 8, 9, 10, 12) in planar lipid bilayers, liposomes and isolated mitochondria. NBD-C10 induced proton conductivity in planar lipid membranes, while NBD-C4 was ineffective. The NBD-Cn compounds readily provoked proton permeability of neutral liposomes being less effective in negatively charged liposomes. NBD-Cn increased the respiration rate and reduced the membrane potential of isolated rat liver mitochondria. Remarkably, the bell-shaped dependence of the uncoupling activity of NBD-Cn on the alkyl chain length was found in mitochondria in contrast to the monotonous dependence in liposomes. The effect of NBD-Cn on the respiration correlated with that on proton permeability of the inner mitochondrial membrane, as measured by mitochondria swelling. Binding of NBD-Cn to mitochondria increased with n, as shown by fluorescence correlation spectroscopy. It was concluded that despite a pKa value of the amino group in NBD-Cn being about 10, i.e. far from the physiological pH range, the expected hindering of the uncoupling activity could be overcome by inserting the alkyl chain of a certain length.
... Five subjects did not lose weight, but the remainder lost an average of 7.8 kg over an average period of 88 days. The average dose used in that study was 340 mg/day, resulting in a 33% rise in RMR 56 . If we take an obese male with an RMR of 7.5 MJ/day, a 33% rise in RMR over 88 days (2.5 MJ/day) would result in a predicted weight loss of 5.2 kg. ...
Article
The identification of functional brown adipose tissue in human adults has intensified interest in exploiting thermogenic energy expenditure for the purpose of weight management. However, food intake and energy expenditure are tightly regulated and it is generally accepted that variation in one component results in compensatory changes in the other. In the context of weight loss, additional biological adaptations occur in an attempt to further limit weight loss. In the present review, we discuss the relationship between increasing energy expenditure and body weight in humans, including the effects of cold exposure. The data raise the possibility that some processes, particularly those involved in thermogenesis, induce less compensatory food intake for a given magnitude of additional energy expenditure, a state we term the 'thermogenic disconnect'. Although cold exposure increases thermogenesis and can putatively be exploited to induce weight loss, there are multiple adaptive responses to cold, of which many actually reduce energy expenditure. In order to optimally exploit either cold itself or agents that mimic cold for thermogenic energy expenditure, these non-thermogenic cold responses must be considered. Finally, the relative contribution of brown adipose tissue vs other thermogenic processes in humans remains to be defined. However, overall the data suggest that activation of cold-induced thermogenic processes are promising targets for interventions to treat obesity and its secondary metabolic complications. (J Diabetes Invest, doi:10.1111/j.2040-1124.2011.00158.x, 2011).
... In the 1930s, DNP was administered to humans as part of weight-reduction programs. However, due to reports of serious side effects including cataracts, gastrointestinal, cardiorespiratory, and other types of complications, even deaths in individuals subjected to high concentrations of DNP, the U.S. Food and Drug Administration (FDA) banned the use of DNP in 1938 (De Felice andFerreira, 2006;Tainter et al., 1935). As noted above, however, recent studies have demonstrated that low, sub-toxic doses of DNP can have interesting neuroprotective actions against a variety of insults (reviewed in De Felice and Ferreira, 2006;De Felice et al., 2007). ...
Article
Preventing the harm caused by nerve degeneration is a major challenge in neurodegenerative diseases and in various forms of trauma to the nervous system. The aim of the current work was to investigate the effects of systemic administration of 2,4-dinitrophenol (DNP), a compound with newly recognized neuroprotective properties, on sciatic-nerve degeneration following a crush injury. Sciatic-nerve injury was induced by unilateral application of an aneurysm clip. Four groups of mice were used: uninjured, injured treated with vehicle (PBS), injured treated with two intraperitoneal doses of DNP (0.06 mg DNP/kg every 24 h), and injured treated with four doses of DNP (every 12 h). Animals were sacrificed 48 h post injury and both injured and uninjured (contralateral) sciatic nerves were processed for light and electron microscopy. Morphometric, ultrastructural, and immunohistochemical analysis of injured nerves established that DNP prevented axonal degeneration, blocked cytoskeletal disintegration, and preserved the immunoreactivity of amyloid precursor protein (APP) and Neuregulin 1 (Nrg1), proteins implicated in neuronal survival and myelination. Functional tests revealed preservation of limb function following injury in DNP-treated animals. Results indicate that DNP prevents nerve degeneration and suggest that it may be a useful small-molecule adjuvant in the development of novel therapeutic approaches in nerve injury.
... Moreover, it is well known that DNP has very narrow therapeutic window since in rodents the toxic concentrations of DNP exceeded therapeutic concentration only 2-3 fold [56,57]. DNP was widely used in clinical practice for weight loss at the beginning of the 20th century and was banned by the FDA due to multiple deaths caused by sideeffects associated with overdosing and severe uncoupling of mitochondria [58][59][60][61]. Thus, the classical and well studied uncouplers, DNP and FCCP, seem not to have further perspectives to be used in clinics as neuroprotectors, and there is a need for developing new ones for effective stroke treatment. ...
... The activation of respiration caused by the use of uncouplers leads to increased mobilization of oxidative substrates and significant activation of oxidative metabolism, while, as the depletion of carbohydrate substrates occurs, the mobilization of fat resources takes place, which is desirable to combat obesity [35][36][37][38]. It should be noted that obesity is one of the risk factors for stroke, including in young adults [31]. ...
