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Actions and uses of dinitrophenol: Promising metabolic applications

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Abstract

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

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... Serious study into pharmacological treatment of obesity can probably be said to have started in the late 1930s, with high protein diets (i.e. low carb, low fat), amphetamines, thyroid extract, and 2,4-dinitrophenol all understood as potential weight loss agent and under intense scrutiny for their efficacy [229][230][231] . Much of the research conducted on these drugs at that time has meaningful implications for the study of weight loss today. ...
... Decreased energy use efficiency: dinitrophenol (an oxidative phosphorylation decoupler discovered when ammunition manufacturers during WWI lost weight by chronic inhalation of the chemical) 230,231,233 2. ...
Article
From 1960-2016, U.S. obesity prevalence increased 13-40% and diabetes increased from 3-15%. There is an epidemic of metabesity, the aggregate metabolic disorders produced by chronic overeating. Drugs for metabesity were developed in the 1930s with limited effectiveness; agents today rely on the same principles and are similarly ineffective. Particularly surprising has been the failure of satiety enhancers; this indicates it may not be that physiologic hunger drives chronic overeating. Although hunger and satiety affect traditional reward circuitry (Cassidy & Tong 2017), evidence for the primacy of this effect is mixed. Being hungry reduces anxiety-like behavior in mice; whether the act of eating also reduces anxiety is not well-known. If true, this represents a different avenue for the beneficial effects of eating than just reward manipulation or satiation. The aim of this dissertation is to discover hypothalamic neurocircuits involved in this relationship. This body of work is the result of two projects in mice. In the first project, I demonstrate that GABAergic eating neurons in the lateral hypothalamus (LH) inhibit GABAergic anxiety neurons in the basal forebrain (BF). Activating this circuit causes feeding and reduces anxiety; fiber photometry shows LH neurons are active both during food approach and food consumption, but BF neurons only drop in activity during eating. Conversely, BF neurons activate in response to environmental anxiogenic stimuli. It appears that the act of eating can, through the LH-BF circuit, directly reduce sensitivity to threatening stimuli The second project is in collaboration with Yuanzhong Xu and Yungang Lu on a parallel circuit from the paraventricular hypothalamus (PVH) glutamatergic projections to the ventral lateral septum (LSv) GABA neurons. My work with fiber photometry shows that both the PVH and LS respond to anxiety-provoking stimuli and are silenced by food, but with divergent activation/deactivation dynamics. This data shows at the circuit level that the act of eating itself, not hunger per se, reduces activity of anxiety regions in the brain via hypothalamic neurocircuits. It may be that some metabesity arises from chronic overeating of food eaten for anxiolytic manipulation of these circuits, a concept popularly called "stress eating". Until this behavior is addressed by new psychotherapy or pharmacology, these patients will likely struggle to recover.
... Historically, DNP was used~80-years ago in clinical studies conducted at Stanford University to determine the merits of DNP as a weight loss agent in obese patients. DNP was an ingredient in ammunition and it was learned by Dr Tainter, Dr Cutting and Dr Stockton that when factory workers or soldiers were exposed to high doses of DNP orally or inhaled, that they subsequently lost weight [75]. This initial observation of DNP-associated weight loss interested many to explore the compound as a treatment for obesity [38,[75][76][77]. ...
... DNP was an ingredient in ammunition and it was learned by Dr Tainter, Dr Cutting and Dr Stockton that when factory workers or soldiers were exposed to high doses of DNP orally or inhaled, that they subsequently lost weight [75]. 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]. ...
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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).
... 2,4-Dinitrophenol (2,4-DNP) is a crystalline solid that is slightly soluble in water, and more soluble in organic solvents such as ethanol and ether. 1 The chemical has been used as a component of explosives and fungicides; with its yellow color, it has also been used in fabric and food colorings since the late 19 th century. 2 Subacute and acute 2,4-DNP compound poisoning cases were reported among workers in munitions factories during World War I, which included fatalities. 3 Clinical symptoms include anorexia, nausea, vomiting, headache, dizziness, respiratory distress, as well as generalized weakness and weight loss. Profuse yellow-tinted sweating is pathognomonic of this poisoning. ...
... 4,9,15,17 As a slimming agent, 2,4-DNP has reportedly resurfaced, probably with the increasing convenience of purchase over the Internet. 4,9 In 2003, 70 years after Cutting et al 1,5 reported about the fat-burning properties of 2,4-DNP, the Food Standards Agency in the UK issued an urgent advisory about the use of 2,4-DNP when a Finnish body-builder was hospitalized after taking the compound. Our two cases demonstrate that the use of the compound can similarly be a threat to Chinese populations where consciousness of body image is apparent. ...
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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.
... One of the most efficacious weight loss drugs in recent history was 2,4-dinitrophenol (DNP). DNP was discovered during the first world war when French munitions factory workers experienced significant weight loss and toxicity from exposure [4]. In the early 1930s, Tainter and colleagues started investigating DNP as a weight loss agent by looking at the pharmacodynamic effects of the drug in rats [5]. ...
... In the early 1930s, Tainter and colleagues started investigating DNP as a weight loss agent by looking at the pharmacodynamic effects of the drug in rats [5]. Next they ran a limited clinical trial in which they were able to show a fourfold increase in metabolic rate, as well as a 9 kg (20 pound) decrease in body weight over a 3-month period [4]. DNP was marketed as an over-thecounter supplement for weight loss shortly thereafter with little oversight from the Food and Drug Administration (FDA). ...
