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Use of Dinitrophenol in Nutritional Disorders : A Critical Survey of Clinical Results.

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... DNP was also commonly used as a dye, for wood preservation, photographic development, and as an herbicide (Harper et al., 2001;Grundlingh et al., 2011). An overdose of DNP results in overheating, fever, and eventually death (Perkins, 1919;Tainter et al., 1934). In the decade following 1910, more than 35 cases of fatal DNP intoxication were recorded (Horner, 1941;Grundlingh et al., 2011). ...
... The pharmacological effect resided in the ability of DNP to increase metabolic rate via enhanced mitochondrial uncoupling, thus favoring heat production over ATP synthesis Tainter et al., 1933Tainter et al., , 1935. When used in a dose of 300 mg/d, weight loss induced by DNP seemed to be well tolerated and associated with an increase in metabolic rate of ;50% (Tainter et al., , 1934Dunlop, 1934). In subsequent clinical studies, metabolic rate was shown to increase in average by 11% per 100 mg DNP (Dunlop, 1934;Tainter, 1935;Harper et al., 2001). ...
... Following its introduction as a weight loss pharmacotherapy in 1933, the interest in DNP was tremendous. In 1934 alone, Stanford Clinics supplied over 1,200,000 DNP capsules to physicians, or directly to patients with physician prescriptions (Tainter et al., 1934). Stanford scientists estimated that within this 1 year, more than 100,000 people in the United States were treated with DNP. ...
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With their ever-growing prevalence, obesity and diabetes represent major health threats of our society. Based on estimations by the World Health Organization, approximately 300 million people will be obese in 2035. In 2015 alone there were more than 1.6 million fatalities attributable to hyperglycemia and diabetes. In addition, treatment of these diseases places an enormous burden on our health care system. As a result, the development of pharmacotherapies to tackle this life-threatening pandemic is of utmost importance. Since the beginning of the 19th century, a variety of drugs have been evaluated for their ability to decrease body weight and/or to improve deranged glycemic control. The list of evaluated drugs includes, among many others, sheep-derived thyroid extracts, mitochondrial uncouplers, amphetamines, serotonergics, lipase inhibitors, and a variety of hormones produced and secreted by the gastrointestinal tract or adipose tissue. Unfortunately, when used as a single hormone therapy, most of these drugs are underwhelming in their efficacy or safety, and placebo-subtracted weight loss attributed to such therapy is typically not more than 10%. In 2009, the generation of a single molecule with agonism at the receptors for glucagon and the glucagon-like peptide 1 broke new ground in obesity pharmacology. This molecule combined the beneficial anorectic and glycemic effects of glucagon-like peptide 1 with the thermogenic effect of glucagon into a single molecule with enhanced potency and sustained action. Several other unimolecular dual agonists have subsequently been developed, and, based on their preclinical success, these molecules illuminate the path to a new and more fruitful era in obesity pharmacology. In this review, we focus on the historical pharmacological approaches to treat obesity and glucose intolerance and describe how the knowledge obtained by these studies led to the discovery of unimolecular polypharmacology.
... This initial observation of DNP-associated weight loss interested many to explore the compound as a treatment for obesity [38,[75][76][77]. With an overwhelming appeal, within one year of publishing the first clinical study with DNP in 1933, well over 100,000 people had already taken this unapproved drug, of unknown purity or impurities or toxicities as a weight loss agent [78]. It appeared that many consumers of the drug were taking it without a prescription or knowledge on how much or monitoring at all. ...
... or~300 mg/day) was achieved, viewed as the "optimal" steady-state dose. Toxicities, such as rashes (~7%) and cataracts (0.1%-1%), started to appear at higher DNP doses [78][79][80]. The rashes appeared to go away with discontinuation of DNP, however, in most cases, cataracts required surgery to replace the lens [80]. ...
... Starting with a new chemical uncoupler throws away the wealth of data in humans (>100,000 people) as all new molecules have their own unknown toxicological risks in humans. The doses where various toxicities have been encountered is already partly known from both studies in humans and non-human animal work [78,80,81]. It is also predicted from studies in a host of neurodegenerative models, that the therapeutic window for desired neuroprotective effects is far below those doses where toxicity is first encountered [28,29,52,[85][86][87][88]. ...
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Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the gene huntingtin. There is no treatment to prevent or delay the disease course of HD currently. Oxidative stress and mitochondrial dysfunction have emerged as key determinants of the disease progression in HD. Therefore, counteracting mutant huntingtin (mHtt)-induced oxidative stress and mitochondrial dysfunction appears as a new approach to treat this devastating disease. Interestingly, mild mitochondrial uncoupling improves neuronal resistance to stress and facilitates neuronal survival. Mild mitochondrial uncoupling can be induced by the proper dose of 2,4-dinitrophenol (DNP), a proton ionophore that was previously used for weight loss. In this study, we evaluated the effects of chronic administration of DNP at three doses (0.5, 1, 5mg/kg/day) on mHtt-induced behavioral deficits and cellular abnormalities in the N171-82Q HD mouse model. DNP at a low dose (1mg/kg/day) significantly improved motor function and preserved medium spiny neuronal marker DARPP32 and postsynaptic protein PSD95 in the striatum of HD mice. Further mechanistic study suggests that DNP at this dose reduced oxidative stress in HD mice, which was indicated by reduced levels of F2-isoprostanes in the brain of HD mice treated with DNP. Our data indicated that DNP provided behavioral benefit and neuroprotective effect at a weight neutral dose in HD mice, suggesting that the potential value of repositioning DNP to HD treatment is warranted in well-controlled clinical trials in HD.
... This initial observation of DNP-associated weight loss interested many to explore the compound as a treatment for obesity [38,[75][76][77]. With an overwhelming appeal, within one year of publishing the first clinical study with DNP in 1933, well over 100,000 people had already taken this unapproved drug, of unknown purity or impurities or toxicities as a weight loss agent [78]. It appeared that many consumers of the drug were taking it without a prescription or knowledge on how much or monitoring at all. ...
... or~300 mg/day) was achieved, viewed as the "optimal" steady-state dose. Toxicities, such as rashes (~7%) and cataracts (0.1%-1%), started to appear at higher DNP doses [78][79][80]. The rashes appeared to go away with discontinuation of DNP, however, in most cases, cataracts required surgery to replace the lens [80]. ...
... Starting with a new chemical uncoupler throws away the wealth of data in humans (>100,000 people) as all new molecules have their own unknown toxicological risks in humans. The doses where various toxicities have been encountered is already partly known from both studies in humans and non-human animal work [78,80,81]. It is also predicted from studies in a host of neurodegenerative models, that the therapeutic window for desired neuroprotective effects is far below those doses where toxicity is first encountered [28,29,52,[85][86][87][88]. ...
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In the sanctity of pure drug discovery, objective reasoning can become clouded when pursuing ideas that appear unorthodox, but are spot on physiologically. To put this into historical perspective, it was an unorthodox idea in the 1950’s to suggest that warfarin, a rat poison, could be repositioned into a breakthrough drug in humans to protect against strokes as a blood thinner. Yet it was approved in 1954 as Coumadin® and has been prescribed to billions of patients as a standard of care. Similarly, no one can forget the horrific effects of thalidomide, prescribed or available without a prescription, as both a sleeping pill and “morning sickness” anti-nausea medication targeting pregnant women in the 1950’s. The “thalidomide babies” became the case-in-point for the need of strict guidelines by the U.S. Food & Drug Administration (FDA) or full multi-species teratogenicity testing before drug approval. More recently it was found that thalidomide is useful in graft versus host disease, leprosy and resistant tuberculosis treatment, and as an anti-angiogenesis agent as a breakthrough drug for multiple myeloma (except for pregnant female patients). Decades of diabetes drug discovery research has historically focused on every possible angle, except, the energy-out side of the equation, namely, raising mitochondrial energy expenditure with chemical uncouplers. The idea of “social responsibility” allowed energy-in agents to be explored and the portfolio is robust with medicines of insulin sensitizers, insulin analogues, secretagogues, SGLT2 inhibitors, etc., but not energy-out medicines. The primary reason? It appeared unorthodox, to return to exploring a drug platform used in the 1930s in over 100,000 obese patients used for weight loss. This is over 80-years ago and prior to Dr Peter Mitchell explaining the mechanism of how mitochondrial uncouplers, like 2,4-dinitrophenol (DNP) even worked by three decades later in 1961. Although there is a clear application for metabolic disease, it was not until recently that this platform was explored for its merit at very low, weight-neutral doses, for treating insidious human illnesses and completely unrelated to weight reduction. It is known that mitochondrial uncouplers specifically target the entire organelle’s physiology non-genomically. It has been known for years that many neuromuscular and neurodegenerative diseases are associated with overt production of reactive oxygen species (ROSs), a rise in isoprostanes (biomarker of mitochondrial ROSs in urine or blood) and poor calcium (Ca2+) handing. It has also been known that mitochondrial uncouplers lower ROS production and Ca2+ overload. There is evidence that elevation of isoprostanes precedes disease onset, in Alzheimer’s Disease (AD). It is also curious, why so many neurodegenerative diseases of known and unknown etiology start at mid-life or later, such as Multiple Sclerosis (MS), Huntington Disease (HD), AD, Parkinson Disease, and Amyotrophic Lateral Sclerosis (ALS). Is there a relationship to a buildup of mutations that are sequestered over time due to ROSs exceeding the rate of repair? If ROS production were managed, could disease onset due to aging be delayed or prevented? Is it possible that most, if not all neurodegenerative diseases are manifested through mitochondrial dysfunction? Although DNP, a historic mitochondrial uncoupler, was used in the 1930s at high doses for obesity in well over 100,000 humans, and so far, it has never been an FDA-approved drug. This review will focus on the application of using DNP, but now, repositioned as a potential disease-modifying drug for a legion of insidious diseases at much lower and paradoxically, weight neutral doses. DNP will be addressed as a treatment for “metabesity”, an emerging term related to the global comorbidities associated with the over-nutritional phenotype; obesity, diabetes, nonalcoholic steatohepatitis (NASH), metabolic syndrome, cardiovascular disease, but including neurodegenerative disorders and accelerated aging. Some unexpected drug findings will be discussed, such as DNP’s induction of neurotrophic growth factors involved in neuronal heath, learning and cognition. For the first time in 80’s years, the FDA has granted (to Mitochon Pharmaceutical, Inc., Blue Bell, PA, USA) an open Investigational New Drug (IND) approval to begin rigorous clinical testing of DNP for safety and tolerability, including for the first ever, pharmacokinetic profiling in humans. Successful completion of Phase I clinical trial will open the door to explore the merits of DNP as a possible treatment of people with many truly unmet medical needs, including those suffering from HD, MS, PD, AD, ALS, Duchenne Muscular Dystrophy (DMD), and Traumatic Brain Injury (TBI).
... While some of the animal studies were translated to humans, others were not. Earlier clinical observations in humans demonstrated that both cold exposure [19,36,37] and treatment with mitochondrial uncouplers [38][39][40] result in increased energy expenditure and weight loss [41]. More recent BAT-targeted pharmacological studies have failed to demonstrate that BAT activation results in a significant weight loss by increasing overall energy expenditure [42][43][44]. ...