Article
Full-text available
There has been an explosion of interest in the use of uncouplers of oxidative phosphorylation in mitochondria in the treatment of several pathologies, including neurological ones. In this review, we analyzed all the mechanisms associated with mitochondrial uncoupling and the metabolic and signaling cascades triggered by uncouplers. We provide a full set of positive and negative effects that should be taken into account when using uncouplers in experiments and clinical practice.
... Pharmacological agents, such as 2,4-dintirophenol (DNP), can induce mitochondrial uncoupling by transporting protons across the mitochondrial inner membrane into the matrix. DNP was successfully used as an anti-obesity agent in the 1930s, suggesting that increased energy expenditure through mitochondrial uncoupling could have therapeutic potential (129). However, due to its narrow therapeutic window, overdoses led to serious imbalances of energy metabolism (and even to death), and DNP had to be taken off the market in 1938. ...
Article
Full-text available
Mitochondrial dysfunction has been implicated in the development of insulin resistance, however a large variety of association and intervention studies, as well as genetic manipulations in rodents have reported contrasting results. Indeed, even 39 years after the first publication describing a relationship between insulin resistance and diminished mitochondrial function, it is still unclear if a direct relationship exists, and more importantly if changes in mitochondrial capacity are a cause or consequence of insulin resistance. This review will take a journey through the past and summarize the debate about the occurrence of mitochondrial dysfunction and its possible role in causing decreased insulin action in obesity and type 2 diabetes. Evidence will be presented from studies in various human populations, as well as rodents with genetic manipulations of pathways known to affect mitochondrial function and insulin action. Finally, we will discuss if mitochondria are a potential target for the treatment of insulin resistance.
... There is often accompanying pruritis and subsequent desquamation [39,41,42]. Prolonged peripheral neuritis has been reported, often affecting the hands and feet and associated with skin changes [11,43,44]. A common complaint is that of yellow discoloration of the skin, sclera and urine [45][46][47][48]. ...
Article
Full-text available
2,4-Dinitrophenol (DNP) is reported to cause rapid loss of weight, but unfortunately is associated with an unacceptably high rate of significant adverse effects. DNP is sold mostly over the internet under a number of different names as a weight loss/slimming aid. It causes uncoupling of oxidative phosphorylation; the classic symptom complex associated with toxicity of phenol-based products such as DNP is a combination of hyperthermia, tachycardia, diaphoresis and tachypnoea, eventually leading to death. Fatalities related to exposure to DNP have been reported since the turn of the twentieth century. To date, there have been 62 published deaths in the medical literature attributed to DNP. In this review, we will describe the pattern and pathophysiology of DNP toxicity and summarise the previous fatalities associated with exposure to DNP.
... Debatably the single most potent antiobesity drug ever used clinically was 2,4-dinitrophenol (DNP). This compound is a mitochondrial proton ionophore, acting as an artificial uncoupling protein to destroy the proton gradient across the inner membrane of mitochondria (125). As cells scramble to utilize available fuel sources to rebuild the proton gradient, energy is lost in the form of heat. ...
Article
Metabolic disease, specifically obesity, has now become the greatest challenge to improving cardiovascular health. The renin-angiotensin system (RAS) exists as both a circulating hormone system and as a local paracrine signaling mechanism within various tissues including the brain, kidney, and adipose, and this system is strongly implicated in cardiovascular health and disease. Growing evidence also implicates the RAS in the control of energy balance, supporting the concept that the RAS may be mechanistically involved in the pathogenesis of obesity and obesity-hypertension. Here, we review the involvement of the RAS in the entire spectrum of whole-organism energy balance mechanisms, including behaviors (food ingestion and spontaneous physical activity) and biological processes (digestive efficiency and both aerobic and non-aerobic resting metabolic rates). We hypothesize that opposing, tissue-specific effects of the RAS to modulate these various components of energy balance can explain the apparently paradoxical results reported by energy-balance studies that involve stimulating, versus disrupting, the RAS. We propose a model in which such opposing and tissue-specific effects of the RAS can explain the failure of simple, global RAS blockade to result in weight loss in humans, and hypothesize that obesity-mediated uncoupling of endogenous metabolic rate control mechanisms can explain the phenomenon of obesity-hypertension.
... The effect of 2,4-dinitrophenol (DNP) 3 to increase metabolic rate has been known since the late 1800s and was studied during World War I (4). In the early 1930s, DNP was widely used as a weight loss drug (5); however, enthusiasm for DNP therapy waned due to its low therapeutic index and serious toxicities, including hyperthermia, skin reactions, cataracts, and death (6,7). In 1948, its mechanism of action was discovered, revealing that DNP is a protonophore, able to move protons through lipid bilayers and thus to chemically uncouple substrate oxidation from ATP production (8). ...