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New approaches in drug development are needed to address the growing epidemic of obesity as the prevalence of obesity increases worldwide. 2,4-Dinitrophenol (DNP) is an oxidative phosphorylation uncoupling agent that was widely used in the early 1930s for weight loss but was quickly banned by the FDA due to the severe toxicities associated with the compound. One of the limitations leading to the demise of DNP as a pharmaceutical was a lack of understanding about the pharmacokinetic–pharmacodynamic relationship. The purpose of this study was to investigate whole body disposition of DNP in order to understand the relationship between the pharmacokinetics, efficacy and toxicity in the C57BL/6J diet induced obese mouse model. Following intravenous administration of 1 mg/kg, and intraperitoneal administration of 5 mg/kg and 15 mg/kg of DNP, we found limited DNP distribution to tissues. Experimentally measured partition coefficients were found to be less than 1 for all analyzed tissues. In addition, DNP exhibits significant nonlinear pharmacokinetics, which we have attributed to nonlinear plasma protein binding and nonlinear partitioning into liver and kidney. By enhancing our understanding of the PK–PD relationship, we can develop new approaches to leverage oxidative phosphorylation uncoupling as a weight loss strategy.
... The mitochondrial uncoupler 2,4-dinitrophenol (DNP) shows proof-of-principle that mitochondrial protonophores have weight-loss effects in humans as~90% of patients taking 300 mg DNP per day (3 mg/kg for a 100 kg person) lost 2-3 pounds per week without changes in food intake 20,21 . However, DNP has a narrow window between effective and toxic doses 22,23 and it was banned for human use by the FDA in 1938. To overcome the narrow therapeutic window of DNP, researchers have developed less-toxic derivatives that are targeted to mitochondria, targeted to the liver, or formulated DNP for controlled-release. ...
... Mitochondrial uncoupling also does not cause complications associated with either undereating or overeating, indicating that it does not trigger the adaptive responses caused by calorie restriction or treatment with the SGLT2 inhibitor canagliflozin 37 . The lack of compensatory food intake in mice fed BAM15 is consistent with human data showing that people taking DNP did not report increased hunger 22 . The lack of altered food intake is psychologically important because the mesolimbic reward center in the brain is intimately connected with food consumption 39,40 ; therefore, targeting metabolic efficiency with mitochondrial uncoupling may not be associated with the same psychological risk profile as dieting or using pharmacological agents that target satiety. ...
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Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake. Obesity is a global pandemic with limited treatment options. Here, the authors show evidence in mice that the mitochondrial uncoupler BAM15 effectively induces fat loss without affecting food intake or compromising lean body mass.
... DNP was administered in a daily dose between 3 and 5 mg/kg, and the reported weight loss was in the range of 1.5 kg per week. The pharmacological effect resided in the ability of DNP to increase metabolic rate via enhanced mitochondrial uncoupling, thus favoring heat produc- tion over ATP synthesis ( Cutting et al., 1933;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). ...
... Repeated daily administration of DNP leads to accu- mulation, and with it the risk for fatal intoxication is increased. In line with this notion, early clinical studies showed that metabolic rate gradually increases with daily administration of 3-5 mg/kg DNP, and plateaued at ;40% above baseline after a few weeks of treatment ( Cutting et al., 1933;Harper et al., 2001). Following its introduction as a weight loss pharmacotherapy in 1933, the interest in DNP was tremendous. ...
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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.
... Historically, DNP was used~80-years ago in clinical studies conducted at Stanford University to determine the merits of DNP as a weight loss agent in obese patients. DNP was an ingredient in ammunition and it was learned by Dr Tainter, Dr Cutting and Dr Stockton that when factory workers or soldiers were exposed to high doses of DNP orally or inhaled, that they subsequently lost weight [75]. This initial observation of DNP-associated weight loss interested many to explore the compound as a treatment for obesity [38,[75][76][77]. ...
... DNP was an ingredient in ammunition and it was learned by Dr Tainter, Dr Cutting and Dr Stockton that when factory workers or soldiers were exposed to high doses of DNP orally or inhaled, that they subsequently lost weight [75]. 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]. ...
Article
Full-text available
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.
... 2 It acts as a metabolic stimulant, but it is far too toxic for human consumption 3,4 and a number of deaths 1 have been reported since its evaluation in clinical trials 5 in the 1930s as a weight loss treatment. [6][7][8][9][10][11] It is believed to function by the uncoupling of oxidative phosphorylation. [12][13][14][15][16] The clinical trials reported some euphoria and for other psychological reasons overdose is easy, but a small overdose of the recommended 200-300 mg per day can be fatal after a few days. ...
... [12][13][14][15][16] The clinical trials reported some euphoria and for other psychological reasons overdose is easy, but a small overdose of the recommended 200-300 mg per day can be fatal after a few days. [9][10][11] Death occurs from overheating or hyperthermia and other very unpleasant side effects such as tachycardia, diaphoresis and tachypnoea. 1 Currently, there is no antidote for DNP poisoning 8 apart from using ice packs 3 or a cold bath 1 to lower the body temperature. There appears to be little guidance about its use on the Internet, and it does not have the classification of a recreational drug. ...
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Different drugs containing a basic nitrogen atom were crystallised with 2,4-dinitrophenol to study the mode of complexation in search of an antidote to 2,4-dinitrophenol poisoning. The protonated forms of quininium, quinidinium and trazodonium form N–H···O hydrogen bonds to the deprotonated O atom of the 2,4-dinitrophenolate anion, whereas haloperidolium forms a bifurcated N–H···(O,O) hydrogen bond to the deprotonated O atom of 2,4-dinitrophenol and an O atom of the adjacent nitro group. Hydrogen-bonded chains occur in the quininium, quinidinium and haloperidolium crystal structures, whereas the trazodonium structure consists of ion pairs. These results are discussed with a view to lowering the toxicity of 2,4-dinitrophenol in the body in the case of an overdose.
