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Ann. N.Y. Acad. Sci. ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Mitochondrial Research in Translational Medicine

Persistent organic pollutants, mitochondrial dysfunction, and metabolic syndrome Soo Lim,1,2 Young Min Cho,1 Kyong Soo Park,1 and Hong Kyu Lee1,3 1 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. 2 Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea. 3 Department of Internal Medicine, Eulji University College of Medicine, Seoul, Korea

Address for correspondence: Hong K. Lee M.D., Ph.D., Department of Internal Medicine, Eulji University College of Medicine, 280-1, Hagye-Dong, Nowon-Gu, Seoul, 139-231, Korea. [email protected]

The number of individuals with metabolic syndrome is increasing worldwide, constituting a major social problem in many countries. Recently, epidemiological and experimental studies have associated insulin resistance or type 2 diabetes with elevated body burdens of persistent organic pollutants (POPs). It has been proposed that mitochondrial dysfunction plays a key role in this association. Mitochondrial DNA abnormalities are known to cause pancreas beta cell damage, insulin resistance, and diabetes mellitus. Recently, much evidence has emerged showing that environmental toxins, including POPs, affect mitochondrial function and subsequently induce insulin resistance. In this review, we present a novel concept in which metabolic syndrome is the result of mitochondrial dysfunction, which in turn is caused by exposure to POPs. The potential mechanism including POPs for mitochondrial dysfunction on metabolic syndrome is also discussed. We propose that the mitochondrial paradigm for the etiology of metabolic syndrome will facilitate the prevention and treatment of this major health problem. Keywords: persistent organic pollutants; mitochondrial dysfunction; metabolic syndrome; insulin resistance

Introduction

What is metabolic syndrome? During the past few decades, cardiovascular disease has been ranked as the main cause of morbidity and mortality in developed countries. Multiple cardiovascular disease risk factors, such as obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, and hypertension are often present.1 This clustering of risk factors and its association with insulin resistance led investigators to propose a pathophysiological condition called “metabolic” or “insulin resistance” syndrome.2 While the definition of metabolic syndrome emphasizes its clinical aspect, insulin resistance is regarded as its common pathophysiological abnormality. Insulin resistance is an important pathophysiological factor in the development of T2DM and cardiovascular disease. Insulin resistance is caused by a complex interplay between nutrient overload, systemic fatty acid excess, oxidative damage, inflammation, hypoad-

iponectinemia, and endoplasmic reticulum (ER) stress. Reactive oxygen species and oxidative damage. During the process of reduction of oxygen to water by the electron transport chain, reactive oxygen species (ROS), such as superoxide, hydrogen peroxide, the hydroxyl radical, and nitric oxide, are generated and cause oxidative damage to target tissues.3 An imbalance between the production of ROS and antioxidant defenses plays a major role in inducing alterations in insulin signaling pathways.4 Close associations between ROS and insulin resistance and between reduced insulin resistance and antioxidant treatment have been demonstrated.5,6 Inflammation. Obesity, insulin resistance, and T2DM are closely associated with chronic “inflammation” characterized by abnormal cytokine production, increased levels of acute-phase reactants, and activation of a network of inflammatory signaling pathways. There is much experimental and doi: 10.1111/j.1749-6632.2010.05622.x

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clinical evidence for a causal link between inflammation, or the molecules and networks integral to inflammatory responses, and the development of obesity or insulin resistance. Tumor necrosis factor (TNF)-␣ is the most well-known factor linking obesity, diabetes, and chronic inflammation.7 Various other inflammatory mediators and cytokines are overexpressed in adipose and other tissues in experimental mouse models of obesity and in humans.8

is present, ATP production and oxygen consumption are impaired and ROS production is elevated, which stimulates proinflammatory processes. These factors collectively contribute to insulin resistance in metabolic tissues (e.g., skeletal muscle, fat, and liver) and nonmetabolic tissues (e.g., cardiovascular tissue). Thus, insulin resistance induced by mitochondrial dysfunction contributes to metabolic abnormalities and subsequent obesity, T2DM, and cardiovascular disease.

Adiponectin. Hypoadiponectinemia appears to play an important causal role in insulin resistance, T2DM, and metabolic syndrome. Adiponectin and adiponectin receptors represent potential versatile therapeutic targets for combating obesity-linked diseases characterized by insulin resistance.9 In support of this, there is substantial evidence showing that a lack of adiponectin is a major risk factor for metabolic syndrome.10–13

Mitochondrial DNA density According to a study by Morino et al.,29 decreased mtDNA density causes functional decline of mitochondria, which can cause insulin resistance and obesity. Other studies, including ours, indicate that mtDNA density is closely associated with oxidative function in humans and animals.30,31 Oxidative phosphorylation is associated with insulin sensitivity. A population-based prospective cohort study found that a decrease in mtDNA density in peripheral blood cells preceded the development of T2DM.32 In addition, peripheral blood mtDNA density was associated with abdominal obesity before the onset of T2DM in this cohort, supporting the association between peripheral blood mtDNA density and insulin sensitivity.33–35

ER stress. There is evidence for a role for ER stress in the development of insulin resistance.14,15 A direct correlation between accelerated insulin resistance and elevated levels of ER stress markers (GRP78 and PERK phosphorylation) in obesity and T2DM has been demonstrated.16 ER stress-inducing agents promote the activation of NF-kB, a transcription factor involved in inflammatory processes.17,18 Conversely, overexpression of chaperone proteins19 and the use of pioglitazone20 appears to reduce ER stress and improve the control of diabetes. Association between mitochondrial dysfunction and insulin resistance