Article
The chemical uncoupler 2,4-dinitrophenol (DNP) was an effective and widely used weight loss drug in the early 1930s. However, DNP's physiology has not been studied in detail as toxicity, including hyperthermia and death, reduced interest in the clinical use of chemical uncouplers. To investigate DNP action, mice fed a high fat diet and housed at 30C (to minimize facultative thermogenesis) were treated with 800 mg/l DNP in drinking water. DNP treatment increased energy expenditure by ~17%, but did not change food intake. DNP-treated mice weighed 26% less than controls after 2 months of treatment due to decreased fat mass, without a change in lean mass. DNP improved glucose tolerance and reduced hepatic steatosis without observed toxicity. DNP treatment also reduced circulating T3 and T4 levels, Ucp1 expression, and brown adipose tissue activity, demonstrating that DNP-mediated heat generation substituted for brown adipose tissue thermogenesis. At 22C, a typical vivarium temperature that is below thermoneutrality, DNP treatment had no effect on body weight, adiposity, or glucose homeostasis. Thus, environmental temperature should be considered when assessing an anti-obesity drug in mice, particularly agents acting on energy expenditure. Furthermore, the beneficial effects of DNP suggest that chemical uncouplers deserve further investigation for the treatment of obesity and its comorbidities.
... 2,4-Dinitrophenol, an ingredient in agricultural pesticides is well absorbed via skin, iinhalation, and orally. All dinitrophenols (DNP) uncouple mitochondrial glycolytic oxidative phosphorylation with increased metabolism of lipids which made dinitrophenols attractive as weight loss medications in the 1930s [38]. ...
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Global warming, primarily caused by emissions of too much carbon dioxide, and climate change is a reality. This will lead to more extreme weather events with heatwaves and flooding. Some studies propose an association between thermal exposures and the prevalence of obesity with an increasing trend towards time spent in the thermal comfort zone. Longterm exposure to the thermal comfort zone can lead to a reduction of brown adipose tissue activity with an impact on energy expenditure and thermogenesis. Reduced seasonal cold exposure in combination with reduced diet-induced thermogenesis by a highly palatable high-fat and high-sugar diet and reduced physical activity contribute to the prevalence of obesity and the metabolic syndrome.
... Considerable symptoms of poisoning (like nausea, sweating, and headaches) and a reduction of body weight were observed in workmen [1,2]. So the idea arose to use DNP as an anti-obesity drug [3,4]. An increase of the basal metabolic rate by 50 % in healthy humans is considered to be the reason for the weight reduction [5]. ...
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We report the case of a 50-year-old obese man (115 kg body mass at 1.77 m height), who started taking 2,4-dinitrophenol (DNP) for weight reduction 44 days before his death. After 43 days of taking DNP, the man showed signs of intoxication with nausea, vomiting, and attacks of sweating. After admission to a hospital where the man concealed his DNP intake, sinus tachycardia, tachypnea, and general unrest were noted. The patient died 9 h after the onset of those symptoms. Upon autopsy, a yellowing of palms and soles was striking. The initially uncertain cause of death could only be clarified by the forensic toxicological examinations and subsequent police investigations. Finally, the man had a total intake of 12.3 g of DNP in 44 days which is relatively high compared to other lethal DNP intoxications.
... In the 1930s, a group of physicians published a paper describing the beneficial weight loss properties of a compound called dinitrophenol (DNP) [27]. Despite their recommendation that the compound be used only in controlled research settings the popularity of DNP rose with the lay population, and soon case reports of deaths associated with DNP appeared in the literature [28,29,30]. ...
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Body temperature regulation involves a homeostatic balance between heat production and dissipation. Sympathetic agents such as 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) can disrupt this balance and as a result produce an often life-threatening hyperthermia. The hyperthermia induced by MDMA appears to result from the activation of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-thyroid/adrenal axis. Norepinephrine release mediated by MDMA creates a double-edged sword of heat generation through activation of uncoupling protein (UCP3) along with alpha1- and beta3-adrenoreceptors and loss of heat dissipation through SNS-mediated vasoconstriction. This review examines cellular mechanisms involved in MDMA-induced thermogenesis from UCP activation to vasoconstriction and how these mechanisms are related to other thermogenic conditions and potential treatment modalities.
... Historically in the early 1930s, 2,4-dinitrophenol [97] was widely used as a treatment of obesity. But serious side effects of this drug, such as fatal hyperthermia, agranulocytosis and cataract, were recognized [98]. ...
Article
In recent decades, obesity has become a pandemic disease and appears to be an ultimate medical and social problem. Existing antiobesity drugs show low efficiency and a wide variety of side effects. In this review, we discuss possible mechanisms underlying brain–gut–adipose tissue axis, as well as molecular biochemical characteristics of various neurochemical regulators of body weight and appetite. Multiple brain regions are responsible for eating behavior, hedonic eating and food addiction. The existing pharmacological targets for treatment of obesity were reviewed as well.
... Mitochondrial uncouplers [for example, 2,4-dinitrophenol (DNP)] shuttle protons across the inner mitochondrial membrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncoupling nutrient oxidation from ATP production (20). DNP has been known to increase metabolic rates since the late 1800s and was an effective and widely used weight loss drug in the 1930s (21)(22)(23)(24). Unfortunately, chronic ingestion of DNP is associated with a number of unwanted side effects, including fatal hyperthermia and death, and was banned by the U.S. Food and Drug Administration (FDA) in 1938 (25). ...
