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Metabolic actions of dinitrophenol with the use of balanced and unbalanced diets

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Abstract

Dinitrophenol (1-2-4) has been shown to increase promptly the metabolic rate in man and laboratory animals to almost any desired level. This action is peripheral, in the tissues, and independent of nervous and glandular functions. Small doses cause a slight increase in oxygen consumption; larger doses cause heat production that may surpass the ability of the animal to dissipate it, so that death occurs from heat rigor.1 We2 have suggested that, in proper dosage, dinitrophenol would be a potent therapeutic agent in obesity and in conditions in which a heightened metabolism might be desired. In a consideration of such possible uses the question arose of the source of the fuel for the increased metabolism. That is, dinitrophenol might promote the burning of carbohydrate, fat or protein, or all these fuels equally readily. A selective action on some one fuel appeared unlikely. An attempt was made, therefore, to study

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... 2,4-DNP was used in diet pills for obesity treatment between 1933 and 1938 under brand names of Dinitriso, Nitromet, Dinitrenal, and Alpha Dinitrophenol. Owing to its severe side effects, diet pills containing 2,4-DNP were withdrawn from the market in 1938 (21,22). Over 100,000 people were prescribed the drug, with claims of increasing metabolism by up to 50% at a harmless dose (21,22). ...
... Owing to its severe side effects, diet pills containing 2,4-DNP were withdrawn from the market in 1938 (21,22). Over 100,000 people were prescribed the drug, with claims of increasing metabolism by up to 50% at a harmless dose (21,22). However, it was disputed whether the drug was as effective and harmless as evidence suggested; alongside DNP's release to the public, warnings of the potential toxicity of the compound were issued by the council on Pharmacy and Chemistry (23). ...
... It was later discovered that it behaved as a protonophore in the human body which allowed the movement of protons from the mitochondrial intermembrane space across the inner mitochondrial membrane, acting as a strong uncoupler within oxidative phosphorylation (27). The outcome of this process causes the breakdown of carbohydrates and fats (21). This allows energy from cellular respiration to be released as heat rather than being stored as adenosine triphosphate, resulting in reduced fat stores and a rise in body temperature (27). ...
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Background2,4-Dinitrophenol (2,4-DNP) is an effective but highly dangerous fat burner, not licensed for human consumption. Death cases reported for 2,4-DNP overdose, particularly among young adults, have raised concerns about the ineffective regulatory control, lack of education and risks associated with impurity, and the unknown concentration of 2,4-DNP purchased on the Internet.Methods Using a sequential mixed method design and based on a hypothetical scenario as if 2,4-DNP was a licensed pharmaceutical drug, first we conducted a qualitative study to explore what product attributes people consider when buying a weight-loss aid. Focus group interviews with six females and three males (mean age = 21.6 ± 1.8 years) were audiorecorded, transcribed verbatim, and subjected to thematic analysis. Sixteen attributes were identified for the Best–Worst Scale (BWS) in the quantitative survey with 106 participants (64% female, mean age = 27.1 ± 11.9 years), focusing on 2,4-DNP. Demographics, weight satisfaction, and risk for eating disorder data were collected.ResultsIn contrast to experienced users such as bodybuilders, our study participants approached 2,4-DNP cautiously. Attributes of 2,4-DNP as a hypothetical weight-loss drug comprised a range of desirable and avoidable features. Of the 16 selected attributes, BWS suggested that long-term side effects were the most and branding was the least important attribute. Effectiveness and short-term side effects were also essential. Those in the >25 year group showed least concerns for legality. Neutral BWS scores for cost, treatment, degree of lifestyle changes required, and specificity required for the hypothetical weight-loss drug to be effective were likely caused by disagreement about their importance among the participants, not indifference.Conclusion With advances in research, 2,4-DNP as a pharmaceutical drug in the future for treating neurodegenerative diseases and potentially for weight loss is not inconceivable. Caution is warranted for interpreting the BWS scores. Owing to the difference in what data represent at individual vs. population levels, with pooled data, the method correctly identifies attributes by which most people are satisfied but misrepresents attributes that are individually very important but not universally agreed. Whilst this may be an advantage in marketing applications, it limits the utility of BWS as a research tool.
... The system must remain completely functional for energy expenditure to be maintained without inhibition to any of the complexes or to ATP synthase. It was established as early as 1933 that the mitochondrial source of energy comes specifically from the oxidation of lipids and sugars, but not catabolism of proteins [38]. It was not established until 1961 by Nobel Laureate, Dr. Peter Mitchell, how mitochondrial uncouplers modify oxidative phosphorylation [39]. ...
... 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).