... In the late 1880s, a weak lipophilic acid commonly used to manufacture explosives and dyes, [2,4]-dinitrophenol (DNP), was shown to markedly enhance energy expenditure in dogs. Tainter and Cutting then demonstrated that 300-400 mg/day of DNP could induce rapid weight loss by enhancing resting metabolism in humans [264,265]. DNP is a weak uncoupler that induces diffusion of protons across the inner membrane (i.e., bypassing ATP synthase) and thus increasing oxidative metabolism. Recently, Bertholet et al. challenged the idea that protonophores induce proton leak through protein-independent mechanisms by demonstrating that protonophores, including DNP, activate ANT and UCP1 to facilitate protonophoric activity [96]. ...
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Metabolic demands of skeletal muscle are substantial and are characterized normally as highly flexible and with a large dynamic range. Skeletal muscle composition (e.g., fiber type and mitochondrial content) and metabolism (e.g., capacity to switch between fatty acid and glucose substrates) are altered in obesity, with some changes proceeding and some following the development of the disease. Nonetheless, there are marked interindividual differences in skeletal muscle composition and metabolism in obesity, some of which have been associated with obesity risk and weight loss capacity. In this review, we discuss related molecular mechanisms and how current and novel treatment strategies may enhance weight loss capacity, particularly in diet-resistant obesity.
... DNP has been shown to be quite effective to induce weight loss in mice (46), and it has also been utilized in humans in the past. Between 1933 to 1938, DNP was sold as an over-the-counter weight loss drug in the United States (47,48). However, there was a major downside: DNP and other uncoupling agents have very narrow therapeutic ranges and carry substantial risks of toxicity ranging from cataracts to death (49)(50)(51). ...
Article
Obesity is a widespread public health problem with profound medical consequences and its burden is increasing worldwide. Obesity causes significant morbidity and mortality and is associated with conditions including cardio-vascular disease and diabetes mellitus. Conventional treatment options are insufficient, or in the case of bariatric surgery, quite invasive. The etiology of obesity is complex, but at its core is often a caloric imbalance with an inability to burn off enough calories to exceed caloric intake, resulting in storage. Interventions such as dieting often lead to decreased resting energy expenditure (REE), with a rebound in weight ('yo-yo effect' or weight cycling). Strategies that increase REE are an attractive treatment option. Brown fat tissue engages in non-shivering thermogenesis whereby mitochondrial respiration is uncoupled from ATP production, increasing REE. Medications that replicate brown fat metabolism by mitochondrial uncoupling (e.g. 2,4-dinitrophenol) effectively promote weight loss but are limited by toxicity to a narrow therapeutic range. This review explores the possibility of a new therapeutic approach to engineer autologous T cells into acquiring a thermogenic phenotype like brown fat. Engineered autologous T cells have been used successfully for years in the treatment of cancers (Chimeric Antigen Receptor T cells), and the principle of engineering T cells ex vivo and transferring them back to the patient is established. Engineering T cells to acquire a brown fat-like metabolism could increase REE without the risks of pharmacologic mitochondrial uncoupling. These thermogenic T cells may increase basal metabolic rate and are therefore a potentially novel therapeutic strategy for obesity.
... 2,4-Dinitrophenol (DNP) pertains to nitroaromatic compounds. It represents a crystalline solid, which is slightly soluble in water and readily soluble in boiling water and in organic solvents, such as ethanol and diethyl ether [1]. DNP is widely used in chemical industry [2] as a component of explosives and fungicides, as well as in textile industry as a dye for fabrics [3][4][5][6]. ...
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The method for the detection of 2,4-dinitrophenol (DNP) in solution is proposed. This method employs the sensors based on silicon nanowire field-effect transistors with protective layers of high- k dielectrics, whose surface is functionalized with an amino silane. Direct highly sensitive detection of DNP has been demonstrated, and the lowest detectable concentration of DNP was determined to be 10 ⁻¹⁴ M. Silicon-on-insulator nanowire (SOI-NW) sensors can well be employed for the rapid detection of a wide range of toxic and explosive compounds by selection of sensor surface modification techniques.
... Since time is critical after a concussion or TBI to block the penumbra from releasing ROS and killing the surrounding cells, MP201 should be considered as a first line therapy to protect the threatened tissue. Literature shows that chronic, controlled-release DNP administration results in no evidence of toxic effects in mice(Cutting, Mehrtens, & Tainter, 1933;Perry, Zhang, Zhang, Boyer, & Shulman, 2015), thereby lending itself to potential chronic administration. In the current study, we utilize a clinically relevant therapeutic window for initiation of treatment of 2-hr post-injury.On-going experiments are assessing the extent of this therapeutic window as we have demonstrated a window of at least 24-hr post-injury for other mitochondrial uncouplers. ...
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Traumatic brain injury (TBI) results in cognitive impairment, which can be long‐lasting after moderate to severe TBI. Currently, there are no FDA‐approved therapeutics to treat the devastating consequences of TBI and improve recovery. This study utilizes a prodrug of 2,4‐dinitrophenol, MP201, a mitochondrial uncoupler with extended elimination time, that was administered after TBI to target mitochondrial dysfunction, a hallmark of TBI. Using a model of cortical impact in male C57/BL6 mice, MP201 (80 mg/kg) was provided via oral gavage 2‐hr post‐injury and daily afterwards. At 25‐hr post‐injury, mice were euthanized and the acute rescue of mitochondrial bioenergetics was assessed demonstrating a significant improvement in both the ipsilateral cortex and ipsilateral hippocampus after treatment with MP201. Additionally, oxidative markers, 4‐hydroxyneneal and protein carbonyls, were reduced compared to vehicle animals after MP201 administration. At 2‐weeks post‐injury, mice treated with MP201 post‐injury (80 mg/kg; q.d.) displayed significantly increased cortical sparing (p = .0059; 38% lesion spared) and improved cognitive outcome (p = .0133) compared to vehicle‐treated mice. Additionally, vehicle‐treated mice had significantly lower (p = .0019) CA3 neuron count compared to sham while MP201‐treated mice were not significantly different from sham levels. These results suggest that acute mitochondrial dysfunction can be targeted to impart neuroprotection from reactive oxygen species, but chronic administration may have an added benefit in recovery. This study highlights the potential for safe, effective therapy by MP201 to alleviate negative outcomes of TBI. Mitochondrial uncoupling is a promising therapeutic intervention targeting mitochondrial dysfunction after traumatic brain injury. Here, we show a novel prodrug MP201 restoring mitochondrial function, thereby reducing lesion volume and improving cognitive function after traumatic brain injury.