Article
Nonalcoholic fatty liver disease (NAFLD) is estimated to affect up to one-third of the general population, and new therapies are urgently required. Our laboratory previously developed a controlled-release mitochondrial protonophore (CRMP) that is functionally liver-targeted and promotes oxidation of hepatic triglycerides. Although we previously demonstrated that CRMP safely reverses hypertriglyceridemia, fatty liver, hepatic inflammation, and fibrosis in diet-induced rodent models of obesity, there remains a critical need to assess its safety and efficacy in a model highly relevant to humans. Here, we evaluated the impact of longer-term CRMP treatment on hepatic mitochondrial oxidation and on the reversal of hypertriglyceridemia, NAFLD, and insulin resistance in high-fat, fructose-fed cynomolgus macaques ( n = 6) and spontaneously obese dysmetabolic rhesus macaques ( n = 12). Using positional isotopomer nuclear magnetic resonance tracer analysis (PINTA), we demonstrated that acute CRMP treatment (single dose, 5 mg/kg) increased rates of hepatic mitochondrial fat oxidation by 40%. Six weeks of CRMP treatment reduced hepatic triglycerides in both nonhuman primate models independently of changes in body weight, food intake, body temperature, or adverse reactions. CRMP treatment was also associated with a 20 to 30% reduction in fasting plasma triglycerides and low-density lipoprotein (LDL)–cholesterol in dysmetabolic nonhuman primates. Oral administration of CRMP reduced endogenous glucose production by 18%, attributable to a 20% reduction in hepatic acetyl–coenzyme A (CoA) content [as assessed by whole-body β-hydroxybutyrate (β-OHB) turnover] and pyruvate carboxylase flux. Collectively, these studies provide proof-of-concept data to support the development of liver-targeted mitochondrial uncouplers for the treatment of metabolic syndrome in humans.
... The first mitochondrial uncoupler, 2,4-dinitrophenol (DNP), was originally used as a component of explosives during World War I (156,157). After it was observed that many of the workers who handled this compound lost weight, researchers began to investigate the possibility of using DNP as a weight loss drug, and studies by multiple groups demonstrated the efficacy of this approach in obese humans (158)(159)(160)(161). The drug was available as an over-the-counter medication and was widely taken for weight loss in the United States, but reports of toxic effects, including several deaths, led to its withdrawal from the market by the US Food and Drug Administration in 1938 (162). ...
Article
Type 2 diabetes (T2D) is characterized by persistent hyperglycemia despite hyperinsulinemia, affects more than 400 million people worldwide, and is a major cause of morbidity and mortality. Insulin resistance, of which ectopic lipid accumulation in the liver [nonalcoholic fatty liver disease (NAFLD)] and skeletal muscle is the root cause, plays a major role in the development of T2D. Although lifestyle interventions and weight loss are highly effective at reversing NAFLD and T2D, weight loss is difficult to sustain, and newer approaches aimed at treating the root cause of T2D are urgently needed. In this review, we highlight emerging pharmacological strategies aimed at improving insulin sensitivity and T2D by altering hepatic energy balance or inhibiting key enzymes involved in hepatic lipid synthesis. We also summarize recent research suggesting that liver-targeted mitochondrial uncoupling may be an attractive therapeutic approach to treat NAFLD, nonalcoholic steatohepatitis, and T2D.
... Recently, several lines of evidence showed that at low doses, uncouplers reduced reactive oxygen species (ROS), [6][7][8] increased energy expenditure [6,7] and improved longevity. [6,8] Historically, uncoupling agents were used as so-called 'weight-loss agents', [9] and their excessive use due to psychological problems has led to the increase in core body temperature and even death. [10] These weight loss agents are also associated with a danger of overuse due to the image of so-called ideal beauty. ...
Article
Objectives Excessive use of uncoupling agents, previously used as weight loss agents, has led to the increase in body temperature and death. The aim of the present study was to evaluate the acute cardiac effects of mitochondrial protonophore in a rat model at a high dose, and its specific influence on cardiac substrate uptake. Methods Eight‐week‐old male Sprague–Dawley rats were intraperitoneally injected with the protonophore carbonyl cyanide m‐chloro phenyl hydrazone (CCCP; 4 mg/kg) or vehicle (dimethyl sulfoxide). Blood pressure, heart rate (HR) and systolic function were recorded. Substrate uptake was monitored by radioactive tracers. Key findings Compared to the control group, the respiratory rate and body temperature increased, the left ventricle was dilated, and systolic function transiently deteriorated in the CCCP group. There was no difference in blood pressure and HR between the two groups. In cardiac substrate uptake, glucose uptake showed a 95% increase (P < 0.05), and fatty acid uptake showed a 52% decrease (P < 0.05) in CCCP‐administered group. Conclusions The deleterious effects on cardiac function and the changes in substrate uptake were observed when administered with the protonophore at a high dose.
... 2,4-DNP raised interest upon discovering that ingestion caused significant weight loss ( Harris & Cocoran, 1995) and consequently, the compound was prescribed as a weight loss aid ( Hardgrove & Stem, 1938;Harris & Cocoran, 1995;Horner, 1942;Parascandola, 1974). Between 1933 and 1935, an estimated 100,000 patients were given 2,4-DNP ( Tainter, Stockton & Cutting, 1935). Studies concerning human oral exposure comprise primarily of case reports and clinical studies dating between 1932 and 1938 ( Harris & Cocoran, 1995). ...