... It has been shown through the use of chemical uncouplers that increasing the metabolic rate can cause weight loss and supports the hypothesis that increasing energy expenditure by decreasing metabolic efficiency is a potential mechanism to induce a negative energy balance [39,40]. However, chemical uncouplers and adrenergic inducers of thermogenesis have several disadvantages and risks related to their safety, including their lack of tissue specificity and the potential disruption of other functions of mitochondria that are membrane potential-dependent [93,94]. ...
Article
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Obesity results from an imbalance in energy homeostasis, whereby excessive energy intake exceeds caloric expenditure. Energy can be dissipated out of an organism by producing heat (thermogenesis), explaining the long-standing interest in exploiting thermogenic processes to counteract obesity. Mitochondrial uncoupling is a process that expends energy by oxidizing nutrients to produce heat, instead of ATP synthesis. Energy can also be dissipated through mechanisms that do not involve mitochondrial uncoupling. Such mechanisms include futile cycles described as metabolic reactions that consume ATP to produce a product from a substrate but then converting the product back into the original substrate, releasing the energy as heat. Energy dissipation driven by cellular ATP demand can be regulated by adjusting the speed and number of futile cycles. Energy consuming futile cycles that are reviewed here are lipolysis/fatty acid re-esterification cycle, creatine/phosphocreatine cycle, and the SERCA-mediated calcium import and export cycle. Their reliance on ATP emphasizes that mitochondrial oxidative function coupled to ATP synthesis, and not just uncoupling, can play a role in thermogenic energy dissipation. Here, we review ATP consuming futile cycles, the evidence for their function in humans, and their potential employment as a strategy to dissipate energy and counteract obesity.
... 2,4-Dinitrophenol (DNP) has been known since the mid-1930s as an effective component of "diet pills" that is capable of reducing obesity by increasing the basal metabolic rate [1]. Severe side effects forced its withdrawal from the pharmaceutical market [2,3]. However, DNP can still be illegally purchased under Biomolecules 2021, 11, 1178 2 of 14 different names over the internet as a drug conferring rapid and supposedly safe weight loss, and is also used as an illegal food supplement [4]. ...
... We now hypothesize that DNP's protonophoric function may be also potentiated by mitochondrial proton-transporting proteins, in addition to the DNP-mediated increase in the selective lipid membrane's permeability for protons. To test this hypothesis, we used a well-defined model of lipid bilayer membranes reconstituted with recombinant ANT1 or UCPs (1) to investigate the contribution of these proteins to DNP-mediated proton leakage, (2) to evaluate the efficiency of the inhibitors of proton transport mediated by ANT1/UCP, and (3) to reveal the amino acids crucial for ANT1 activation by DNP. ...
Article
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2,4-Dinitrophenol (DNP) is a classic uncoupler of oxidative phosphorylation in mitochondria which is still used in “diet pills”, despite its high toxicity and lack of antidotes. DNP increases the proton current through pure lipid membranes, similar to other chemical uncouplers. However, the molecular mechanism of its action in the mitochondria is far from being understood. The sensitivity of DNP’s uncoupling action in mitochondria to carboxyatractyloside, a specific inhibitor of adenine nucleotide translocase (ANT), suggests the involvement of ANT and probably other mitochondrial proton-transporting proteins in the DNP’s protonophoric activity. To test this hypothesis, we investigated the contribution of recombinant ANT1 and the uncoupling proteins UCP1-UCP3 to DNP-mediated proton leakage using the well-defined model of planar bilayer lipid membranes. All four proteins significantly enhanced the protonophoric effect of DNP. Notably, only long-chain free fatty acids were previously shown to be co-factors of UCPs and ANT1. Using site-directed mutagenesis and molecular dynamics simulations, we showed that arginine 79 of ANT1 is crucial for the DNP-mediated increase of membrane conductance, implying that this amino acid participates in DNP binding to ANT1.
... 2,4-Dinitrophenol (DNP) is a known mitochondrial uncoupler that was widely used as a weight loss drug in the 1930's 1 . As a dieting drug, it was found to increase the rate of metabolism in patients by 50% or more 1 . In the 1930's, it was discovered that DNP caused several negative side effects and there were several deaths associated with its use 1 . ...
... As a dieting drug, it was found to increase the rate of metabolism in patients by 50% or more 1 . In the 1930's, it was discovered that DNP caused several negative side effects and there were several deaths associated with its use 1 . DNP was banned as a dieting drug in the U.S. in 1938 2 . ...
Article
2,4-Dinitrophenol (DNP) is a well-documented mitochondrial uncoupler that was widely used as a dieting drug in the 1930’s. It was later banned in 1938 due its negative side effects which included extreme weight loss, the formation of cataracts, skin rashes, and death. Triclosan (TCS) is a common antimicrobial agent that is a component in soaps, toothpastes, and other household products. In addition to its antimicrobial role, TCS has been found to alleviate skin inflammation and dermatitis. However, TCS has also been linked to several health issues including increased cases of asthma and allergy, developmental problems, and decreased fertility. Previous studies in the Gosse laboratory found that TCS inhibits the primary functions of mast cells, key players in the immune system. More recent studies have found that in addition to increasing oxygen consumption, TCS significantly inhibits ATP production in rat basophilic leukemia cells, clone 2H3 (RBL-2H3) at non-cytotoxic doses with an EC50 of 7.5 µM to 9.6 µM. These results strongly indicate that, like DNP, TCS is a mitochondrial uncoupler. Since DNP is a known, dangerous mitochondrial uncoupler, it serves as a useful comparison to assess the potential danger of TCS. In this study, cultured RBL-2H3 cells were exposed to increasing concentrations of DNP and were assessed for ATP production and cytotoxicity. DNP was found to significantly inhibit ATP production at non-cytotoxic doses with an EC50 of 389 µM to 677 µM. These results indicate that TCS is ~60-fold more potent as a mitochondrial uncoupler in RBL cells than in DNP. More related, comparative research with DNP is needed to fully explore triclosan’s mitochondrial toxicity.
... 11 This partially reversible uncoupling can increase metabolism whilst maintaining adequate adenosine triphosphate production. 16 DNP was initially used in obesity, 29 but due to lack of tissue specificity and reports of fatal hyperthermia with systemic use, 17 research now focusses on organ-directed defatting. 12 Perry et al. found that liver-targeted DNP decreased liver triglycerides and reversed non-alcoholic fatty liver disease (NAFLD) in a rat model. ...
Article
Introduction: Normothermic machine perfusion (NMP) provides a platform for drug-delivery. However, pharmacological considerations for therapeutics delivered during NMP are scarcely reported. We aimed to demonstrate the ability of NMP as a platform for pharmacological testing, using a drug which increases metabolism (2,4-Dinitrophenol; DNP) as an example therapeutic. Methods: We performed 25 hours of NMP on human livers which had been declined for transplant due to steatosis (n=7). Three livers received a DNP bolus, three were controls, and one received a DNP infusion. Results: Toxicity studies revealed DNP delivery was safe, without hepatotoxic effects. Liver surface temperature was increased in the DNP group (P=0.046), but no livers suffered hyperthermia - the mechanism of DNP toxicity in vivo. Pharmacokinetic studies revealed DNP elimination with first-order kinetics and 7.7 hour half-life (95% CI=5.1-15.9hrs). Clearance of DNP in bile was negligible. As expected, DNP significantly increased oxygen consumption (P=0.023); this increase was closely correlated with perfusate DNP concentration (r2 =0.975; P=0.002) and the effect was lost as DNP was eliminated by the liver. A DNP infusion rate, calculated using our pharmacokinetic data, successfully maintained perfusate DNP concentration. Discussion: Detailed pharmacological testing can be performed during NMP. Our therapeutic (DNP) is rapidly eliminated by the ex-vivo liver, meaning the drug effect of increased metabolism is only transient. This demonstrates the importance of assessing pharmacokinetics when delivering therapeutics during NMP, especially for prolonged perfusion of organs with established roles in drug elimination. Rigorous pharmacological testing is needed to unlock the potential of NMP as a clinical drug-delivery platform.
... Pre-clinical and clinical studies have reported acute toxic effects like hyperthermia and weight loss with the use of 2,4 DNP (Ennis and Keep 2006;Grundlingh et al. 2011). Some studies have also shown the long-term toxic effects of 2,4 DNP (Boardman 1935;Koch et al. 1935;Tainter et al. 1934). However, we did not observe any serious adverse effects on single administration of 2,4 DNP in optimal dose (5 mg/kg). ...
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Following anoxia, a rapid and marked mitochondrial-linked cell death occurs in the cerebral cortex of newborn rats which leads to insult advancement within a couple of days and causes lifelong neurobehavioral abnormalities. The present study investigated the role of 2,4 dinitrophenol (2,4 DNP) in three doses, i.e.,1, 2.5, and 5 mg/kg on anoxia-induced time-dependent mitochondrial dysfunction and associated neurobehavioral outcome using a well-established global model of anoxia. Briefly, rat pups of 30-h age (P2) were subjected to two episodes of anoxia (10 min each) at 24 h of the time interval in an enclosed chamber supplied with 100% N2 and immersed in a water bath (35–37 °C) to avoid hypothermia. Results demonstrated that the uncoupler 2,4 DNP, in the dose 2.5 and 5 mg/kg injected i.p. within 5 min after second anoxic episode significantly (P < 0.05) preserved mitochondrial function on day 7 preferentially by maintaining mitochondrial membrane potential (MMP) and inhibiting mitochondrial permeability transition (MPT) pore. Further, 2,4 DNP preserved mitochondrial function by improving different states of mitochondrial respiration (s2, s3, s4, s5), respiratory control ratio (RCR), antioxidant enzyme system like superoxide dismutase (SOD) and catalase (CAT), and mitochondrial complex enzymes (I, II, IV, V) after anoxia. Furthermore, a marked decrease in the levels of expression of cytochrome C (cyt C) and pro-apoptotic (Bcl-2 family) and apoptotic (caspase-9/3) proteins was observed on day 7 indicating that the treatment with 2,4 DNP prevented mitochondrial dysfunction and further insult progression (day 1 to day 7). Moreover, 2,4 DNP decreased the apoptotic cell death on day 7 and overall improved the neurobehavioral outcomes like reflex latency and hanging latency which suggests its role in treating neonatal anoxia.
... The first and best-studied example is the artificial uncoupler DNP, a lipid-soluble weak acid which acts as a chemical protonophore and allows protons to leak across the inner mitochondrial membrane [21], mimicking the uncoupling effect of activated UCPs. In the 1930s, DNP was widely used to treat obesity [22]. Nevertheless, because at high doses nonspecific uncoupling in all tissues causes dangerous side effects including hyperthermia and death [23], DNP was withdrawn from the market by the US Food and Drug Administration (FDA) in 1938. ...