... The potential safety of DNP at lower doses distributed over time is supported by recent studies showing no evidence of toxic effects during chronic administration of controlled-release of DNP [66]. Previous literature supports this idea, as chronic low dose treatment of DNP in drinking water (mimicking controlled release) increased longevity with low levels of oxidative proteins and DNA damage in mice [67]. One eye-related potential side effect of DNP is cataracts, which were reported in some patients treated with high doses of DNP [68], but the result was not replicated in follow-up experiments [69]. ...
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The ability of novel mitochondrial uncoupler prodrug of 2,4-dinitrophenol (DNP), MP201, to prevent neuronal damage and preserve visual function in an experimental autoimmune encephalomyelitis (EAE) model of optic neuritis was evaluated. Optic nerve inflammation, demyelination, and axonal loss are prominent features of optic neuritis, an inflammatory optic neuropathy often associated with the central nervous system demyelinating disease multiple sclerosis. Currently, optic neuritis is frequently treated with high-dose corticosteroids, but treatment fails to prevent permanent neuronal damage and associated vision changes that occur as optic neuritis resolves, thus suggesting that additional therapies are required. MP201 administered orally, once per day, attenuated visual dysfunction, preserved retinal ganglion cells (RGCs), and reduced RGC axonal loss and demyelination in the optic nerves of EAE mice, with limited effects on inflammation. The prominent mild mitochondrial uncoupling properties of MP201, with slow elimination of DNP, may contribute to the neuroprotective effect by modulating the entire mitochondria’s physiology directly. Results suggest that MP201 is a potential novel treatment for optic neuritis.
... DNP had historically been caused a marked increase in fat metabolism [9,10], but it was banned for two death caused by orally DNP and the concentration of 2,4-DNP in the admission blood samples of the two deaths were 36.1 and 28 mg/L, respectively [1]. ...
... DNP is a relatively polar molecule with a low lipophilicity thus its uncoupling activity is limited. DNP and other uncouplers increase the global metabolism rate: they enhance glycolysis and cleavage of fatty acids thus reducing body weight (Cutting et al., 1933), therefore DNP was used for weight loss starting from the 1930s. Unfortunately, the range of DNP therapeutic concentrations is not wide enough and this prevented its use in treatment of obesity and other pathologies. ...
Article
Systemic inflammatory response syndrome (SIRS) development is accompanied by mitochondrial dysfunction and excessive ROS production. Mitochondrial dysfunctions also occur in many SIRS-related diseases and may be critical for their pathogenesis; therefore a use of mitochondria-targeted drugs is a promising trend in SIRS research and therapy. Here we review recent studies concerning the application of the mitochondria-targeted antioxidants and uncouplers of oxidative phosphorylation in animal models of SIRS and related diseases. We propose that a new class of uncouplers of oxidative phosphorylation, lipophilic cations could be a base for a new generation of drugs for SIRS treatment. This article is protected by copyright. All rights reserved
... 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]. DNP is an artificial uncoupler of the oxidative phosphorylation and blocks the creation of energy rich phosphates (as ATP) [6,7]. ...
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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.
... 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). ...
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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.
... Pyrexia was induced by administration of 10 ml/kg of DNP intraperitoneally. It is known that DNP induces febrile through uncoupling oxidative phosphorylation [30] resulting in fast consumption of energy without generating adenosine triphosphate. The energy of the proton gradient is then lost as heat (pyrexia) [31]. ...
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Abstract - Phragmanthera capitata is parasitic plant (mistletoe) that colonizes many plants including avocado trees. The whole plant infusion/decoction is used in Cameroon folk medicine to relief fever and abdominal pain. This study was aimed at assessing anti-pyretic and analgesic potentials of aqueous extract of Phragmanthera capitata (AEPC) in Wistar rats at doses of 100, 200 and 300 mg/kg body weight. To assess anti-pyretic potential; 2, 4-dinitrophenol (DNP) and turpentine were used to induce pyrexia with standard drug being diclofenac sodium (50 mg/kg). To assess peripheral analgesic effect, acetic acid-induced writhing test was used. To assess central analgesic potential, formalin-induced licking test was used with standard drug being pethidine (5 mg/kg). Data obtained were analyzed using analysis of variance (ANOVA) with Tukey test used as post hoc. In DNP-induced pyrexia, results revealed that AEPC at 200 and 300 mg/kg significantly (P <0.05 and P <0.01) reduced rat body temperature by 0.80±0.02 and 1.20±0.10 OC respectively as compared to 0.90±0.05 OC for standard drug. In turpentine induced pyrexia, same inhibition trend was shown as in DNP induced pyrexia. In peripheral analgesic activity, AEPC (300 mg/kg) maximally inhibited (P <0.05) number of writhes to 4.25±0.10 as compared to 9.27±0.51 for standard drug and 31.50±2.32 for control. In central analgesic activity, the number of licks was reduced to 4.99±0.13 as compared to 4.21±0.09 for standard drug and 39.25±3.13 for control. Therefore, AEPC possesses enormous anti-pyretic and analgesic properties in a dose-dependent manner. These properties corroborate the extract being used in Cameroon folk medicine to relief fever and abdominal pain. Keywords - Phragmanthera Capitata, Anti-Pyretic, Analgesic, Dose-Dependent, Loranthaceae
... DNP was used extensively in diet pills from 1933 to 1938 after Cutting and Tainter at Stanford University made their first report on the drug's ability to increase the metabolic rate (Cutting, Mehrtens, & Tainter, 1933;Tainter, Stockton, & Cutting, 1933). 2,4-Dinitrophenol is a yellow, crystalline solid that has a sweet, musty odor. ...