... The system must remain completely functional for energy expenditure to be maintained without inhibition to any of the complexes or to ATP synthase. It was established as early as 1933 that the mitochondrial source of energy comes specifically from the oxidation of lipids and sugars, but not catabolism of proteins [38]. It was not established until 1961 by Nobel Laureate, Dr. Peter Mitchell, how mitochondrial uncouplers modify oxidative phosphorylation [39]. ...
... 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
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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.
... The use of this compound was particularly attractive when apparently only fat and carbohydrates were broken down, but not proteins, with no change in nitrogen excretion caused by 2,4-DNP. 5 This all occurred despite the warning issued by the Council on Pharmacy and Chemistry concerning the potential toxicities of the compound, 6 which inevitably resulted in some instances of uncontrolled administration. 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. ...
... 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. ...
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.
... Most fatal cases have, however, been among workers in the agricultural industry since DNP was used as a pesticide and herbicide (Bidstrup and Payne 1951). The symptoms of intoxication in man consist of body temperature exceeding 40ºC, extreme fatigue, profuse sweating and dehydration, laboured respiration and rapid onset of rigor mortis after death (Figure 5) (Perkins 1919; Cutting and Tainter 1933; Poole and Haining 1934; Horner 1942). Fatal doses of DNP in the treatment of obesity have been between 2.66 mg/kg/day for 14 days and 46 mg twice 7 days apart (Masserman and Goldsmith 1934; Poole and Haining 1934). ...
... The liver mitochondrial ATP/ADP ratio was unaffected by treatment with high oral doses of entacapone (II). The ratio decreased significantly after treatment with tolcapone or DNP, indicating uncoupling of oxidative phosphorylation at the cellular level (Cutting and Tainter 1933; Kaiser 1964; Bakke and Laurence 1965). Both tolcapone and DNP have earlier been shown to be potent uncouplers in vitro in isolated rat liver mitochondria (Loomis and Lipmann 1948; Terada 1990; Nissinen et al. 1997). ...
... Mitochondrial uncouplers [for example, 2,4-dinitrophenol (DNP)] shuttle protons across the inner mitochondrial membrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncoupling nutrient oxidation from ATP production (20). DNP has been known to increase metabolic rates since the late 1800s and was an effective and widely used weight loss drug in the 1930s (21)(22)(23)(24). Unfortunately, chronic ingestion of DNP is associated with a number of unwanted side effects, including fatal hyperthermia and death, and was banned by the U.S. Food and Drug Administration (FDA) in 1938 (25). ...
Article
Nonalcoholic fatty liver disease (NAFLD) is estimated to affect up to one-third of the general population, and new therapies are urgently required. Our laboratory previously developed a controlled-release mitochondrial protonophore (CRMP) that is functionally liver-targeted and promotes oxidation of hepatic triglycerides. Although we previously demonstrated that CRMP safely reverses hypertriglyceridemia, fatty liver, hepatic inflammation, and fibrosis in diet-induced rodent models of obesity, there remains a critical need to assess its safety and efficacy in a model highly relevant to humans. Here, we evaluated the impact of longer-term CRMP treatment on hepatic mitochondrial oxidation and on the reversal of hypertriglyceridemia, NAFLD, and insulin resistance in high-fat, fructose-fed cynomolgus macaques ( n = 6) and spontaneously obese dysmetabolic rhesus macaques ( n = 12). Using positional isotopomer nuclear magnetic resonance tracer analysis (PINTA), we demonstrated that acute CRMP treatment (single dose, 5 mg/kg) increased rates of hepatic mitochondrial fat oxidation by 40%. Six weeks of CRMP treatment reduced hepatic triglycerides in both nonhuman primate models independently of changes in body weight, food intake, body temperature, or adverse reactions. CRMP treatment was also associated with a 20 to 30% reduction in fasting plasma triglycerides and low-density lipoprotein (LDL)–cholesterol in dysmetabolic nonhuman primates. Oral administration of CRMP reduced endogenous glucose production by 18%, attributable to a 20% reduction in hepatic acetyl–coenzyme A (CoA) content [as assessed by whole-body β-hydroxybutyrate (β-OHB) turnover] and pyruvate carboxylase flux. Collectively, these studies provide proof-of-concept data to support the development of liver-targeted mitochondrial uncouplers for the treatment of metabolic syndrome in humans.
... The first mitochondrial uncoupler, 2,4-dinitrophenol (DNP), was originally used as a component of explosives during World War I (156,157). After it was observed that many of the workers who handled this compound lost weight, researchers began to investigate the possibility of using DNP as a weight loss drug, and studies by multiple groups demonstrated the efficacy of this approach in obese humans (158)(159)(160)(161). The drug was available as an over-the-counter medication and was widely taken for weight loss in the United States, but reports of toxic effects, including several deaths, led to its withdrawal from the market by the US Food and Drug Administration in 1938 (162). ...