Article
In the early 1930s, the chemical uncoupling agent 2,4-dinitrophenol (DNP) was promoted for the very first time as a powerful and effective weight loss pill but quickly withdrawn from the market due to its lack of tissue-selectivity with resulting dangerous side effects, including hyperthermia and death. Today, novel mitochondria- or tissue-targeted chemical uncouplers with higher safety and therapeutic values are under investigation in order to tackle obesity, diabetes and fatty liver disease. Moreover, in the past 20 years, transgenic mouse models were generated to understand the molecular and metabolic consequences of targeted uncoupling, expressing functional uncoupling protein 1 (UCP1) ectopically in white adipose tissue or skeletal muscle. Similar to the action of chemical mitochondrial uncouplers, UCP1 protein dissipates the proton gradient across the inner mitochondrial membrane, thus allowing maximum activity of the respiratory chain and compensatory increase in oxygen consumption, uncoupled from ATP synthesis. Consequently, targeted mitochondrial uncoupling in adipose tissue and skeletal muscle of UCP1-transgenic mice increased substrate metabolism and ameliorates obesity, hypertriglyceridemia and insulin resistance. Further, muscle-specific decrease in mitochondrial efficiency promotes a cell-autonomous and cell-non-autonomous adaptive metabolic remodeling with increased oxidative stress tolerance. This review provides an overview of novel chemical uncouplers as well as the metabolic consequences and adaptive processes of targeted mitochondrial uncoupling on metabolic health and survival.
... This effect has been demonstrated in humans taking DNP. This artificial uncoupler was used as a weight-loss drug in the 1930s, but was later withdrawn, due to its side-effects (rashes, cataract) and some deaths from overdose [41,42]. The narrow therapeutic window of DNP and related uncouplers is the main drawback to their use as anti-obesity drugs, and this problem must be overcome before pharmacological decrease in coupling efficiency becomes a practical possibility in treating obesity. ...
Article
Chemical study of Verbesina virgata collected in several localities afforded two eudesmane triols as 4-cinnamates. Their structures were determined by chemical and spectroscopic means. The structure and stereochemistry of one of the triols was confirmed by X-ray crystallography.
... 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 addition to the positive metabolic effects associated with mitochondrial uncouplers in the presence of nutrient excess, significant negative side effects have been associated with uncoupling agents, including 2,4 dinitrophenol [73,74]. The present manuscript is an important message from not only a therapeutic perspective, but also from a potential side effects perspective, and future work examining salicylate-based compounds should consider the fact that salicylate uncouples mitochondria. ...
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Salsalate is a prodrug of salicylate that lowers blood glucose in patients with type 2 diabetes (T2D) and reduces non-alcoholic fatty liver disease (NAFLD) in animal models; however, the mechanism mediating these effects is unclear. Salicylate directly activates AMP-activated protein kinase (AMPK) via the β1 subunit but whether salsalate requires AMPK β1 to improve T2D and NAFLD has not been examined. Therefore, wild-type (WT) and AMPK β1 knockout mice (AMPK β1KO) were treated with a salsalate dose resulting in clinically relevant serum salicylate concentrations (∼1 mM). Salsalate treatment increased oxygen consumption, lowered fasting glucose, improved glucose tolerance and led to an ∼55% reduction in liver lipid content; effects observed in both WT and AMPK β1KO mice. To explain these AMPK-independent effects, it was found that salicylate increases oligomycin-insensitive respiration (state 4o) and directly increases mitochondrial proton conductance at clinical concentrations. This uncoupling effect is tightly correlated with the suppression of de novo lipogenesis. Salicylate is also able to stimulate brown adipose tissue respiration independent of UCP1. These data indicate that the primary mechanism by which salsalate improves glucose homeostasis and NAFLD is via salicylate-driven mitochondrial uncoupling.
... Protonophores, such as 2,4-dinitrophenol (DNP), increase mitochondrial proton leakage and have been used to treat obesity 5,6 . However, a slight increase in the DNP concentration above the therapeutically effective individual dose is toxic, and DNP was consequently withdrawn from clinical use 7 . ...
Article
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Background: A membrane-penetrating cation, dodecyltriphenylphosphonium (C12TPP), facilitates the recycling of fatty acids in the artificial lipid membrane and mitochondria. C12TPP can dissipate mitochondrial membrane potential and may affect total energy expenditure and body weight in animals and humans. Methods: We investigated the metabolic effects of C12TPP in isolated brown-fat mitochondria, brown adipocyte cultures and mice in vivo. Experimental approaches included the measurement of oxygen consumption, carbon dioxide production, Western blotting, magnetic resonance imaging and bomb calorimetry. Results: In mice, C12TPP (50 μmol/(day • kg body weight)) in the drinking water significantly reduced body weight (12%, P<0.001) and body fat mass (24%, P<0.001) during the first 7 days of treatment. C12TPP did not affect water palatability and intake or the energy and lipid content in feces. The addition of C12TPP to isolated brown-fat mitochondria resulted in increased oxygen consumption. Three hours of pre-treatment with C12TPP also increased oligomycin-insensitive oxygen consumption in brown adipocyte cultures (P<0.01). The effects of C12TPP on mitochondria, cells and mice were independent of uncoupling protein 1 (UCP1). However, C12TPP treatment increased the mitochondrial protein levels in the brown adipose tissue (BAT) of both wild-type and UCP1-KO mice. Pair-feeding revealed that one-third of the body weight loss in C12TPP-treated mice was due to reduced food intake. C12TPP treatment elevated the resting metabolic rate (RMR) by up to 18% (P<0.05) compared with pair-fed animals. C12TPP reduced the respiratory exchange ratio (RER), indicating enhanced fatty acid oxidation in mice. Conclusions: C12TPP combats diet-induced obesity by reducing food intake, increasing the RMR and enhancing fatty acid oxidation.International Journal of Obesity accepted article preview online, 18 August 2016. doi:10.1038/ijo.2016.146.
... Management of DNP toxicity is limited, as there is no specific antidote (Dempsey, 1999). Severe side effects and deaths attributed to DNP are well documented (Tainter et al., 1934;Lehninger, 1987;Hsiao et al., 2005). However, some cases highlight the possibility for people to acquire and ingest exotic poisons, like DNP (Bartlett et al., 2010). ...
Article
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Numerous hazardous chemicals from various industrial sources enter the environment daily; some of them can be used both as drugs and as toxins. Many of these compounds, including dinitrophenols, such as 2,4-dinitrophenol (2,4-DNP), 4,6-dinitrocresol (DNOC), and 2-sec-butyl-4,6-dinitrophenol (dinoseb), are widely used pesticides that persist in some contaminated soils. They have been found in groundwater, causing health and environmental hazards, and are subjects of forensic toxicology. Dinitrophenols have multiple biological and noxious effects based on a mechanism of action characteristic to metabolic inhibitors. Although banned, they have pharmaceutical activity and can be purchased on the Internet as ingredients of weight-loss pills. Many death cases have been reported as accidents in agriculture or as overdoses in weight-loss diets. In this article, we discuss legal aspects of dinitrophenol usage, as well as their biological effect and possible mechanisms of toxicity.
... Used in 1933 as one of the first anti-obesity therapy therapies, 2-4 dinitrophenol (DNP) was found to cause weight loss by uncoupling oxidative phosphorylation, leading to a heightened metabolic rate and increased fat metabolism (21). In its first year, DNP was used by 100,000 individuals in the USA alone (22). However, by 1938, toxic hyperthermic effects were noted and the drug was discontinued. ...
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Aims: To describe the treatment of obesity from ancient times to present day. Methods: Articles reporting the development of anti-obesity therapies were identified through a search for 'anti-obesity' AND 'pharmacotherapy' AND 'development' within the title or abstract on PubMed and 'obesity' in ClinicalTrials.gov. Relevant articles and related literature were selected for inclusion. Results: Stone-age miniature obese female statuettes indicate the existence and cultural significance of obesity as long as 30,000 years ago. Records from Ancient Egyptian and Biblical eras through Greco-Roman to Medieval times indicate that obesity was present throughout the major periods of history, although peoples of previous centuries would probably have experienced overweight and obesity as exceptional rather than normal. Health risks of obesity were noted by the Greek physician Hippocrates (460-377 BCE) when the earliest anti-obesity recommendations on diet, exercise, lifestyle and use of emetics and cathartics were born. These recommendations remained largely unchanged until the early 20th century, when spreading urbanisation, increasingly sedentary jobs and greater availability of processed foods produced a sharp rise in obesity. This led to the need for new, more effective, ways to lose weight, to address comorbidities associated with obesity, and to attain the current cultural ideal of slimness. Drug companies of the 1940s and 1950s produced a series of anti-obesity pharmacotherapies in short succession, based largely on amphetamines. Increased regulation of drug development in the 1960s and new efficacy requirements for weight-loss drugs led to rapid reduction in anti-obesity therapies available by the early 1990s. Conclusion: In the last two decades, several new and emerging therapies have been approved or are in development to provide safe, long-term pharmacological agents for the treatment of obesity.
... Besides 2-DG, it has been demonstrated that high concentration of mitochondrial toxins such as 2,4-dinitrophenol (DNP) (0.5 mM) can stimulate AMPK in a number of cell types, especially in adipocytes and skeletal muscle cells through a mechanism possessing a remarkable increase in AMP : ATP ratio and phosphorylation on Thr172 of the AMPKα subunit [132,148,149]. From the 1930s, DNP was extensively used as a dieting aid in the treatment of nutritional disorders [150], but it is considered too harmful for that application nowadays. DNP actually is a cell permeable and benzene-based chemical compound, which generally behaves as a proton ionophore in biological membranes and particularly defeats the proton gradient across the inner mitochondrial membrane. ...
Article
The development and strategic application of effective anticancer therapies have turned out to be one of the most critical approaches of managing human cancers. Nevertheless, drug resistance is the major obstacle for clinical management of these diseases especially ovarian cancer. In the past years, substantial studies have been carried out with the aim of exploring alternative therapeutic approaches to enhance efficacy of current chemotherapeutic regimes and reduce the side effects caused in order to produce significant advantages in overall survival and to improve patients' quality of life. Targeting cancer cell metabolism by the application of AMP-activated protein kinase (AMPK)-activating agents is believed to be one of the most plausible attempts. AMPK activators such as 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside, A23187, metformin, and bitter melon extract not only prevent cancer progression and metastasis but can also be applied as a supplement to enhance the efficacy of cisplatin-based chemotherapy in human cancers such as ovarian cancer. However, because of the undesirable outcomes along with the frequent toxic side effects of most pharmaceutical AMPK activators that have been utilized in clinical trials, attentions of current studies have been aimed at the identification of replaceable reagents from nutraceuticals or traditional medicines. However, the underlying molecular mechanisms of many nutraceuticals in anticancer still remain obscure. Therefore, better understanding of the functional characterization and regulatory mechanism of natural AMPK activators would help pharmaceutical development in opening an area to intervene ovarian cancer and other human cancers.
... In the early 1930s, dinitrophenol (DNP), a chemical uncoupler, was introduced as a means of increasing metabolism for the purpose of weight loss [52][53][54] . It was found to be highly effective at increasing metabolic rate and resulted predominantly in a loss of fat with a conservation of muscle mass. ...
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).
... DNP, which was used in the 1930s for weight loss, is a very well-studied mitochondrial uncoupler. It was banned in the USA by the FDA in 1938 after skin rashes, cataracts (Boardman, 1935;Rodin, 1936), hepatic dysfunction, gastroenteritis, cardiac arrhythmias (Tainter et al., 1934) and death due to hyperthermia (Grundlingh et al., 2011) were reported. However, in a recent study using an in vitro model of cerebral ischemia, DNP produced a partial uncoupling of cortical neurons, thus reducing neuronal death induced by oxygen deprivation (Mattiasson et al., 2003). ...