Article
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This paper describes the interaction between 2,4-dinitrophenol (DNP) with the two drug carrier proteins - human serum albumin (HSA) and human holo transferrin (HTF). Hence, binding characteristics of DNP to HSA and HTF were analyzed by spectroscopic and molecular modeling techniques. Based on results obtained from fluorescence spectroscopy, DNP had a strong ability to quench the intrinsic fluorescence of HSA and HTF through a static quenching procedure. The binding constant and the number of binding sites were calculated as 2.3 × 10(11) M(-1) and .98 for HSA, and 1.7 × 10(11) M(-1) and 1.06 for HTF, respectively. In addition, synchronous fluorescence results showed that the microenvironment of Trp had a slight tendency of increasing its hydrophobicity, whereas the microenvironment of the Tyr residues of HSA did not change and that of HTF showed a significant trend (red shift of about 4 nm) of an increase in polarity. The distance between donor and acceptor was obtained by the Förster energy according to fluorescence resonance energy transfer, and was found to be 3.99 and 3.72 nm for HSA and HTF, respectively. The critical induced aggregation concentration (CCIAC) of the drug on both proteins was determined and confirmed by an inflection point of the zeta potential behavior. Circular dichroism data revealed that the presence of DNP caused a decrease of the α-helical content of HSA and HTF, and induced a remarkable mild denaturation of both proteins. The molecular modeling data confirmed our experimental results. This study is deemed useful for determining drug dosage.
... The mitochondria uncoupler DNP (2,4-dinitrophenol) was used in the 1930's for the treatment of obesity with moderate success [18]. However, this concept was abandoned and DNP withdrawn from the market in 1938 due to adverse effects [19]. ...
Article
Mitochondrial quality control is essential for maintaining a healthy population of mitochondria. Two proteins associated with Parkinson disease, the kinase PINK1 and the E3 ubiquitin ligase PRKN, play a central role in the selective degradation of heavily damaged mitochondria (mitophagy), thus avoiding their toxic accumulation. Most of the knowledge on PINK1-PRKN mitophagy comes from in vitro experiments involving the treatment of mammalian cells with high concentrations of mitochondrial uncouplers, such as CCCP. These chemicals have been shown to mediate off target effects, other than mitochondrial depolarization. A matter of controversy between mitochondrial physiologists and cell biologists is the discrepancy between concentrations of CCCP needed to activate mitophagy (usually >10 μM), when compared to the much lower concentrations used to depolarize mitochondria (<1 μM). Thus, there is an urgent need for optimizing the current methods to assess PINK1-PRKN mitophagy in vitro. In this study, we address the utilization of high CCCP concentrations commonly used to activate mitophagy. Combining live fluorescence microscopy and biochemistry, we show that the FBS/BSA in the cell culture medium reduces the ability of CCCP to induce PINK1 accumulation at depolarized mitochondria, subsequent PRKN recruitment and ubiquitin phosphorylation, and ultimately mitochondrial clearance. As a result, high concentrations of CCCP are required to induce mitophagy in FBS/BSA containing media. These data unite mitochondrial physiology and mitophagy studies and are a first step toward a consensus on optimal experimental conditions for PINK1-PRKN mitophagy and mitochondrial physiology investigations to be carried out in parallel.
... Liver-targeted hepatic mitochondrial uncoupling, whereby the mitochondrial proton gradient is dissipated, thereby dissipating stored energy (fat) in the liver (155), has recently gained increasing attention as a potential therapeutic approach to burn fat and combat the life-and health-limiting consequences of T2D. The first mitochondrial uncoupler, 2,4-dinitrophenol (DNP), was originally used as a component of explosives during World War I (156,157). After it was observed that many of the workers who handled this compound lost weight, researchers began to investigate the possibility of using DNP as a weight loss drug, and studies by multiple groups demonstrated the efficacy of this approach in obese humans (158)(159)(160)(161). ...
Article
Type 2 diabetes (T2D) is characterized by persistent hyperglycemia despite hyperinsulinemia, affects more than 400 million people worldwide, and is a major cause of morbidity and mortality. Insulin resistance, of which ectopic lipid accumulation in the liver [nonalcoholic fatty liver disease (NAFLD)] and skeletal muscle is the root cause, plays a major role in the development of T2D. Although lifestyle interventions and weight loss are highly effective at reversing NAFLD and T2D, weight loss is difficult to sustain, and newer approaches aimed at treating the root cause of T2D are urgently needed. In this review, we highlight emerging pharmacological strategies aimed at improving insulin sensitivity and T2D by altering hepatic energy balance or inhibiting key enzymes involved in hepatic lipid synthesis. We also summarize recent research suggesting that liver-targeted mitochondrial uncoupling may be an attractive therapeutic approach to treat NAFLD, nonalcoholic steatohepatitis, and T2D.
... One of the best known mitochondrial uncouplers used in humans is 2,4-dinitrophenol. This compound increased basal metabolic rate up to 50%, which was followed by a weight loss of ~900 g per week (Cutting et al., 1933). However, high doses caused deaths, leading to the banning of 2,4-dinitrophenol commercialization in many countries (Harper et al., 2008). ...
Article
The present "obesogenic' environment has favored excessive energy intake resulting in the current obesity epidemic and its associated diseases. The epidemic has incentivized scientists to develop novel behavioral and pharmacological strategies that enhance energy expenditure to compensate for excessive energy intake. Although physical activity is effective to increase total energy expenditure, it is insufficient to induce negative energy balance and weight loss. With the discovery of brown adipose tissue (BAT) in adult humans, BAT activation soon emerged as a potential strategy for elevating energy expenditure. BAT is the only tissue that expresses uncoupling protein 1, conferring on this tissue high thermogenic capacity due to a low efficiency for mitochondrial ATP generation. Potential manipulation of BAT mass and activity has fueled the interest in altering whole-body energy balance through increased energy expenditure. Remarkable advances have been made in quantifying the amount and activity of BAT in humans. Many studies have concluded that the amount of active BAT appears insufficient to induce meaningful increases in energy expenditure. Thus, the majority of studies report that BAT activation does not influence body weight and metabolic control in humans. Strategies to increase BAT mass and/or to potentiate BAT activity seem necessary.