Article
Background: 2,4-Dinitrophenol (2,4-DNP) is a compound with multiple industrial purposes. Currently unlicensed for human consumption, it is used by the gym-going population for drastic, short-term body fat loss. Nonetheless, physiological mechanisms can lead to potentially fatal hyperthermia. Reported fatal incidents have caused concern and highlighted the need for intervention. Understanding decision-making leading to 2,4-DNP use alongside the perceived outgroup attitudes is vital to forming effective harm minimisation policies targeting current and potential users. First-hand accounts from this elusive population are scarce. Methods: Fourteen novel and experienced users (13 male, 1 female) were recruited via "snowballing" techniques. Semi-structured interviews were conducted, comprising 28 questions. Thematic content analysis was conducted using 37 codes. Results: Four characteristic themes emerged: 1. Users considered the Internet to be a crucial multifunctional resource directly impacting their 2,4-DNP use. 2. Users "respected" 2,4-DNP, proactively taking harm reduction measures. 3. Attitudinal polarisation towards 2,4-DNP within the gym-going community was consistent in all accounts. 4. Users perceived outgroup populations to have inherently negative attitudes towards their use. These themes fell under the all-encompassing theme of "being in control". Conclusion: For the first time, this study offers a rich detail of attitudes toward 2,4-DNP use by giving a collective voice to users. The element of control over every aspect of the users' life appears to be a significant contributor to the successful risk-management of 2,4-DNP use. In the absence of an established safe upper limit and effective regulatory control, education is critical to harm minimisation.
... Capsules containing up to 100 mg of DNP or its sodium salt, C 6 H 3 (NO 2 )2(ONa).H 2 O, were generally taken l -3 times a day, depending on the desired total dose. It is estimated that 100,000 patients (mostly women) took DNP for weight reduction between 1933 and 1935 (2). Knowledge on the toxicity of DNP caused by human oral exposure comes almost entirely from clinical studies and case reports related to its medical use from 1932 to about 1938. ...
Article
In Roman mythology, Janus was the god of gates, doors, beginnings and endings. He was usually depicted with two faces looking in opposite directions. Janus was frequently used to symbolize change and transitions, such as the progression from past to future or from one viewpoint to another. 2,4-dinitrophenol (DNP) and other nitrophenols have long been known to be toxic at high concentrations (the 'bad' face of DNP), an effect that appears essentially related to interference with cellular energy metabolism due to uncoupling of mitochondrial oxidative phosphorylation. Five years ago, however, we published the first report showing that low concentrations of DNP protect neurons against the toxicity of the amyloid-beta peptide (De Felice et al. (2001) FASEB J. 15:1297 - 1299]. Since then, other studies have provided evidence of beneficial actions of DNP (at low concentrations), including neuroprotection against different types of insult, blockade of amyloid aggregation, stimulation of neurite outgrowth and neuronal differentiation, and even extension of lifespan in certain organisms. Some of these effects appear to be due to mild mitochondrial uncoupling and prevention of cellular oxidative stress, whereas other actions are related to activation of additional intracellular signaling pathways. Thus, a novel and 'gentle' face of DNP is emerging from such studies. In this review, we discuss both toxic and beneficial actions of DNP. The evidence available so far suggests that DNP and other compounds with similar biological activities may be of significant interest to the development of novel therapeutic approaches for neurodegenerative diseases and other neurological disorders.
... Therefore, preservation of RGCs and improved visual function mediated by MP201 in the current studies may be related to its mitochondrial uncoupling properties after conversion to DNP. DNP was used as a medication in the 1930's for weight loss, but a host of adverse side effects prompted a ban on its use as a prescription drug [63][64][65]. For our present study, we used MP201, a prodrug of DNP that may reduce the risk of overdose and abuse of DNP, and we used MP201 doses that generate DNP at doses~10 to 50 times lower than the dose used in the past for weight loss [25], suggesting that this hormetic-like therapy may be much better tolerated than past treatment with DNP directly. ...
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The ability of novel mitochondrial uncoupler prodrug of 2,4-dinitrophenol (DNP), MP201, to prevent neuronal damage and preserve visual function in an experimental autoimmune encephalomyelitis (EAE) model of optic neuritis was evaluated. Optic nerve inflammation, demyelination, and axonal loss are prominent features of optic neuritis, an inflammatory optic neuropathy often associated with the central nervous system demyelinating disease multiple sclerosis. Currently, optic neuritis is frequently treated with high-dose corticosteroids, but treatment fails to prevent permanent neuronal damage and associated vision changes that occur as optic neuritis resolves, thus suggesting that additional therapies are required. MP201 administered orally, once per day, attenuated visual dysfunction, preserved retinal ganglion cells (RGCs), and reduced RGC axonal loss and demyelination in the optic nerves of EAE mice, with limited effects on inflammation. The prominent mild mitochondrial uncoupling properties of MP201, with slow elimination of DNP, may contribute to the neuroprotective effect by modulating the entire mitochondria’s physiology directly. Results suggest that MP201 is a potential novel treatment for optic neuritis.
... DNP was first used as a component of the explosive trinitrotoluene (TNT) and is currently used as an agricultural insecticide and as a component of fabric and food dyes, such 283 FATALITY FOLLOWING INGESTION OF DINITROPHENOL as Saffron Substitute 1 and Martius Yellow 1 (6). Dinitrophenol was first used as a diet agent in the 1930s during clinical studies by Cutting et al., whom demonstrated that DNP was able to induce significant weight loss, leading to its use as a diet aid (13,14). Its popularity stemmed from the fact that people were able to lose weight without exercise or limiting caloric intake; even today that remains the holy grail of diet agents. ...