Article
Type 2 diabetes (T2D) is characterized by persistent hyperglycemia despite hyperinsulinemia, affects more than 400 million people worldwide, and is a major cause of morbidity and mortality. Insulin resistance, of which ectopic lipid accumulation in the liver [nonalcoholic fatty liver disease (NAFLD)] and skeletal muscle is the root cause, plays a major role in the development of T2D. Although lifestyle interventions and weight loss are highly effective at reversing NAFLD and T2D, weight loss is difficult to sustain, and newer approaches aimed at treating the root cause of T2D are urgently needed. In this review, we highlight emerging pharmacological strategies aimed at improving insulin sensitivity and T2D by altering hepatic energy balance or inhibiting key enzymes involved in hepatic lipid synthesis. We also summarize recent research suggesting that liver-targeted mitochondrial uncoupling may be an attractive therapeutic approach to treat NAFLD, nonalcoholic steatohepatitis, and T2D.
... There was an average 11% increase in metabolic rate for each dosage increment of 0.1 g of DNP (44,48). Doses up to 0.5 g (about 5 mg kg -1 ) were generally well-tolerated apart from patients almost always reporting a feeling of warmth together with increased perspiration (45,46,48). Between about 5-10 mg kg -1 , patients reported profuse sweating but, surprisingly, there was no evidence of increased body temperature or heart rate. ...
Article
Mitochondrial proton cycling is responsible for a significant proportion of basal or standard metabolic rate, so further uncoupling of mitochondria may be a good way to increase energy expenditure and represents a good pharmacological target for the treatment of obesity. Uncoupling by 2,4-dinitrophenol has been used in this way in the past with notable success, and some of the effects of thyroid hormone treatment to induce weight loss may also be due to uncoupling. Diet can alter the pattern of phospholipid fatty acyl groups in the mitochondrial membrane, and this may be a route to uncoupling in vivo. Energy expenditure can be increased by stimulating the activity of uncoupling protein 1 (UCP1) in brown adipocytes either directly or through beta 3-adrenoceptor agonists. UCP2 in a number of tissues, UCP3 in skeletal muscle and the adenine nucleotide translocase have also been proposed as possible drug targets. Specific uncoupling of muscle or brown adipocyte mitochondria remains an attractive target for the development of antiobesity drugs.
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.
Chapter
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].
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.
Article
The toxicity profiles of entacapone and tolcapone, novel catechol-O-methyl-transferase (COMT) inhibitors, have been reported to differ from each other. It has also been shown that tolcapone, but not entacapone, is a potent uncoupler of oxidative phosphorylation in vitro at low micromolar concentrations. Signs of hepatotoxicity induced by tolcapone treatment have been previously reported in toxicological studies and in clinical use. The present study was designed to investigate the mechanism of hepatotoxicity of tolcapone and its possible relationship to uncoupling of oxidative phosphorylation in vivo. A 15-day oral toxicity study with entacapone or tolcapone (300 and 500 mg/kg/day) was carried out, and 2, 4-dinitrophenol (DNP), a known uncoupling agent of oxidative phosphorylation, served as a positive reference substance (20 mg/kg/day). No treatment related findings were observed in entacapone-treated rats. Clinical chemistry parameters regarding hepatocellular damage were increased in tolcapone and DNP-treated animals. The energy status measured as ATP/ADP ratio from the liver samples and energy charge (EC) in liver cell mitochondria were diminished both in tolcapone- and in DNP-treated rats. These signs together with clinical symptoms consisting of increased respiration, decreased activity and drowsiness, and elevation of the rectal body temperature observed in tolcapone- and DNP-treated animals suggest a relationship between the treatment and uncoupling of oxidative phosphorylation in vivo.
Article
The safety of obesity drugs has historically been poor. This and the stigmatisation of obesity in society ensured that a higher standard of safety for obesity drugs must be met. The authors review the safety disasters of obesity drugs that were withdrawn. The authors then review the safety of presently available drugs--benzphetamine, phendimetrazine, diethylpropion, phentermine, sibutramine and orlistat. The safety of rimonabant, a drug with a pending new drug application that has an independent effect on metabolic syndrome, is also reviewed. The authors compare the stage of obesity drug development to that of hypertension in the 1950s. As new and safer drugs with more downstream mechanisms are developed that have independent effects on the cardiovascular risks associated with obesity, third party reimbursement for obesity medicine is likely to improve. This may lead to obesity being treated like hypertension and other chronic diseases with long-term medication. With improved technological tools, the authors believe this process will be more rapid for obesity than it was for hypertension.
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