... Criteria. All human RCTs with or without blinding were considered if they (1) involved adult participants (18+ years) irrespective of gender or ethnic background and were overweight or obese as diagnosed according to the standard cut-off points for body weight, BMI, and/or waist circumference [16]; (2) applied oral administration of CHM formulations consisting two or more herbs in the treatment group; (3) compared CHM treatment with placebo, no treatment, Western medication (WM), or lifestyle intervention (LI, including diet and exercise); or (4) included body weight (kilograms) and/or BMI (kilograms/metre 2 ) as outcome measures. Cointervention was allowed as long as the same cointervention was applied in both arms. ...
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Objective: This review investigated the effects and safety of Chinese herbal medicine (CHM) formulas on weight management. Methods: Eighteen databases in English, Chinese, Korean, and Japanese were searched from their inceptions to September 2019. The treatment groups included CHM formulations, and the control included placebo, Western medication (WM), and lifestyle intervention (LI), with or without cointerventions (WM and/or LI). Quality of studies was assessed using Cochrane Collaboration's risk of bias assessment tool. Body weight and body mass index (BMI) were analysed in RevMan v5.4.1 and expressed as mean differences with 95% confidence intervals (CI), while adverse events were expressed as risk ratio with 95% CI. Results: Thirty-nine RCTs were eligible for qualitative analysis, 34 of which were included in the meta-analyses. The majority of studies had a high or unclear risk of selection, performance, and detection bias. Twenty-five CHM studies involving cointerventions revealed that CHM had significant adjunct effects on body weight and BMI at the end of treatment compared to control. No serious adverse events were reported in the CHM groups. Conclusion: CHM indicates a promising adjunct to facilitate WM or lifestyle change for weight management. However, methodological barriers such as lack of allocation concealment and double-blinding may have led to challenges in data synthesis. More rigorously designed RCTs involving cointerventions are warranted.
... Consequently, mitochondria have long been a focus of T2D preventative medicine and therapeutics due to their involvement in both the maintenance of lipid and redox homeostasisprocesses that when dysregulated are well-established to contribute to the pathophysiology of insulin resistance in skeletal muscle [17][18][19]. For instance, in 1933, the non-selective mitochondrial uncoupler DNP (2,4-dinitrophenola protonophore that dissipates mitochondrial membrane potential and increases substrate oxidation) was found to promote wholebody energy expenditure and was marketed as a compound to promote weight loss [20,21]. Unfortunately, a consequence of uncoupling is heat generation and decreased aerobic energy (ATP) production, which is associated with a high incidence of lethal hyperthermia and adverse cardiac events [22]. ...
Article
While the etiology of type 2 diabetes is multifaceted, the induction of insulin resistance in skeletal muscle is a key phenomenon, and impairments in insulin signaling in this tissue directly contribute to hyperglycemia. Despite the lack of clarity regarding the specific mechanisms whereby insulin signaling is impaired, the key role of a high lipid environment within skeletal muscle has been recognized for decades. Many of the proposed mechanisms leading to the attenuation of insulin signaling — namely the accumulation of reactive lipids and the pathological production of reactive oxygen species (ROS), appear to rely on this high lipid environment. Mitochondrial biology is a central component to these processes, as these organelles are almost exclusively responsible for the oxidation and metabolism of lipids within skeletal muscle and are a primary source of ROS production. Classic studies have suggested that reductions in skeletal muscle mitochondrial content and/or function contribute to lipid-induced insulin resistance; however, in recent years the role of mitochondria in the pathophysiology of insulin resistance has been gradually re-evaluated to consider the biological effects of alterations in mitochondrial content. In this respect, while reductions in mitochondrial content are not required for the induction of insulin resistance, mechanisms that increase mitochondrial content are thought to enhance mitochondrial substrate sensitivity and submaximal adenosine diphosphate (ADP) kinetics. Thus, this review will describe the central role of a high lipid environment in the pathophysiology of insulin resistance, and present both classic and contemporary views of how mitochondrial biology contributes to insulin resistance in skeletal muscle.
... 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]. ...
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.
... Although the uncoupling of oxidative phosphorylation (OxPhos) in the mitochondria was long ago proposed as a target for treating obesity, no breakthrough therapy has yet been established. 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]. ...
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.
... Increasing energy expenditure via thermogenesis brings with it the obvious risk that the additional heat that accompanies an increased metabolic rate could result in hyperthermia, an acute risk not shared with strategies that decrease caloric intake. This risk is borne out by the misuse of the chemical uncoupler dinitrophenol, which has been shown to be highly efficacious in producing weight loss, but has also resulted in overdose deaths [2][3][4]. Thus, it may be challenging for any thermogenic-based therapeutic to clear necessary safety and regulatory hurdles. One suggestion to the challenge of safely inducing thermogenesis has been to utilize the increased heat loss caused by processes such as vasodilation to trigger thermogenesis. ...