Article
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Dinitrophenol, a chemical currently used as an insecticide, is known to uncouple mitochondrial oxidative phosphorylation. A component of explosives, it has also been used in the past as a food coloring and clothing dye. In the 1930s, physicians prescribed it for weight loss, but this practice was discontinued when reports of cataracts, deaths, and other adverse outcomes came to light. We describe in our report the overdose and fatality of a teenager who purchased the product as a weight loss dietary supplement by mail order. We also describe a laboratory method that allowed postmortem determination of the dinitrophenol concentration in the victim's serum. Her death, despite prompt medical treatment, underscores the danger of dinitrophenol. The easy accessibility and apparent resurgent interest in dinitrophenol as a weight loss agent is extremely timely and troubling.
... Potential obesity treatments that strongly increase MR include peripheral mechanisms, such as adrenergic (particularly ␤ 3 -adrenergic) activation (Arch, 2008), chemical uncouplers (such as dinitrophenol) (Tainter et al., 1935), and thyroid hormone (Kaptein et al., 2009); with these mechanisms, there is often a compensatory increase in food intake. In contrast, most centrally acting obesity treatments have beneficial effects on both MR and food intake, with the MR effect generally being modest (Aronne and Thornton-Jones, 2007;Adan et al., 2008). ...
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Bombesin receptor subtype-3 (BRS-3) is an orphan G protein-coupled receptor implicated in the regulation of energy homeostasis. Here, we report the biologic effects of a highly optimized BRS-3 agonist, (2S)-1,1,1-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)propan-2-ol (MK-5046). Single oral doses of MK-5046 inhibited 2-h and overnight food intake and increased fasting metabolic rate in wild-type but not Brs3 knockout mice. Upon dosing for 14 days, MK-5046 at 25 mg · kg(-1) · day(-1) reduced body weight of diet-induced obese mouse by 9% compared with vehicle-dosed controls. In mice, 50% brain receptor occupancy was achieved at a plasma concentration of 0.34 ± 0.23 μM. With chronic dosing, effects on metabolic rate, rather than food intake, seem to be the predominant mechanism for weight reduction by MK-5046. The compound also effectively reduced body weight in rats and caused modest increases in body temperature, heart rate, and blood pressure. These latter effects on temperature, heart rate, and blood pressure were transient in nature and desensitized with continued dosing. MK-5046 is the first BRS-3 agonist with properties suitable for use in larger mammals. In dogs, MK-5046 treatment produced statistically significant and persistent weight loss, which was initially accompanied by increases in body temperature and heart rate that abated with continued dosing. Our results demonstrate antiobesity efficacy for MK-5046 in rodents and dogs and further support BRS-3 agonism as a new approach to the treatment of obesity.
Article
Ischemic stroke is caused by acute neuronal degeneration provoked by interruption of cerebral blood flow. Although the mechanisms contributing to ischemic neuronal degeneration are myriad, mitochondrial dysfunction is now recognized as a pivotal event that can lead to either necrotic or apoptotic neuronal death. Lack of suitable 'upstream' targets to prevent loss of mitochondrial homeostasis has, so far, restricted the development of mechanistically based interventions to promote neuronal survival. Here, we show that the uncoupling agent 2,4 dinitrophenol (DNP) reduces infarct volume approximately 40% in a model of focal ischemia-reperfusion injury in the rat brain. The mechanism of protection involves an early decrease in mitochondrial reactive oxygen species formation and calcium uptake leading to improved mitochondrial function and a reduction in the release of cytochrome c into the cytoplasm. The observed effects of DNP were not associated with enhanced cerebral perfusion. These findings indicate that compounds with uncoupling properties may confer neuroprotection through a mechanism involving stabilization of mitochondrial function.
Article
In the early 1930s, the industrial chemical dinitrophenol found widespread favor as a weight-loss drug, due principally to the work of Maurice Tainter, a clinical pharmacologist from Stanford University. Unfortunately the compound's therapeutic index was razor thin and it was not until thousands of people suffered irreversible harm that mainstream physicians realized that dinitrophenol's risks outweighed its benefits and abandoned its use. Yet, it took passage of the Food, Drug, and Cosmetic Act in 1938 before federal regulators had the ability to stop patent medicine men from selling dinitrophenol to Americans lured by the promise of a drug that would safely melt one's fat away.
Article
The subject of the paper is the history of dinitrophenol compounds in relationship to bioenergetics. The history of the interaction between dinitrophenols and bioenergetics can be traced back to 1885 whenCazeneuve andLpine discovered the thermogenic effects of dinitronapthol. Dinitronapthol and dinitrocresol were used as food colors in the late 19th century although a growing awareness of their toxic properties led to the prohibition of their use for this purpose in certain countries. The toxicity of dinitrophenol was studied in some detail byMayer and his colleagues in France during World War I since it was used by the French in the manufacture of munitions. They recognized that the compound stimulated cellular metabolism, but they did not publish their results until many years later and as a result their work was at first not widely known. In the late 1920's and early 1930's, CorneilleHeymans and his colleagues at Ghent andCutting andTainter and their colleagues at Stanford demonstrated the metabolic stimulating powers of dinitronapthol and dinitrophenol. The Stanford group introduced dinitrophenol into therapeutics for the treatment of obesity, and the drug soon found its way into numerous anti-fat patent medicines. Several fatalities, a number of cases of cataract, and other reported toxic effects led to widespread concern about the use of dinitrophenol. The FDA could not take effective action against the drug, however, until after its powers had been expanded by the 1938 Food, Drug and Cosmetic Act. The use of dinitrophenol and related compounds for treating obesity was essentially discontinued after the 1930's. Studies on the mode of action of dinitrophenol in the 1930's and 1940's led ultimately to the establishment of the fact that it uncouples oxidative phosphorylation (Loomis andLipmann, 1948).