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Triclosan (TCS) is an antimicrobial used widely in hospitals and personal care products, at ~10 mm. Human skin efficiently absorbs TCS. Mast cells are ubiquitous key players both in physiological processes and in disease, including asthma, cancer and autism. We previously showed that non-cytotoxic levels of TCS inhibit degranulation, the release of histamine and other mediators, from rat basophilic leukemia mast cells (RBL-2H3), and in this study, we replicate this finding in human mast cells (HMC-1.2). Our investigation into the molecular mechanisms underlying this effect led to the discovery that TCS disrupts adenosine triphosphate (ATP) production in RBL-2H3 cells in glucose-free, galactose-containing media (95% confidence interval EC50 = 7.5-9.7 µm), without causing cytotoxicity. Using these same glucose-free conditions, 15 µm TCS dampens RBL-2H3 degranulation by 40%. The same ATP disruption was found with human HMC-1.2 cells (EC50 4.2-13.7 µm), NIH-3 T3 mouse fibroblasts (EC50 4.8-7.4 µm) and primary human keratinocytes (EC50 3.0-4.1 µm) all with no cytotoxicity. TCS increases oxygen consumption rate in RBL-2H3 cells. Known mitochondrial uncouplers (e.g., carbonyl cyanide 3-chlorophenylhydrazone) previously were found to inhibit mast cell function. TCS-methyl, which has a methyl group in place of the TCS ionizable proton, affects neither degranulation nor ATP production at non-cytotoxic doses. Thus, the effects of TCS on mast cell function are due to its proton ionophore structure. In addition, 5 µm TCS inhibits thapsigargin-stimulated degranulation of RBL-2H3 cells: further evidence that TCS disrupts mast cell signaling. Our data indicate that TCS is a mitochondrial uncoupler, and TCS may affect numerous cell types and functions via this mechanism. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
... It is interesting to note that, under identical experimental conditions in RBL mast cells, TCS is a 60-fold more potent uncoupler, compared to the potent weight loss drug and uncoupler DNP (Tainter et al. 1934). Due to numerous adverse health effects, pharmacological usage of DNP was banned in the U.S. in 1938 (Harris and Corcoran 1995). ...
Article
The antimicrobial agent triclosan (TCS) is used in products such as toothpaste and surgical soaps and is readily absorbed into oral mucosa and human skin. These and many other tissues contain mast cells, which are involved in numerous physiologies and diseases. Mast cells release chemical mediators through a process termed degranulation, which is inhibited by TCS. Investigation into the underlying mechanisms led to the finding that TCS is a mitochondrial uncoupler at non-cytotoxic, low-micromolar doses in several cell types and live zebrafish. Our aim was to determine the mechanisms underlying TCS disruption of mitochondrial function and of mast cell signaling. We combined super-resolution (fluorescence photoactivation localization) microscopy and multiple fluorescence-based assays to detail triclosan's effects in living mast cells, fibroblasts, and primary human keratinocytes. TCS disrupts mitochondrial nanostructure, causing mitochondria to undergo fission and to form a toroidal, "donut" shape. TCS increases reactive oxygen species production, decreases mitochondrial membrane potential, and disrupts ER and mitochondrial Ca2+levels, processes that cause mitochondrial fission. TCS is 60 × more potent than the banned uncoupler 2,4-dinitrophenol. TCS inhibits mast cell degranulation by decreasing mitochondrial membrane potential, disrupting microtubule polymerization, and inhibiting mitochondrial translocation, which reduces Ca2+influx into the cell. Our findings provide mechanisms for both triclosan's inhibition of mast cell signaling and its universal disruption of mitochondria. These mechanisms provide partial explanations for triclosan's adverse effects on human reproduction, immunology, and development. This study is the first to utilize super-resolution microscopy in the field of toxicology.
... BMR includes cellular turnover, repair and basic functions (e.g., maintenance of ion gradients, transmembrane metabolite transfer), basal synthetic reactions (e.g., RNA, DNA protein synthesis), and mitochondrial proton leak; it also includes obligatory thermogenesis (e. g., digestion and absorption) [7,46]. Mitochondria are central to the regulation of energy expenditure, and targeting their activity has been a prospect for obesity therapies for decades [47][48][49]. Therapies that mimic physiological, antiobesogenic effects are likely to prove most effective. For example, overexpression of uncoupling protein 1 (UCP1), which increases substrate utilization and electron transport chain turnover, in white adipose tissue [50] or skeletal muscle [51] can prevent diet-induced obesity in mice, suggesting that uncoupling of oxidative phosphorylation in these two organs is sufficient to regulate body composition. ...
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Obesity is a risk factor for developing type 2 diabetes and cardiovascular disease and has quickly become a world-wide pandemic with few tangible and safe treatment options. While it is generally accepted that the primary cause of obesity is energy imbalance, i.e., the calories consumed are greater than are utilized, understanding how caloric balance is regulated has proven a challenge. Many "distal" causes of obesity, such as the structural environment, occupation, and social influences, are exceedingly difficult to change or manipulate. Hence, molecular processes and pathways more proximal to the origins of obesity-those that directly regulate energy metabolism or caloric intake-appear to be more feasible targets for therapy. In particular, nitric oxide (NO) is emerging as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance. This review discusses the role of NO in regulating adiposity and insulin sensitivity and places its modes of action into context with the known causes and consequences of metabolic disease.
... 7 At the same time, the spectrum of adverse effects from the use of 2,4-DNP expanded: these included maculopapular erythematous skin eruptions in 7% of the cases, 5 in addition to gastrointestinal discomfort, cataract, hepatoxicity, nephrotoxicity, cardiotoxicity, and agranulocytosis. 7,8 There were deaths reported following administration of the compound within the recommended dosage, 7 and the chemical was finally banned in 1938. 2 Conflicts of interest: The authors declare that there are no conflicts of interest related to the subject matter or materials discussed in this article. ...
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2,4-Dinitrophenol (2,4-DNP), a yellowish compound, has historically been used in the manufacture of dyes, explosives, and fungicides. As it uncouples mitochondrial oxidative phosphorylation, the compound was also used as an antiobesity agent early in the past century. The compound was subsequently banned by the United States Food and Drug Administration in 1938 due to its potentially fatal adverse effects, including hyperthermia, cataract, agranulocytosis, hepatoxicity, nephrotoxicity, and cardiotoxicity. However, the popularity of 2,4-DNP as a slimming aid has appeared to increase again in recent years. The Hong Kong Hospital Authority Toxicology Reference Laboratory recently confirmed two cases of self-administered 2,4-DNP with different clinical presentations to hospitals in the area. Here we describe those two cases, in an attempt to underscore the potential of misuse of this substance by body-conscious groups among the Chinese population.
... How and why many disorders like type 2 diabetes and cardiovascular disorders arise from obesity are hotly researched topics, but it is clear that obesity may be reduced only by affecting either side of the energy balance equation. Proof that increases in metabolic rate can ameliorate obesity in humans comes from clinical experience with the compound dinitrophenol (DNP) in the era of the 1930s (Tainter et al., 1934). Exposure to this compound first occurred in munitions factories, where people experienced weight loss linked to elevations in metabolic rates. ...
Article
Brown and beige adipocytes can catabolize stored energy to generate heat, and this distinct capacity for thermogenesis could be leveraged as a therapy for metabolic diseases like obesity and type 2 diabetes. Thermogenic adipocytes drive heat production through close coordination of substrate supply with the mitochondrial oxidative machinery and effectors that control the rate of substrate oxidation. Together, this apparatus affords these adipocytes with tremendous capacity to drive thermogenesis. The best characterized thermogenic effector is uncoupling protein 1 (UCP1). Importantly, additional mechanisms for activating thermogenesis beyond UCP1 have been identified and characterized to varying extents. Acute regulation of these thermogenic pathways has been an active area of study, and numerous regulatory factors have been uncovered in recent years. Here we will review the evidence for regulators of heat production in thermogenic adipocytes in the context of the thermodynamic and kinetic principles that govern their therapeutic utility.
... The most notable mitochondrial uncoupler, 2,4-dinitrophenol (DNP), is widely used as a weight-loss agent in obese humans [184]. However, a series of toxic side effects, including hyperthermia, cataracts, agranulocytosis, and death, were reported continuously, which caused the US Food and Drug Administration (FDA) to ban its use in the 1930s [185]. ...
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Mitochondrial biology and behavior are central to the physiology of liver. Multiple mitochondrial quality control mechanisms remodel mitochondrial homeostasis under physiological and pathological conditions. Mitochondrial dysfunction and damage induced by overnutrition lead to oxidative stress, inflammation, liver cell death, and collagen production, which advance hepatic steatosis to nonalcoholic steatohepatitis (NASH). Accumulating evidence suggests that specific interventions that target mitochondrial homeostasis, including energy metabolism, antioxidant effects, and mitochondrial quality control, have emerged as promising strategies for NASH treatment. However, clinical translation of these findings is challenging due to the complex and unclear mechanisms of mitochondrial homeostasis in the pathophysiology of NASH.
... Medicines that have been investigated in obesity include agents as diverse as mitochondrial uncouplers [54][55][56] , sympathomimetics 33,34 , serotonergic agonists 57-65 , lipase inhibitors 64,66 , cannabinoid receptor antagonists [67][68][69] and a growing family of gastrointestinal-derived peptides chemically optimized for pharmaceutical use 34 . A sobering realization across most of these approaches is the common inability to achieve placebo-adjusted mean weight loss greater than 10% of initial body weight when chronically administered at tolerable doses. ...
Article
Enormous progress has been made in the last half-century in the management of diseases closely integrated with excess body weight, such as hypertension, adult-onset diabetes and elevated cholesterol. However, the treatment of obesity itself has proven largely resistant to therapy, with anti-obesity medications (AOMs) often delivering insufficient efficacy and dubious safety. Here, we provide an overview of the history of AOM development, focusing on lessons learned and ongoing obstacles. Recent advances, including increased understanding of the molecular gut–brain communication, are inspiring the pursuit of next-generation AOMs that appear capable of safely achieving sizeable and sustained body weight loss.
... DNP contributes to weigh management by increasing the basal metabolic rate . However, serious adverse effects occurred so often that it was withdrawn from the market, and it was labelled as an 'extremely dangerous' drug (Supplementary Table S3; Tainter et al., 1934;McFee et al., 2004;Colman, 2007). The side-effects of DNP are associated with its mechanism of action: DNP induces a hyper-metabolic state of the body via uncoupling oxidative phosphorylation, and the excess energy becomes thermal energy in the mitochondria. ...
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Background : Slimming products represent a dynamically growing group of food supplements worldwide. The efficacy of safely usable natural ingredients is usually below consumers’ expectations. Certain manufacturers add unauthorized or prohibited ingredients to weight loss supplements in order to increase their efficacy. Hence, many of these products are adulterated and may pose a risk to the consumers’ health. Aims : The aim of our work was to give an overview on natural ingredients used in slimming products, to summarize the frequently used synthetic adulterants and also to assess the trends of adulterated and illegal food supplements in the European Union based on the warnings of the Rapid Alert System for Food and Feed (RASFF) in the time period of 1988–2019. Methods : Reports between 1988–2019 were extracted from the RASFF portal on January 1, 2020. Each entry was individually reviewed. Results : 2,559 records of food supplements with quality problems were identified in the RASFF, several of which [319 (12,5%)] were marketed to facilitate weight loss. 202 (63,3%) contained unapproved, synthetic drug ingredients. The major adulterant (113 of 319, 35.4%) was DNP (2,4-dinitrophenol), whereas sibutramine was the second most frequent adulterant agent (69 products, 21,6%) between 1988 and 2019. Conclusion : The number of approved medicines for the indication of weight loss is relatively low and their efficacy (and also that of the natural ingredients) is limited. Therefore, a significant number of weight loss supplements is adulterated to satisfy patients’ expectations. Hence, these products may cause serious adverse effects in sensitive patients.