Article
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While it is now understood that the proper expansion of adipose tissue is critically important for metabolic homeostasis, it is also appreciated that adipose tissues perform far more functions than simply maintaining energy balance. Adipose tissue performs endocrine functions, secreting hormones or adipokines that affect the regulation of extra-adipose tissues, and, under certain conditions, can also be major contributors to energy expenditure and the systemic metabolic rate via the activation of thermogenesis. Adipose thermogenesis takes place in brown and beige adipocytes. While brown adipocytes have been relatively well studied, the study of beige adipocytes has only recently become an area of considerable exploration. Numerous suggestions have been made that beige adipocytes can elicit beneficial metabolic effects on body weight, insulin sensitivity, and lipid levels. However, the potential impact of beige adipocyte thermogenesis on systemic metabolism is not yet clear and an understanding of beige adipocyte development and regulation is also limited. This review will highlight our current understanding of beige adipocytes and select factors that have been reported to elicit the development and activation of thermogenesis in beige cells, with a focus on factors that may represent a link between exercise and ‘beiging’, as well as the role that thyroid hormone signaling plays in beige adipocyte regulation.
... Chemical uncoupling agents such as 2,4-Dinitrophenol (DNP) effectively reduce weight and were one of the first anti-obesity therapeutics (149). Functioning as a protonophore, DNP disrupts the normal proton gradient across the mitochondrial membrane. ...
Article
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Obesity is a disease of the nervous system. While some will view this statement as provocative, others will take it as obvious. Whatever our side is, the pharmacology tells us that targeting the nervous system works for promoting weight loss. It works, but at what cost? Is the nervous system a safe target for sustainable treatment of obesity? What have we learned – and unlearned – about the central control of energy balance in the last few years? In this Mini-Review, we provide a thought-provoking exploration of obesity as a disorder of neurotransmission. We discuss the state of knowledge on the brain pathways regulating energy homeostasis that are commonly targeted in anti-obesity therapy and explore how medications affecting neurotransmission such as atypical antipsychotics, antidepressants and antihistamines relate to body weight. Our goal is to provide the endocrine community with a conceptual framework that will help expending our understanding of the pathophysiology of obesity, a disease of the nervous system.
... 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]. ...
Article
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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.
... Alternatively, the treatment of primary eWAT adipocytes from HFD-fed mice with palmitate has been shown to result in adenine nucleotide translocase 2 (ANT 2)-dependent uncoupling and greater oxygen consumption, which may contribute to a hypoxic environment (39). However, mitochondrial uncoupling would be expected to decrease mtROS (7,43,50), likely accounting for well-established protective effect of dinitrophenol (DNP) in the context of insulin resistance and diabetes (14,60). Therefore, whereas lipid-mediated uncoupling may contribute to hypoxia-induced signaling events, it is unlikely to directly contribute to the observed increase in mtROS in the present study. ...
Article
White adipose tissue (WAT) dysfunction in obesity is implicated in the onset of whole-body insulin resistance. Alterations in mitochondrial bioenergetics, namely impaired mitochondrial respiration and increased mitochondrial reactive oxygen species (mtROS) production, have been suggested to contribute to this metabolic dysregulation. However, techniques investigating mitochondrial function are classically normalized to tissue weight, which may be confounding when considering obesity-related adipocyte hypertrophy. Furthermore, the effect of long-term high-fat diet (HFD) on mtROS in WAT has yet to be elucidated. Therefore, we sought to determine the HFD-mediated temporal changes in mitochondrial respiration and mtROS emission in WAT. C57BL/6N mice received low-fat diet or HFD for 1 or 8 weeks and changes in inguinal WAT (iWAT) and epididymal WAT (eWAT) were assessed. While tissue weight-normalized mitochondrial respiration was reduced in iWAT following 8 weeks HFD-feeding, this effect was mitigated when adipocyte cell-size and/or number were considered. These data suggest HFD does not impair mitochondrial respiratory capacity per adipocyte within WAT. In support of this assertion, within eWAT compensatory increases in lipid-supported and maximal succinate-supported respiration occurred at 8-weeks despite cell hypertrophy and increases in WAT inflammation. Although these data suggest impairments in mitochondrial respiration do not contribute to HFD-mediated WAT phenotype, lipid-supported mtROS emission increased following 1-week HFD in eWAT, while both lipid and carbohydrate-supported mtROS were increased at 8 weeks in both depots. Combined, these data establish that while HFD does not impair adipocyte mitochondrial respiratory capacity, increased mtROS is an enduring physiological occurrence within WAT in HFD-induced obesity.
... The mitochondria uncoupler DNP (2,4-dinitrophenol) was used in the 1930's for the treatment of obesity with moderate success [18]. However, this concept was abandoned and DNP withdrawn from the market in 1938 due to adverse effects [19]. ...
Article
Mitochondrial quality control is essential for maintaining a healthy population of mitochondria. Two proteins associated with Parkinson disease, the kinase PINK1 and the E3 ubiquitin ligase PRKN, play a central role in the selective degradation of heavily damaged mitochondria (mitophagy), thus avoiding their toxic accumulation. Most of the knowledge on PINK1-PRKN mitophagy comes from in vitro experiments involving the treatment of mammalian cells with high concentrations of mitochondrial uncouplers, such as CCCP. These chemicals have been shown to mediate off target effects, other than mitochondrial depolarization. A matter of controversy between mitochondrial physiologists and cell biologists is the discrepancy between concentrations of CCCP needed to activate mitophagy (usually >10 μM), when compared to the much lower concentrations used to depolarize mitochondria (<1 μM). Thus, there is an urgent need for optimizing the current methods to assess PINK1-PRKN mitophagy in vitro. In this study, we address the utilization of high CCCP concentrations commonly used to activate mitophagy. Combining live fluorescence microscopy and biochemistry, we show that the FBS/BSA in the cell culture medium reduces the ability of CCCP to induce PINK1 accumulation at depolarized mitochondria, subsequent PRKN recruitment and ubiquitin phosphorylation, and ultimately mitochondrial clearance. As a result, high concentrations of CCCP are required to induce mitophagy in FBS/BSA containing media. These data unite mitochondrial physiology and mitophagy studies and are a first step toward a consensus on optimal experimental conditions for PINK1-PRKN mitophagy and mitochondrial physiology investigations to be carried out in parallel.