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We have discovered that some weak uncouplers (typified by butylated hydroxytoluene) have a dynamic range of more than 10(6) in vitro: the concentration giving measurable uncoupling is less than one millionth of the concentration causing full uncoupling. They achieve this through a high-affinity interaction with the mitochondrial adenine nucleotide translocase that causes significant but limited uncoupling at extremely low uncoupler concentrations, together with more conventional uncoupling at much higher concentrations. Uncoupling at the translocase is not by a conventional weak acid/anion cycling mechanism since it is also caused by substituted triphenylphosphonium molecules, which are not anionic and cannot protonate. Covalent attachment of the uncoupler to a mitochondrially targeted hydrophobic cation sensitizes it to membrane potential, giving a small additional effect. The wide dynamic range of these uncouplers in isolated mitochondria and intact cells reveals a novel allosteric activation of proton transport through the adenine nucleotide translocase and provides a promising starting point for designing safer uncouplers for obesity therapy.
Article
Background Fatal intoxications can only be recognized in exceptional cases during an external examination of corpses, as poisoning does not leave any characteristic findings on the deceased. A case report on a fatal 2,4-dinitrophenol (DNP) intoxication in a 50-year-old man with yellow discoloration of parts of the hands and feet led to the hypothesis that these morphological findings could indicate the cause of death.Objective Are there morphological findings hinting at this diagnosis in persons after DNP ingestion/intoxication?Material and methodsVia a selective literature search information about the occurrence and localization of abnormal pathomorphological external and/or internal findings in cases of DNP ingestion/intoxication was gathered.ResultsA total of 13 case reports and 4 original articles with information on morphological findings due to DNP ingestion/intoxication were found. The external findings were dominated by yellowing of the skin, followed by exanthemas/rashes and yellowing of the sclera. The internal findings included yellowing of the internal organs, yellow color of the stomach contents, yellowing of the mucous membranes and the intense yellow color of the urine.Conclusion Yellowish discoloration of the skin, sclera, mucous membranes, internal organs, sweat and/or an intensive yellow discoloration of the urine are not observed in every DNP intoxication; however, when they do occur, they are a characteristic hint for DNP ingestion and, if localized to the skin, indicate prolonged consumption. Most likely, the discoloration is caused by deposits of yellow DNP crystals in the tissue.
It should be obvious from the foregoing discussion that, at the present time, there is not an acceptably safe and effective pharmacological treatment for obesity. This patent inadequacy of present drug regimens has spawned the investigation into the diverse pharmacological approaches reviewed in this paper as well as investigation into the intestinal bypass operation (see Chapter 10). We feel that the eventual, safe and effective therapy for obesity will come from the pharmacological realm. Glucose-blocking drugs, growth hormone analogues, and hydroxycitrate are but three of the potentially safe and effective approaches to the problem for the future. It will be truly fascinating to watch the development in the treatment of obesity and, specifically, the pharmacological treatment for this problem over the next five to ten years.
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Decreasing mitochondrial coupling efficiency has been shown to be an effective therapy for obesity and related metabolic symptoms. Here we identified a novel mitochondrial uncoupler that promoted uncoupled respiration in a cell type-specific manner and investigated its effects on modulation of energy metabolism in vivo and in vitro. We screened a collection of mitochondrial membrane potential depolarising compounds for a novel chemical uncoupler on isolated skeletal muscle mitochondria using a channel oxygen system. The effect on respiration of metabolic cells (L6 myotubes, 3T3-L1 adipocytes and rat primary hepatocytes) was examined and metabolic pathways sensitive to cellular ATP content were also evaluated. The chronic metabolic effects were investigated in high-fat diet-induced obese mice and standard diet-fed (SD) lean mice. The novel uncoupler, CZ5, promoted uncoupled respiration in a cell type-specific manner. It stimulated fuel oxidation in L6 myotubes and reduced lipid accumulation in 3T3-L1 adipocytes but did not affect gluconeogenesis or the triacylglycerol content in hepatocytes. The administration of CZ5 to SD mice increased energy expenditure (EE) but did not affect body weight or adiposity. Chronic studies in mice on high-fat diet showed that CZ5 reduced body weight and improved glucose and lipid metabolism via both increased EE and suppressed energy intake. The reduced adiposity was associated with the restoration of expression of key metabolic genes in visceral adipose tissue. This work demonstrates that a cell type-specific mitochondrial chemical uncoupler may have therapeutic potential for treating high-fat diet-induced metabolic diseases.
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Drugs and natural compounds that affect the thermoregulatory system can induce or contribute to hyperthermia when used in excess. Hyperthermia associated with drug overdose is dangerous and potentially lethal. This article reviews the body's process of maintaining thermodynamic equilibrium, and describes the mechanisms by which it is influenced by sympathomimetic and anticholinergic drugs, salicylates, and thyroid replacement medications. Appropriate treatment strategies such as cooling and the administration of counteractive medications are discussed.