... Limited availability and efficacy are due, in part, to the difficulty in identifying bioactive compounds with a wide therapeutic range that addresses the multifaceted causes and effects of obesity (Gadde et al, 2018). Interestingly, one of the earliest pharmacologic approaches to the treatment of obesity was the mitochondrial protonophore 2,4-dinitrophenol (DNP) (Tainter et al, 1934). DNP increases systemic energy expenditure by decreasing the proton and cation gradients of the inner mitochondrial membrane. ...
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Obesity is a leading cause of preventable death worldwide. Despite this, current strategies for the treatment of obesity remain ineffective at achieving long-term weight control. This is due, in part, to difficulties in identifying tolerable and efficacious small molecules or biologics capable of regulating systemic nutrient homeostasis. Here, we demonstrate that BAM15, a mitochondrially targeted small molecule protonophore, stimulates energy expenditure and glucose and lipid metabolism to protect against diet-induced obesity. Exposure to BAM15 in vitro enhanced mitochondrial respiratory kinetics, improved insulin action, and stimulated nutrient uptake by sustained activation of AMPK. C57BL/6J mice treated with BAM15 were resistant to weight gain. Furthermore, BAM15-treated mice exhibited improved body composition and glycemic control independent of weight loss, effects attributable to drug targeting of lipid-rich tissues. We provide the first phenotypic characterization and demonstration of pre-clinical efficacy for BAM15 as a pharmacological approach for the treatment of obesity and related diseases.
... Manipulation of mitochondrial metabolism using uncoupling agents such as 2, 4 dinitrophenol (DNP) as a means for weight loss was widespread in the U.S. in the 1930s [135,136], but also had adverse side effects including fatal hyperthermia, resulting in action by the FDA by 1938, declaring DNP toxicity was too great to be used under any circumstance [137]. ...
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The incidence of common, metabolic diseases (e.g. obesity, cardiovascular disease, diabetes) with complex genetic etiology has been steadily increasing nationally and globally. While identification of a genetic model that explains susceptibility and risk for these diseases has been pursued over several decades, no clear paradigm has yet been found to disentangle the genetic basis of polygenic/complex disease development. Since the evolution of the eukaryotic cell involved a symbiotic interaction between the antecedents of the mitochondrion and nucleus (which itself is a genetic hybrid), we suggest that this history provides a rational basis for investigating whether genetic interaction and co-evolution of these genomes still exists. We propose that both mitochondrial and Mendelian, or “mito-Mendelian” genetics play a significant role in cell function, and thus disease risk. This paradigm contemplates the natural variation and co-evolution of both mitochondrial and nuclear DNA backgrounds on multiple mitochondrial functions that are discussed herein, including energy production, cell signaling and immune response, which collectively can influence disease development. At the nexus of these processes is the economy of mitochondrial metabolism, programmed by both mitochondrial and nuclear genomes.
... Obesity may be reduced by affecting either side of this energy balance equation. Proof of principle that increases in metabolic rate can cause weight loss in humans comes from clinical data following exposure to the protonophore, 2,4-dinitrophenol (DNP) [164]. With increasing knowledge about brown and beige fat, interest in these tissues as targets for safely increasing thermogenic energy expenditure has re-emerged. ...
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Obesity results from energy imbalance, when energy intake exceeds energy expenditure. Brown adipose tissue (BAT) drives non-shivering thermogenesis which represents a powerful mechanism of enhancing the energy expenditure side of the energy balance equation. The best understood thermogenic system in BAT that evolved to protect the body from hypothermia is based on the uncoupling of protonmotive force from oxidative phosphorylation through the actions of uncoupling protein 1 (UCP1), a key regulator of cold-mediated thermogenesis. Similarly, energy expenditure is triggered in response to caloric excess, and animals with reduced thermogenic fat function can succumb to diet-induced obesity. Thus, it was surprising when inactivation of Ucp1 did not potentiate diet-induced obesity. In recent years, it has become clear that multiple thermogenic mechanisms exist, based on ATP sinks centered on creatine, lipid, or calcium cycling, along with Fatty acid-mediated UCP1-independent leak pathways driven by the ADP/ATP carrier (AAC). With a key difference between cold- and diet-induced thermogenesis being the dynamic changes in purine nucleotide (primarily ATP) levels, ATP-dependent thermogenic pathways may play a key role in diet-induced thermogenesis. Additionally, the ubiquitous expression of AAC may facilitate increased energy expenditure in many cell types, in the face of over feeding. Interest in UCP1-independent energy expenditure has begun to showcase the therapeutic potential that lies in refining our understanding of the diversity of biochemical pathways controlling thermogenic respiration.
... In the 1930s, the chemical uncoupler DNP was widely used to treat obesity (Tainter et al., 1934) but was withdrawn from the market in 1938 due to dangerous side effects including hyperthermia and death when overdosing (Grundlingh et al., 2011). But apparently, DNP is still in use as evident from a recent report about a substantial increase in clinical presentations with toxicity and associated high mortality caused by exposure to DNP in the UK (Kamour et al., 2015). ...
Article
Aging has been viewed both as a random process due to accumulation of molecular and cellular damage over time and as a programmed process linked to cellular pathway important for growth and maturation. These views converge on mitochondria as both the major producer of damaging reactive oxidant species (ROS) and as signaling organelles. A finite proton leak across the inner mitochondrial membrane leading to a slight uncoupling of oxidative phosphorylation and respiration is an intrinsic property of all mitochondria and according to the "uncoupling to survive" hypothesis it has evolved to protect against ROS production to minimize oxidative damage. This hypothesis is supported by evidence linking an increased endogenous, uncoupling protein (UCP1) mediated, as well as experimentally induced mitochondrial uncoupling to an increased lifespan in rodents. This is possibly due to the synergistic activation of molecular pathways linked to life extending effects of caloric restriction as well as a mitohormetic response. Mitohormesis is an adaptive stress response through mitonuclear signaling which increases stress resistance resulting in health promoting effects. Part of this response is the induction of fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15), two stress-induced mitokines which elicit beneficial systemic metabolic effects via endocrine action.
... In a small group (n = 6) of obese men with body mass indices of around 30, 2-week treatment with GW501516 induced a coordinate elevation of carnitine palmitoyl transferase 1b expression in skeletal muscle and increased whole body palmitate oxidation when measured as a 13 C-palmitate to 13 CO 2 conversion [57], clearly indicating a response similar to that seen in cell and animal models. [78]; dose response uncoupling of isolated mitochondria and rat thymocytes [37,39] Elevation of body temperature and oxygen consumption in rat and mice [79] Increased basal metabolism, oxygen consumption and temperature in patients [80] PPARγ (troglitazone) glucose uptake in L6 myotubes through AMPK activation [81]; ...
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Background: The use of cellular models as tools in drug discovery is almost universal. However, in disease areas such as metabolic diseases, are they relevant to the process and do they add value? Objective: In this article, we explore the variety of cellular models now used in drug discovery in metabolic diseases as revealed by publication. We have tried to make some connections between drug phenotypes in these models with clinical parallels. We also ask the question as to whether such models add value in the drug discovery process. This overview is not about recombinant cell systems used in target-based screening; rather, we focus on in vitro, including ex vivo, models as physiological systems in drug discovery in obesity and diabetes. Conclusion: In terms of building target confidence, in vitro models are often the only mechanistic link to human systems early in a projects life. Many of the current targets in metabolic diseases in the early discovery phase are not yet clinically supported, let alone validated. In this respect, therefore, in vitro models warrant a place in the critical path in early discovery. In terms of any predictive role for decision-making today, this is much more difficult and is more likely pushed to a supporting role as part of a wider package. However, there is a rapid rate of advancement in this field and future developments hold much promise.
Article
Nonalcoholic fatty liver disease (NAFLD) affects one in three Americans and is a major predisposing condition for the metabolic syndrome and type 2 diabetes (T2D). We examined whether a functionally liver-targeted derivative of 2,4-dinitrophenol (DNP), DNP-methyl ether (DNPME), could safely decrease hypertriglyceridemia, NAFLD, and insulin resistance without systemic toxicities. Treatment with DNPME reversed hypertriglyceridemia, fatty liver, and whole-body insulin resistance in high-fat-fed rats and decreased hyperglycemia in a rat model of T2D with a wide therapeutic index. The reversal of liver and muscle insulin resistance was associated with reductions in tissue diacylglycerol content and reductions in protein kinase C epsilon (PKCε) and PKCθ activity in liver and muscle, respectively. These results demonstrate that the beneficial effects of DNP on hypertriglyceridemia, fatty liver, and insulin resistance can be dissociated from systemic toxicities and suggest the potential utility of liver-targeted mitochondrial uncoupling agents for the treatment of hypertriglyceridemia, NAFLD, metabolic syndrome, and T2D.
Article
An outbreak of cataracts in 1935 caused by dinitrophenol (DNP), the active ingredient of popular diet pills, highlighted the inability of the Food and Drug Administration (FDA) to prevent harmful drugs from entering the marketplace. Just two years earlier, the FDA used horrific images of ocular surface injury caused by cosmetics at the World’s Fair in Chicago to garner public support for legislative reform. The FDA had to walk a fine line between a public awareness campaign and lobbying Congress while lawmakers debated the need for consumer protection. The cataract outbreak of 1935 was conspicuous in the medical literature during the height of New Deal legislation, but questions persist as to how much it affected passage of the proposed Food, Drug, and Cosmetic Act (of 1938). The legislation languished in committee for years. The cataract outbreak probably had little impact on the eventual outcome, but medical opinion concerning the safety of DNP may have contributed to the voluntary withdrawal of the diet drug from the market. We review the DNP cataract outbreak and examine it in context of the challenges facing regulatory reform at that time.
Article
Activating mutations in BRAF are the most common genetic alterations in melanoma. Inhibition of BRAF by small molecules leads to cell-cycle arrest and apoptosis. We show here that BRAF inhibition also induces an oxidative phosphorylation gene program, mitochondrial biogenesis, and the increased expression of the mitochondrial master regulator, PGC1α. We further show that a target of BRAF, the melanocyte lineage factor MITF, directly regulates the expression of PGC1α. Melanomas with activation of the BRAF/MAPK pathway have suppressed levels of MITF and PGC1α and decreased oxidative metabolism. Conversely, treatment of BRAF-mutated melanomas with BRAF inhibitors renders them addicted to oxidative phosphorylation. Our data thus identify an adaptive metabolic program that limits the efficacy of BRAF inhibitors.