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Despite a perception that herbal and dietary supplements (HDS) are safe, devastating liver injury has been reported resulting from their use. The difficulty in characterizing liver injury attributable to HDS stems from the permissive regulatory environment, the complexity of marketed products, and an under reporting by the patients who use them. Despite these limitations, researchers, clinicians, and regulators have increasing awareness of the need for study in this area.
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During a hemorrhagic shock (HS), O2 uptake (V˙O2) decreases as soon as the rate of O2 delivery (DO2DO2) drops below a “critical level”, a response accounted for by the reduction in mitochondrial O2supply. In urethane-anesthetized rats, DO2DO2 was decreased within 20 min from 21.5 to 2.8 ml min−1 by slowly withdrawing 18 ml kg−1 of blood. This led to a reduction in V˙O2 from 6.1 to 2.4 ml min−1 (n = 5, p < 0.01). Decoupling mitochondrial oxidative activity by injecting 2,4-DNP (6 mg kg−1, iv) before HS elevated V˙O2 to 11.9 ± 1.2 ml min−1 (n = 6, p < 0.01), which remained above control HS values throughout most of the hemorrhage. This was associated with higher levels of O2 extraction, cardiac output and ventilation than in control HS. DO2–V˙O2 relationship was shifted upward and to the left following DNP. In conclusion, cellular and systemic mechanisms, decreasing O2demand, account for a large part of HS induced V˙O2 decline resulting in an additional reduction in DO2DO2.
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New appetite‐regulating antiobesity treatments such as semaglutide and agents under investigation such as tirzepatide show promise in achieving weight loss of 15% or more. Energy expenditure, fat oxidation, and lean mass preservation are important determinants of weight loss and weight‐loss maintenance beyond appetite regulation. This review discusses prior failures in clinical development of weight‐loss drugs targeting energy expenditure and explores novel strategies for targeting energy expenditure: mitochondrial proton leak, uncoupling, dynamics, and biogenesis; futile calcium and substrate cycling; leptin for weight maintenance; increased sympathetic nervous system activity; and browning of white fat. Relevant targets for preserving lean mass are also reviewed: growth hormone, activin type II receptor inhibition, and urocortin 2 and 3. We endorse moderate modulation of energy expenditure and preservation of lean mass in combination with efficient appetite reduction as a means of obtaining a significant, safe, and long‐lasting weight loss. Furthermore, we suggest that the regulatory guidelines should be revisited to focus more on the quality of weight loss and its maintenance rather than the absolute weight loss. Commitment to this research focus both from a scientific and from a regulatory point of view could signal the beginning of the next era in obesity therapies.
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Drugs and natural compounds that affect the thermoregulatory system can induce or contribute to hyperthermia when used in excess. Hyperthermia associated with drug overdose is dangerous and potentially lethal. This article reviews the body's process of maintaining thermodynamic equilibrium, and describes the mechanisms by which it is influenced by sympathomimetic and anticholinergic drugs, salicylates, and thyroid replacement medications. Appropriate treatment strategies such as cooling and the administration of counteractive medications are discussed.
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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
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.
An experimental study was carried out to examine the effects of different metabolic inhibitors namely 6-marcaptopurine, 2, 4 dinitrophenol, sodium arsenate, mercuric chlorice, sodium arsenite, 2-thiouracil, sodium azide, malonic acid and sodium fluoride on growth and l-glutamic acid production by the mutant Micrococcus glutamicus AB 100. All these inhibitors showed detrimental effect on growth of l-glutamic acid production.
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.
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Mitochondrial abnormalities have been reported in both insulin-deficient and insulin-resistant states and in the related condition of obesity. The phrase ‘mitochondrial dysfunction’ is often used in this regard. However, beyond dysfunction, there is evidence for defects in mitochondrial biogenesis, number, morphology, and dynamics (fusion and fission). Diabetes and obesity are also associated with the overproduction of mitochondrial reactive oxygen species (ROS), leading to mitochondrial and cellular oxidative damage. This, in turn, contributes to the development and progression of diabetic complications and to worsening of the diabetic state per se . Here we will review the evidence for mitochondrial abnormalities in type 2 diabetes and obesity and consider underlying mechanisms. We will also discuss potential therapeutic interventions targeted at mitochondria.
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The usage of social media is associated with worsening perceptions of body image and increasing access to, and use of, toxic weight loss supplements. Little is known about the effect of nonlethal doses of one mechanistically unique supplement, 2,4-dinitrophenol (DNP). DNP has been banned by the FDA making human studies difficult, but the public still consumes DNP leading to a gap in our knowledge on the effects of DNP. Here we use social media to investigate the use of DNP, providing the largest characterization of its usage to date. The objective of this study was to determine the doses of DNP generally consumed, adverse effects at those doses, and coingestants. We collected publicly available data from 2017-2018 from Internet discussion forums (also called bulletin boards) dedicated to the discussion of weight loss and body building. Our main measure was the distribution of reported doses of DNP consumed. Our secondary measure was the frequency of adverse effects reported at those doses. We collected 661 posts across 5 online forums. The most commonly ingested dose reported was 150 mg (1-2 pills, depending on formulation), followed by 300 mg (2-3 pills). The most commonly reported adverse effects were sweating and a sensation of warmth, followed by yellow discoloration of secretions. The most common coingestants were antihistamines, cetirizine and loratadine. 2,4-dinitrophenol is a mechanistically unique weight loss agent reported to be associated with sweating and a sensation of warmth at the most commonly reported ingested doses. Common co-ingestants are antihistamines, although itching was not directly reported as a side effect. Coingestion of an antihistamine, which can lessen the body's ability to dissipate heat, could worsen the side effects of DNP. This is the first formal description derived from social media of DNP usage at nonlethal doses. Further investigation is needed to determine the therapeutic index of DNP. Less toxic derivatives may provide a starting point for pharmacological adjuncts to weight-loss.
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