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In homoeothermic organisms, the preservation of core temperature represents a primal function, and its costs in terms of energy expenditure can be considerable. In modern humans, the endogenous thermoregulation mechanisms have been replaced by clothing and environmental control, and the maintenance of thermoneutrality has been successfully achieved by manipulation of the micro- and macroenvironment. The rediscovery of the presence and activity of brown adipose tissue in adult humans has renewed the interest on adaptive thermogenesis (AT) as a means to facilitate weight loss and improve carbohydrate metabolism. The aim of this review is to describe the recent advancements in the study of this function, and to assess the potential and limitations of exploiting AT for environmental/behavioral, and pharmacological interventions. Copyright © 2015. Published by Elsevier Ltd.
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A means of “burning fat” — shunting protons to a thermogenic pathway rather than an energy-producing one — is mediated by UCP1, which is expressed in the mitochondria of brown fat. A study in mice has uncovered a similar mechanism in skeletal muscle and white adipose tissue.
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As a mitochondrial uncoupler, 2,4-dinitrophenol (DNP) is proven therapeutically effective against nonalcoholic fatty liver disease (NAFLD) by uncoupling oxidation and phosphorylation. However, a major factor that impedes the clinical application of DNP is the significant side effects derived from its frequent hyperthermia and even death. In this study, we developed an injectable liquid crystal gel (DNP-LC-gel) to reduce the toxicity of DNP. DNP-LC-gel achieved sustained release and maintained DNP plasma concentration at an effective drug level. In a rat model of NAFLD, DNP-LC-gel treated rats reduced hepatic steatosis, liver triglyceride content, plasma triacylglycerol (TG) and total cholesterol (TC) content. Compared with DNP solution (DNP-soln), rats after DNP-LC-gel treatment showed no body temperature toxicity and local irritation. All results above indicated that DNP-LC-gel has a great potential for NAFLD therapy.
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Mitochondria are essential organelles for many aspects of cellular homeostasis, including energy harvesting through oxidative phosphorylation. Alterations of mitochondrial function not only impact on cellular metabolism but also critically influence whole-body metabolism, health, and life span. Diseases defined by mitochondrial dysfunction have also expanded from rare monogenic disorders in a strict sense to now also include many common polygenic diseases, including metabolic, cardiovascular, neurodegenerative, and neuromuscular diseases. This has led to an intensive search for new therapeutic and preventive strategies aimed at invigorating mitochondrial function by exploiting key components of mitochondrial biogenesis, redox metabolism, dynamics, mitophagy, and the mitochondrial unfolded protein response. As such, new findings linking mitochondrial function to the progression or outcome of this ever-increasing list of diseases has stimulated the discovery and development of the first true mitochondrial drugs, which are now entering the clinic and are discussed in this review.
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Mice are widely used for exploring obesity physiology and treatment. However, thermal biology is different between small and large mammals. In this Review, we discuss how the effect of environmental temperature must be understood to ensure applicability of mouse experiments to human obesity. At ambient environmental temperature (~22 °C), over one third of energy expenditure in mice is devoted to maintaining core body temperature, largely by brown adipose tissue. To conserve this energy, mice can enter a regulated hypothermia, while humans do not. Since humans expend little or no energy specifically to keep warm, mice studied at thermoneutrality (~30 °C) may be a better model for human energy homeostasis. Studies indicate that environmental temperature also affects the efficacy of drugs that increase energy expenditure. In mice, dinitrophenol, a protonophore, and CL316243, a β3‐adrenergic agonist, both increase metabolic rate at thermoneutrality, but only CL316243 increases it at 22 °C. Furthermore, mice housed at thermoneutrality may become more obese than mice at 22 °C. Thus, we discuss the importance of studying mice at both thermoneutrality and at lower temperatures in obesity research. This article is protected by copyright. All rights reserved.
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Obesity represents the single greatest ongoing roadblock to improving cardiovascular health. Prolonged obesity is associated with fundamental changes in the integrative control of energy balance, including the development of selective leptin resistance, which is thought to contribute to obesity-associated hypertension, and adaptation of resting metabolic rate (RMR) when excess weight is reduced. Leptin and the melanocortin system within the hypothalamus contribute to the control of both energy balance and blood pressure. While the development of drugs to stimulate RMR and thereby reverse obesity through activation of the melanocortin system has been pursued, most of the resulting compounds simultaneously cause hypertension. Evidence supports the concept that although feeding behaviors, RMR, and blood pressure are controlled through mechanisms that utilize similar molecular mediators, these mechanisms exist in anatomically dissociable networks. New evidence supports a major change in molecular signaling within AgRP (Agouti-related peptide) neurons of the arcuate nucleus of the hypothalamus during prolonged obesity and the existence of multiple distinct subtypes of AgRP neurons that individually contribute to control of feeding, RMR, or blood pressure. Finally, ongoing work by our laboratory and others support a unique role for AT 1 (angiotensin II type 1 receptor) within one specific subtype of AgRP neuron for the control of RMR. We propose that understanding the unique biology of the AT 1 -expressing, RMR-controlling subtype of AgRP neurons will help to resolve the selective dysfunctions in RMR control that develop during prolonged obesity and potentially point toward novel druggable antiobesity targets that will not simultaneously cause hypertension.
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Linking decyl-triphenyl-phosphonium to fluorescein yields a fluorescent probe that accumulates in energized mitochondria, facilitates proton transfer across membranes and stimulates mitochondrial respiration. This features a mitochondria-targeted uncoupler, being of potential interest for therapeutic use against oxidative stress-related diseases.
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