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Public health faces a new kind of drug problem with the growing prevalence of so–called ‘enhancement drugs’ that have the potential to improve human attributes and abilities. The widespread availability of such drugs has generated a new and growing audience of users. People are seeking out enhancement drugs in a quest to improve their bodies and minds—to look younger and more beautiful, to be stronger, happier and more intelligent. These types of drugs share a few similarities with recreational or addictive drugs—such as heroin, cocaine, ecstasy and ‘legal highs’— but also attract people who do not necessarily perceive themselves as ‘drug users’ and are vulnerable to cultural pressures to optimise their bodies. Manufacturers and retailers around the world are tapping into the demand for such drugs by harnessing innovations in science and medicine, as well as improvements in transport and communication networks. Significantly, in the case of illicit markets, retailers are able to circumvent national laws and regulation with creative and persuasive marketing strategies via the Internet. Often their customers are duped or remain unaware of the considerable harms associated with usage of these drugs, a situation that presents a threat to public health and throws up challenges for healthcare systems around the world
Article
4β-cinnamoyloxy,1β,3α-dihydroxyeudesm-7,8-ene (CDE) extracted from Verbesina persicifolia induces bioenergetic collapse in rat liver mitochondria (RLM), monitored as a fall in the respiratory control index and ADP/O values. This fall in energy is accompanied by a protonophore effect and membrane potential (ΔΨ) collapse, demonstrating that CDE behaves as a typical uncoupling agent. However, when examining the effect of CDE in detail, we found that it acts as a "mild" uncoupler because it drops ΔΨ and increases respiratory state 4. The proposed mechanism is based on the interaction of CDE with membrane protein cytochrome C oxidase, which is implicated in proton permeability, and with the respiratory chain for the generation of reactive oxygen species which mediate and regulate the activity of the above membrane protein. Considering the energy collapse, "mild" uncoupling, and the fact that CDE is largely used in folk medicines, this extract may be viewed as a potentially effective anti-obesity drug and a natural lead compound for developing new natural uncouplers against obesity.
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Quiescent cancer cells in malignant tumors can withstand cell-cycle active treatment and cause cancer spread and recurrence. Three-dimensional (3D) cancer cell models have led to the identification of oxidative phosphorylation (OXPHOS) as a context-dependent vulnerability. The limited treatment options for advanced hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) metastatic to the liver include the multikinase inhibitors sorafenib and regorafenib. Off-target effects of sorafenib and regorafenib are related to OXPHOS inhibition; however the importance of this feature to the effect on tumor cells has not been investigated in 3D models. We began by assessing global transcriptional responses in monolayer cell cultures, then moved on to multicellular tumor spheroids (MCTS) and tumoroids generated from a CRC patient. Cells were treated with chemotherapeutics, kinase inhibitors, and the OXPHOS inhibitors. Cells grown in 3D cultures were sensitive to the OXPHOS inhibitor nitazoxanide, sorafenib, and regorafenib and resistant to other multikinase inhibitors and chemotherapeutic drugs. Furthermore, nitazoxanide and sorafenib reduced viability, regrowth potential and inhibited mitochondrial membrane potential in an additive manner at clinically relevant concentrations. This study demonstrates that the OXPHOS inhibition caused by sorafenib and regorafenib parallels 3D activity and can be further investigated for new combination strategies.
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Recent findings have elucidated roles for mitochondrial uncoupling proteins (UCPs) in neuronal plasticity and resistance to metabolic and oxidative stress. UCPs are induced by bioenergetic challenges such as caloric restriction and exercise and may protect neurons against dysfunction and degeneration. The pharmacological uncoupler 2,4-dinitrophenol (DNP), which was once prescribed to >100,000 people as a treatment for obesity, stimulates several adaptive cellular stress-response signaling pathways in neurons including those involving the brain-derived neurotrophic factor, the transcription factor cyclic AMP response element-binding protein (CREB), and autophagy. Preclinical data show that low doses of DNP can protect neurons and improve functional outcome in animal models of Alzheimer's and Parkinson's diseases, epilepsy, and cerebral ischemic stroke. Repurposing of DNP and the development of novel uncoupling agents with hormetic mechanisms of action provide opportunities for new breakthrough therapeutic interventions in a range of acute and chronic insidious neurodegenerative/neuromuscular conditions, all paradoxically at body weight-preserving doses.
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The use of 2,4-dinitrophenol (DNP) has regained popularity as a weight loss aid in the last two decades due to increased marketing to bodybuilders and the increasing availability of this banned substance via the Internet. 2,4-DNP is a drug of narrow therapeutic index and toxicity results in hyperthermia, diaphoresis, tachycardia, tachypnoea and possible cardiac arrest and death. Skin toxicity from 2,4-DNP has not been reported since the 1930s. We report a case of a 21-year-old bodybuilding enthusiast who presented with a toxic exanthem after taking 2,4-DNP, and describe the first skin biopsy findings in a case of 2,4-DNP toxicity.
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Obesity is associated with premature mortality, impaired quality of life, and large healthcare costs. However, treatment options remain quite limited. Here we studied potential anti-obesity effects of a novel cationic mitochondrial uncoupler, C4R1 (derivative of rhodamine 19) in C57Bl/6 mice. Obesity was induced by long-term (eight weeks) high fat diet feeding at thermoneutrality. The treated group of mice received consecutively two doses of C4R1 in drinking water (30 and 12-14 μmol/kg daily) during 30 days. Effects of C4R1 were dose-dependent. After six days of C4R1 treatment at dose 30 μmol/kg daily, food intake was reduced by 68%, body weight by 19%, and fat mass by 21%. Body weight decrease was explained partly by reduced food intake and partly by increased metabolism, likely resulting from uncoupling. Body fat reduction upon C4R1 treatment was associated with improved lipid utilization estimated from decrease in respiratory quotient to the minimal level (0.7). Interestingly, the classical uncoupler 2,4-dinitrophenol at similar dose (27 μmol/kg daily) did not have any effect. Our results are relevant to the search for substances causing mild uncoupling of mitochondria that could be a promising therapeutic strategy to treat obesity.
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L’identification d’un nouveau type d’adipocyte, l’adipocyte brite, distinct des adipocytes blancs et bruns jusqu’ici décrits, associée à la mise en évidence par imagerie de tissu adipeux brun chez l’homme adulte, ont renouvelé nos connaissances sur la biologie des tissus adipeux. Les propriétés de dissipation de l’énergie et de forte consommation de métabolites font des adipocytes bruns et brite des candidats attractifs pour la lutte contre les maladies métaboliques telles que le diabète et l’obésité. Cette revue présente ces récentes découvertes et l’espoir thérapeutique qu’elles révèlent.
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During the early development of mankind, acquisition of food for sustenance was a major physical endeavor. It was also a difficult task due to the paucity of food. Humans have thus evolved by adapting to famine more than plenty [1]. An increased availability of food without the need for physical activity to acquire it is thought to have resulted in obesity, due to a mismatch between energy intake (easy availability of energy dense foods) and energy expenditure (increasingly sedentary lifestyle). This trend for overweight and obese began growing dramatically around 1980 in the United States [2] and is being observed worldwide today [3,4], affecting both adults [5] and adolescents [5]. Which environmental changes explain the increased prevalence of obesity is not clear, but genetic mutations are too slow to be responsible. Obesity predisposes to cardiovascular disease, diabetes, and other medical problems [6], which have both medical and economic consequences. Obesity alone has been estimated to cost the United States $100 billion per year and is clearly a major public health problem [7,8].
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Treatment of obesity and obesity-associated diseases has been challenging, with the first potential cure claimed in 1934 with the protonophore 2,4-dinitrophenol (DNP). This chemical dissipates mitochondrial membrane potential into heat production and is extremely effective in boosting metabolic rate and promoting weight loss ( 1 ). However, severe side effects, including cataract formation, cardiotoxicity, overheating, and death, prevented its further use ( 2 ). In a recent study, Long et al. ( 3 ) report that a secreted enzyme called peptidase M20 domain containing 1 (PM20D1) converts fatty acids and amino acids into N -acyl amino acids, which directly uncouple mitochondrial membrane potential in a way similar to that of DNP, to increase energy expenditure without physical movement. Might these endogenous metabolites be a safe alternative to chemical uncouplers, facilitating effortless fat burning without a fatal consequence?
Chapter
Human brown adipose tissue (BAT) is experimentally modeled to better understand the biology of this important metabolic tissue, and also to enable the potential discovery and development of novel therapeutics for obesity and sequelae resulting from the persistent positive energy balance. This chapter focuses on translation into humans of findings and hypotheses generated in nonhuman models of BAT pharmacology. Given the demonstrated challenges of sustainably reducing caloric intake in modern humans, potential solutions to obesity likely lie in increasing energy expenditure. The energy-transforming activities of a single cell in any given tissue can be conceptualized as a flow of chemical energy from energy-rich substrate molecules into energy-expending, endergonic biological work processes through oxidative degradation of organic molecules ingested as nutrients. Despite the relatively tight coupling between metabolic reactions and products, some expended energy is incidentally lost as heat, and in this manner a significant fraction of the energy originally captured from the environment nonproductively transforms into heat rather than into biological work. In human and other mammalian cells, some processes are even completely uncoupled, and therefore purely energy consuming. These molecular and cellular actions sum up at the physiological level to adaptive thermogenesis, the endogenous physiology in which energy is nonproductively released as heat through uncoupling of mitochondria in brown fat and potentially skeletal muscle. Adaptive thermogenesis in mammals occurs in three forms, mostly in skeletal muscle and brown fat: shivering thermogenesis in skeletal muscle, non-shivering thermogenesis in brown fat, and diet-induced thermogenesis in brown fat. At the cellular level, the greatest energy transformations in humans and other eukaryotes occur in the mitochondria, where creating energetic inefficiency by uncoupling the conversion of energy-rich substrate molecules into ATP usable by all three major forms of biological work occurs by two primary means. Basal uncoupling occurs as a passive, general, nonspecific leak down the proton concentration gradient across the membrane in all mitochondria in the human body, a gradient driving a key step in ATP synthesis. Inducible uncoupling, which is the active conduction of protons across gradients through processes catalyzed by proteins, occurs only in select cell types including BAT. Experiments in rodents revealed UCP1 as the primary mammalian molecule accounting for the regulated, inducible uncoupling of BAT, and responsive to both cold and pharmacological stimulation. Cold stimulation of BAT has convincingly translated into humans, and older clinical observations with nonselective 2,4-DNP validate that human BAT’s participation in pharmacologically mediated, though nonselective, mitochondrial membrane decoupling can provide increased energy expenditure and corresponding body weight loss. In recent times, however, neither beta-adrenergic antagonism nor unselective sympathomimetic agonism by ephedrine and sibutramine provide convincing evidence that more BAT-selective mechanisms can impact energy balance and subsequently body weight. Although BAT activity correlates with leanness, hypothesis-driven selective β3-adrenergic agonism to activate BAT in humans has only provided robust proof of pharmacologic activation of β-adrenergic receptor signaling, limited proof of the mechanism of increased adaptive thermogenesis, and no convincing evidence that body weight loss through negative energy balance upon BAT activation can be accomplished outside of rodents. None of the five demonstrably β3 selective molecules with sufficient clinical experience to merit review provided significant weight loss in clinical trials (BRL 26830A, TAK 677, L-796568, CL 316,243, and BRL 35135). Broader conclusions regarding the human BAT therapeutic hypothesis are limited by the absence of data from most studies demonstrating specific activation of BAT thermogenesis in most studies. Additionally, more limited data sets with older or less selective β3 agonists also did not provide strong evidence of body weight effects. Encouragingly, β3-adrenergic agonists, catechins, capsinoids, and nutritional extracts, even without robust negative energy balance outcomes, all demonstrated increased total energy expenditure that in some cases could be associated with concomitant activation of BAT, though the absence of body weight loss indicates that in no cases did the magnitude of negative energy balance reach sufficient levels. Glucocorticoid receptor agonists, PPARg agonists, and thyroid hormone receptor agonists all possess defined molecular and cellular pharmacology that preclinical models predicted to be efficacious for negative energy balance and body weight loss, yet their effects on human BAT thermogenesis upon translation were inconsistent with predictions and disappointing. A few new mechanisms are nearing the stage of clinical trials and may yet provide a more quantitatively robust translation from preclinical to human experience with BAT. In conclusion, translation into humans has been demonstrated with BAT molecular pharmacology and cell biology, as well as with physiological response to cold. However, despite pharmacologically mediated, statistically significant elevation in total energy expenditure, translation into biologically meaningful negative energy balance was not achieved, as indicated by the absence of measurable loss of body weight over the duration of a clinical study.
Article
O tratamento da obesidade deve ser baseado na percepção de que a obesidade é uma enfermidade crônica, neuroquímica e recidivante. Sendo assim, a combinação de eficácia, sustentabilidade de longo prazo e perfil de segurança de excelência devem nortear a utilização dos medicamentos disponíveis assim como das novas moléculas vindouras. No momento, a liraglutida parece ser a mais completa droga para a obesidade como doença crônica, mas certamente deverá ser superada pelos novos peptídeos de múltiplo agonismo e/ou pela combinação de várias medicações ainda não disponíveis em baixas dosagens para pacientes precisa e individualmente selecionados.
Article
Aims Mitochondrial uncouplers decrease caloric efficiency and have potential therapeutic benefits for the treatment of obesity and related metabolic disorders. Herein we investigate the metabolic and physiologic effects of a recently identified small molecule mitochondrial uncoupler named SHC517 in a mouse model of diet-induced obesity. Methods SHC517 was administered as an admixture in food. The effect of SHC517 on in vivo energy expenditure and respiratory quotient was determined by indirect calorimetry. A dose-finding obesity prevention study was performed by starting SHC517 treatment concomitant with high fat diet for a period of 12 days. An obesity reversal study was performed by feeding mice western diet for 4 weeks prior to SHC517 treatment for 7 weeks. Biochemical assays were used to determine changes in glucose, insulin, triglycerides, and cholesterol. SHC517 concentrations were determined by mass spectrometry. Results SHC517 increased lipid oxidation without affecting body temperature. SHC517 prevented diet-induced obesity when administered at 0.05% and 0.1% w/w in high fat diet and reversed established obesity when tested at the 0.05% dose. In the obesity reversal model, SHC517 restored adiposity to levels similar to chow-fed control mice without affecting food intake or lean body mass. SHC517 improved glucose tolerance and fasting glucose levels when administered in both the obesity prevention and obesity reversal modes. Conclusions SHC517 is a mitochondrial uncoupler with potent anti-obesity and insulin sensitizing effects in mice. SHC517 reversed obesity without altering food intake or compromising lean mass, effects that are highly sought-after in anti-obesity therapeutics.
Article
Natural montmorillonite clay and anthropogenic organic pollutants frequently coexist in the estuarine environment where freshwater from rivers mixes with saltwater from the ocean. In this environment, the sharply changed aqueous chemistry especially salt content could significantly alter the photochemical behaviors of pollutants. However, this process was rarely investigated. In this study, the photodegradation of a representative anthropogenic weight-loss compound 2,4-dinitrophenol in the presence of Fe³⁺-montmorillonite and different halide salts was systematically investigated. Results show that 2,4-dinitrophenol was resistant to photodegradation by Fe³⁺-montmorillonite alone, but the presence of NaCl, NaBr, and sea salts in the system can evoke significant 2,4-dinitrophenol degradation. The enhancement effect was further elucidated as the replacement reaction between the clay associated Fe³⁺ and Na ⁺ which leads to the release of more interlayer Fe³⁺ from montmorillonite, resulting in increased production of high active hydroxyl radicals (˙OH) that can substantially damage 2,4-dinitrophenol molecule. In addition, halogen radicals from the reaction of halide ions with ˙OH were also confirmed to participate in 2,4-dinitrophenol degradation. Overall, this study implied that the changed salty condition in the estuarine water could induce the rapid transformation of organic pollutants that move from freshwater and have relatively stable photochemical properties.
Article
World Health Organization defines obesity as abnormal or excess adipose tissue accumulation. Nowadays, this condition is a serious threat to the public health in most countries around the world. Obesity adversely affects physical, mental, and in most cultures, social well‐being. However, throughout the ages—from ancient times to the 21st century—this condition has been subject to various interpretations. As a matter of fact, obesity has not always been regarded as a disease. For many decades, excessive body weight has been considered rather a symbol of health. It was a marker of wealth and prosperity, as well as a sign of high social status. The centuries that passed on the development of science and medicine have gradually changed its face, but significant progress in understanding the causes and consequences of obesity has been made in the last 30 years. This paper presents the historical outline of obesity and its treatment from ancient times to the present—from its affirmation to the epidemic in the late 20th and 21st century.
Article
Methods for determination of 2-amino-4-nitrophenol and 4-amino-2-nitrophenol, metabolites of 2,4-dinitrophenol, were developed using differential pulse (DP) voltammetry and HPLC with amperometric and spectrophotometric detection. The applicability of these methods was tested by the determination of the analytes in model samples of urine after preliminary separation by solid-phase extraction. Voltammetry enabled parallel determination of both analytes, but its application in real matrix was severely limited due to the interference of other compounds present in urine. HPLC allowed the determination in real urine matrix down to micromolar concentrations; amperometric detection proved to be more sensitive and selective than the spectrophotometric one.
During the clinical use of sodium dinitrophenol (1-2-4) in obese patients, the occasional appearance of subjective symptoms such as tachycardia, dyspnea and profuse diaphoresis1 suggested the necessity of investigating the effects of the drug on the circulation.Thirteen patients with apparently normal cardiovascular systems were selected for this study. Six of the group were placed at bed rest in the hospital, and control observations of blood pressure, pulse rate, vital capacity and venous pressure made regularly at 8 a. m., 2 p. m. and 7 p. m. The control period was continued until at least three consecutive results were in close agreement. A mean of three or more control results was taken as the base. The control period was never less than three days and was sometimes as long as five days. A quantity of 300 mg. of sodium dinitrophenol was then administered orally in three divided doses each day,
Article
Within the past year, dinitrophenol has been used extensively as a means of reducing weight. However, its possible harmful effects have not been realized sufficiently until very recently. In papers by Anderson, Reed and Emerson,1 Geiger,2 Poole and Haining,3 and Tainter and Wood,4 fatal results from the use of dinitrophenol have been reported. In all probability, a great many more poisonings and fatalities have occurred, since many druggists are dispensing dinitrophenol without a physician's prescription, under both the name of dinitrophenol and various proprietary names. A case of toxic hepatitis with intense jaundice following the use of dinitrophenol is here reported.REPORT OF CASE B. R., a white woman, unmarried, aged 26, had used various reducing diets because she weighed too much for her stature (58 inches, 145 cm.). The past history and family history were essentially negative. The patient began taking dinitrophenol, Feb. 18, 1934,
Article
We have recently shown in a series of papers1 that alpha-dinitrophenol markedly augments metabolism in doses which are not demonstrably harmful. As this drug may have a number of important clinical applications, it seems desirable to present a summary report of its pharmacologic and therapeutic effects, and to point out certain potential dangers in, and limitations to, its use.During the World War, dinitrophenol was called to the attention of French physicians by cases of poisoning from it in munitions factories. Only incomplete investigations of the actions of the compound were made at that time, as judged by published reports. Recently, Magne, Mayer, Plantefol and others2 have extended or completed work begun some years previously but reported simultaneously with our entirely independent studies. We are in general agreement with them as to the main pharmacologic actions of the drug. The experimental studies have been extended by us and
Blumgart and his co-workers1 have shown the close relationship that exists between the height of the metabolic rate and the velocity of the blood flow. This relationship was demonstrated on hypothyroid and hyperthyroid patients with the use of the radium method2 for the determination of the speed of the flow of blood. These observations were abundantly confirmed by Tarr, Oppenheimer and Sager3 and by Gargill,3a who used the sodium dehydrocholate method4 in studying circulation time.The conception that the amount of work done by the heart is partly determined by the metabolic rate has been substantiated and clinically applied in recent years. It has become a well established fact that when serious heart disease is associated with hyperthyroidism the cardiac embarrassment is grossly aggravated when the level of the metabolism is high and is much improved when the metabolic rate is lowered.5 This improvement
Prof. C. Heymans of Ghent has recently revived interest in the fever producing properties of nitrated naphthols,1 a demonstration of which stimulated Tainter and his colleagues to study alpha-dinitrophenol. Others had shown also that the latter drug causes an increase in cellular oxidation.2 Because of its metabolic stimulating qualities, this agent was proposed and used by Cutting, Mehrtens and Tainter3 for the clinical treatment of obesity, hypothyroidism and similar depressed metabolic states. They especially warned against its toxicity, stating that "there are limitations to and possible dangers from the use of the drug clinically. It should be used only under strictly controlled conditions." Since hearing this report we have had a case of intolerance to alpha-dinitrophenol which prompted us to inquire into the toxicity of the compound in an effort to determine contraindications to its use and methods for detecting untoward effects.Perkins, in a comprehensive review
In a short note recently published,1 attention was drawn to a fatality that occurred from dinitrophenol poisoning. Since this drug is being widely used as a metabolic stimulant, and since the complete details of this case were available only to us, it seemed desirable to publish a full account of it, together with the pathologic observations. This case report will also emphasize the fact which we have consistently stressed;2 namely, that careless or reckless use of this drug may have unfortunate consequences.REPORT OF CASE History.— H. G., a man, aged 37, a graduate of a Vienna medical school but unlicensed to practice in this country, called on one of us (T.) to obtain information regarding dinitrophenol as a metabolic stimulant. He stated that he was suffering from general glandular dysfunction, including a hypopituitarism resulting from a previous sphenoiditis. His libido was gone and no therapy had been
The increasing number of cases reported in recent years presenting the syndrome of agranulocytic angina or malignant neutropenia has excited comment from many observers. Numerous drugs, organisms and toxins have been connected with the disease entity but definite confirmatory clinical and experimental data have been lacking.Kracke1 in 1932 was able to induce the characteristic blood picture in rabbits with small subcutaneous injections of benzene following the lead of Selling2 in 1916 in demonstrating the leukotoxic effects of benzene on myeloblastic tissues. Kracke also produced a marked leukopenia with subcutaneous injections of orthooxybenzoic acid and by the intravenous injections of hydroquinone. He was unsuccessful in depressing the leukocyte count with a group of other substances, as acetphenatidin, peralga (barbituric acid and amidopyrine), dial, resorcinol, pyrocatechin, orthocresol, para and metaoxybenzoic acid and 50 per cent alcohol. To one rabbit he administered from 5 to 10 grains (0.3 to 0.65
The study here reported was undertaken to determine whether it is possible by the use of the available methods of skin testing to anticipate the skin eruptions and other signs of hypersensitiveness that not infrequently occur with the therapeutic use of dinitrophenol. Without consideration of the controversial subjects of allergy, atopy or anaphylaxis and without referring to the none too clear conceptions of antigen antibody reactions as applied to nonprotein substances, I wish to submit the results of my experiment.METHODS The three possible methods of skin testing were employed for the direct test, and the intradermal method alone was used for the indirect test.
During recent months the medical literature has been characterized by numerous reports of cases illustrating unfavorable reactions and deaths following the use of dinitrophenol, the barbiturates and amidopyrine. In the instances of these reactions following therapy with the barbiturates and amidopyrine, several observers have cited a resulting neutropenia or agranulocytic angina. There is reference made, however, to only one case of agranulocytic angina following the ingestion of dinitrophenol.1 The report includes a case in which agranulocytosis developed after the ingestion of dinitrophenol over a period of two weeks, the patient recovering following treatment. Since no mention was made in this case regarding the amount of the drug taken during the two weeks or of the blood picture, and since in no other report of dinitrophenol poisoning has there been reference made to an ensuing neutropenia (those reports including a blood picture showed essentially normal white blood counts, while the
Toxicity of Dinitrophenol
  • H H Haft
Haft, H. H. Toxicity of Dinitrophenol. J.A.M.A., 101:1171, 1933.
Chronic Toxicity of Dinitrophenol: Renal Function
  • T L Schulte
  • M L Tainter
Schulte, T. L., and Tainter, M. L. Chronic Toxicity of Dinitrophenol: Renal Function. Proc. Soc. Exper. Biol. & Med., 31:1163, 1934.
The Influence of Some New Nitroderivatives on the Cellular Metabolism and on Body Temperature
  • C Heymans
Heymans, C. The Influence of Some New Nitroderivatives on the Cellular Metabolism and on Body Temperature. J. Pharm. Exper. Therap., 51: 144, 1934. 33. Kracke, R. R. Personal Communication.
The Rate of Blood Flow in Patients Receiving Dinitrophenol Agranulocytic Angina Following Ingestion of Dinitrophenol
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Rosenblum, H. The Rate of Blood Flow in Patients Receiving Dinitrophenol. In press. 36. Bohn, S. S. Agranulocytic Angina Following Ingestion of Dinitrophenol. J.A.M.A. 103:249, 1934.
Nitrophenine: Cellular Oxidation
  • Courdouan
Courdouan. Nitrophenine: Cellular Oxidation. Progrps Med., 41:1738, 1933
Hyperthermic and Cardiovascular Actions of Dinitro-a-naphthol in the Dog
  • C Heymans
  • J J Bouckaert
Heymans, C., and Bouckaert, J. J. Hyperthermic and Cardiovascular Actions of Dinitro-a-naphthol in the Dog. Arch. Intern. de Pharm. et de Therap., 35:63, 1928. 3. Leymann. Accidents in the Manufacture of Nitrophenol and Nitrochlor-Compounds. Concordia, 9:55, 1902.
Studies on the Action (Thermol)
  • H Magne
  • Mayer
Magne, H., Mayer, Studies on the Action (Thermol). Ann. de Physiol. Biol., 8:1-167, 1932
Report of a Toxic Manifestation Due to Dinitrenal
  • S Hirsch
Hirsch, S. Report of a Toxic Manifestation Due to Dinitrenal. J.A.M.A., 102:950, 1934
Actions of Dinitrophenol with the Use of Balanced and Unbalanced Diets Promis- 101:193, in the Manufacture of Concordia, A., of Plantefol, Dinitrophenol et de Physicochem. L. ct al. 1-2-4 Actions Febrile, Therap Repeated Antiseptic Doses
  • W C Cutting
  • M L J A M A Tainter
Cutting, W. C., and Tainter, M. L. Actions of Dinitrophenol with the Use of Balanced and Unbalanced Diets. J.A.M.A., 101:2p99, 1933. Promis- 101:193, J.A.M.A., et de Therap., in the Manufacture of Concordia, A., of Plantefol, Dinitrophenol et de Physicochem. L. ct al. 1-2-4 Actions Febrile, Therap., Dinitrophenol. Fatal 48:410, 1933. Repeated Antiseptic Doses, Ibid, 49:187. J. H., and DeEds, in Diabetic Dogs. F. Arch. Carbohydrate Metabolism, in Animals with Dinitrophenol. Basal Am. J. on an Experimental Proc. Soc. Exper. Biol. in Diet, on Life of the White Rat. in Obesity and Re-Report. J.A.M.A., Useof 2-4 Dini-Brit. M. J., Metabolic rDINITROPHENOL IN NUTRITIONAL DISORDERS 105
Detection a-Dinitrophenol, New Drug Obesity
  • A Bolliger
Bolliger, A. Detection a-Dinitrophenol, New Drug Obesity. M. J. Australia, 1:367
Dini-Actions Underactivity The New Eng Sudden Death Report of a Case with 1934. I. and Fowler
  • H Dintenfass
  • An
  • An Report
  • Accelerator
  • Compara-Soc
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  • J H Biol
  • H J Goldsmith
  • R G Hoskins
Dintenfass, H. An Report of An Accelerator of Compara-Soc. Exper. Biol. & J. H., and Goldsmith, H. Dini-Actions Underactivity. in J. Hoskins, R. G. The New Eng. J. Med., 210: A Case of J.A.M.A., 102:1147, Sudden Death Report of a Case with 1934. I. and Fowler, A. F. to Dini-J.A.M.A., 102:1219, Dinitrophenol J.A.M.A., 102:1844, Ear Complication from Dinitrophenol Medication
tive Effects of Dinitrophenol and Thyroxin on Tad-pole Metamorphosis
  • C C Cutting
  • M L Tainter
Cutting, C. C., and Tainter, M. L. tive Effects of Dinitrophenol and Thyroxin on Tad-pole Metamorphosis. Proc. Med., 31:97, 1933
Chronic Toxicity of Dinitrophenol: Renal Function Clinical Circulatory Effects of Dinitrophenol
  • J A M A B Cutting
  • W Todd
  • J C Sanford
  • A Butt
  • E M Hickey
J.A.M.A., 101:1171, 1933. 27. Schulte, T. L., and Tainter, M. L. Chronic Toxicity of Dinitrophenol: Renal Function. Proc. Soc. Exper. Biol. & Med., 31:1163, 1934. 28. Stockton, A. B., and Cutting, W. C. Clinical Circulatory Effects of Dinitrophenol. J.A.M.A. In press. 29. Todd, J. C., and Sanford, A. H. Clinical Diagnosis by Laboratory Methods, 1928. 6th ed., p. 363. 30. Tainter, M. L., Cutting, W. C., Wood, D. A., and Proescher, F. Arch. Path. In press. 31. Hoffman, A. M., Butt, E. M., and Hickey, N.
Use of Dinitrophenol in Obesity and Related Coniditions. A Progress Report The Use of 2-4 Dinitrophenol as a Metabolic Stimulant
  • M L Tainter
  • A B Stockton
  • W Cutting
Tainter, M. L., Stockton, A. B., and Cutting, W. C. Use of Dinitrophenol in Obesity and Related Coniditions. A Progress Report. J.A.M.A., 101:1472, 1933. 7. Dunlop, D. M. The Use of 2-4 Dinitrophenol as a Metabolic Stimulant. Brit. M. J., 3820:524, 1934.
Antiseptic Tests and Actions of Some Isomers Actions of Dinitrophenol in Diabetic Dogs
  • J Pharmacol
  • Exper
  • M L Therap
  • J H Boyes
  • F Deeds
J. Pharmacol. & Exper. Therap., 48:410, 1933. Miscellaneous Actions of Dinitrophenol. Repeated Administrations, Antidotes, Fatal Doses, Antiseptic Tests and Actions of Some Isomers. Ibid, 49:187. Tainter, M. L., Boyes, J. H., and DeEds, F. Actions of Dinitrophenol in Diabetic Dogs. Arch. Intern. de Pharm. et de Therap., 45:235, 1933. Hall, V. E., Field, J., Sahyun, M., Cutting, W.
Report of a Toxic Manifestation Due to " Dinitrenal Allergic Reaction to Dinitrophenol Report of a Case Report of a Case Dintenfass, H. An Ear Complication from Dinitrophenol Medication
  • Dinitrophenol
  • M A J Canad
  • G M Frumess
Dinitrophenol. Canad. M. A. J., 30:128, 1934. 19. Hirsch, S. Report of a Toxic Manifestation Due to " Dinitrenal." J.A.M.A., 102:950, 1934. 20. Frumess, G. M. Allergic Reaction to Dinitrophenol. Report of a Case. J.A.M.A., 102:1219, 1934. 21. Jackson, H., and Duvall, A. I. Dinitrophenol Poisoning. Report of a Case. J.A.M.A., 102:1844, 1934. 22. Dintenfass, H. An Ear Complication from Dinitrophenol Medication. J.A.M.A., 102:838, 1934. 23. Guerbet. L'Expertise Chimique Dans Les Cas D'Intoxication Par le Dinitrophenol, 1918. Ministere de l'Armement et des Fabrications de Guerre. Conference Pour l'Etude de la Toxicite des Explosifs (Paris).
Report of a Case Courdouan. Nitrophenine: An Accelerator of Cellular Oxidation Comparative Effects of Dinitrophenol and Thyroxin on Tadpole Metamorphosis
  • G A Toxicity Of Alpha-Dinitrophrenol
  • C C Tainter
G. A. Toxicity of Alpha-Dinitrophrenol. Report of a Case. J.A.M.A., 101:1053, 1933. 10. Courdouan. Nitrophenine: An Accelerator of Cellular Oxidation. Progrps Med., 41:1738, 1933. 11. Cutting, C. C., and Tainter, M. L. Comparative Effects of Dinitrophenol and Thyroxin on Tadpole Metamorphosis. Proc. Soc. Exper. Biol. & Med., 31:97, 1933. 12. Cutting, W. C., Rytand, D., and Tainter, M.
Sudden Death from Dinitrophenol Poisoning Report of a Case with Autopsy Low Oxygen Tensions and Temperatures on the Actions and Toxicity of Dinitrophenol
  • F E Poole
  • R B Haining
Poole, F. E., and Haining, R. B. Sudden Death from Dinitrophenol Poisoning. Report of a Case with Autopsy. J.A.M.A., 102:1141, 1934. 17. Tainter, M. L. Low Oxygen Tensions and Temperatures on the Actions and Toxicity of Dinitrophenol. J. Pharm. Exper. Therap., 51:45, 1934. 18. Rabinowitch, I. M., and Fowler, A. F.
Detection and Estimation of a-Dinitrophenol, New Drug for the Treatment of Obesity. M. J. Australia, 1:367, 1934. 25. Matzger, E. Can Sensitivity to Dinitrophenol be Determined by Skin Tests?
  • A Bolliger
24. Bolliger, A. Detection and Estimation of a-Dinitrophenol, New Drug for the Treatment of Obesity. M. J. Australia, 1:367, 1934. 25. Matzger, E. Can Sensitivity to Dinitrophenol be Determined by Skin Tests? J.A.M.A., 103:253, 1934. 26. Haft, H. H. Toxicity of Dinitrophenol.