Overview Many studies suggest that mitochondrial dysfunction is critical in the pathogenesis of insulin resistance and metabolic syndrome.21–24 Decreased numbers of mitochondria, decreased mitochondrial gene expression, abnormal morphology of mitochondria, and abnormal oxidative phosphorylation are commonly observed in insulin-resistant metabolic tissues, including skeletal muscle, liver, and fat.25,26 Furthermore, these mitochondrial abnormalities are associated with intracellular lipid accumulation, insulin resistance, and the pathophysiology of T2DM.27,28 Most glucose and lipid metabolism pathways are dependent on mitochondria for generating energy. Therefore, when mitochondrial dysfunction

Association between mitochondrial dysfunction and insulin resistance in vivo Maintenance of normal blood glucose levels depends on a complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by pancreatic beta cells. Defects in skeletal muscle and liver are responsible for insulin resistance. Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of T2DM are caused by mitochondrial dysfunction.27,36 Recent studies using magnetic resonance spectroscopy (MRS) have shown that decreased insulin-stimulated muscle glycogen synthesis caused by a defect in insulin-stimulated glucose transport activity is a major factor in the pathogenesis of T2DM.37 The molecular mechanism underlying defective insulin-stimulated glucose transport activity may involve an increase in intramyocellular lipid metabolites such as long-chain fatty acyl-CoA (LCFA-CoA) and diacylglycerol, which in turn activate a serine/threonine kinase cascade, impairing insulin signaling. A similar mechanism has been

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Figure 1. Molecular mechanism responsible for insulin resistance secondary to mitochondrial dysfunction (modified from Kim et al.76 ). Free fatty acids (FFAs) activate inflammatory signaling and reduce ATP production, which contribute to mitochondrial dysfunction and accumulation of LCFA-CoA and diacylglycerol (DG). Accumulation of lipid metabolites activates PKCs (␤, ␦, and ␪). ROS produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase via angiotensin II causes mitochondrial dysfunction. Conversely, mitochondrial dysfunction increases ROS production, which causes activation of serine/threonine kinases, including I Kappa ␤ kinase (IKK␤), c-Jun N-terminal kinase (JNK), and PKCs, which increases serine phosphorylation of IRS proteins and subsequently results in insulin resistance.

observed in hepatic insulin resistance associated with nonalcoholic fatty liver, which is a common feature of T2DM.36 More recently, MRS studies have demonstrated that reduced mitochondrial function may predispose the healthy, lean insulin-resistant offspring of parents with T2DM to intramyocellular lipid accumulation and insulin resistance. Further analysis has found that the reduction in mitochondrial function in the insulin-resistant offspring can mostly be attributed to a reduction in mitochondrial density.27,36 These data support the hypothesis that a decline in mitochondrial function contributes to insulin sensitivity. Molecular mechanisms responsible for the association between mitochondrial dysfunction and insulin resistance Mitochondrial dysfunction results in the accumulation of fatty acid metabolites, diacylglycerol, and LCFA-CoA.38 Intracellular accumulation of diacylglycerol activates Protein Kinase Cs (PKCs), including PKC-beta, delta, and theta, which increase serine phosphorylation of insulin receptor substrate (IRS) proteins, inhibiting insulin signaling and causing insulin resistance (Fig. 1).38–40 The PKC-delta-deficient mouse is not susceptible to

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fat-induced insulin resistance.41 This suggests that activation of PKCs secondary to mitochondrial dysfunction may cause insulin resistance. Thus, lipidinduced mitochondrial dysfunction impairs insulin signaling both directly and indirectly through generation of excess ROS. In addition, one study illustrated a causal role for muscle peroxisome proliferator-activated receptor gamma coactivator 1-␣ (PGC-1␣) in the maintenance of glucose homeostasis and revealed unexpected cytokine-mediated crosstalk between skeletal muscle and pancreatic islets.42 Another study showed that plasma membrane GLUT4 content and the activity of insulin pathway intermediates are modulated by cellular mtDNA content. In addition, reductions in the expression of IRS-1 and insulin-stimulated phosphorylation of IRS-1 and Akt2/protein kinase B were associated with insulin resistance in mtDNA-depleted myocytes.43 Causes of mitochondrial dysfunction

Factors Many factors, including genetic, environmental, and developmental factors, affect mitochondrial function.

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Genetic factors Many studies have established that dysfunction of the mitochondrial genome is a major abnormality in metabolic syndrome.44,45 Early studies showed that a variant at np 16,189 in the control region of mtDNA is associated with insulin resistance46 and T2DM.47 Subsequent studies on a larger scale confirmed the association between the 16,189 variant and the risk of T2DM among Asians,48 but not among Europeans.49,50 Since there are many nuclear genetic variants that affect mitochondrial function in insulin resistance or T2DM,44,51,52 this discrepancy between ethnic groups may be explained by differences in nuclear genetic backgrounds or differences in environmental factors. The thrifty phenotype and thrifty genotype hypotheses Many epidemiological studies have revealed links between various indexes of reduced intrauterine and early postnatal growth, and susceptibility to insulin resistance syndrome in adult life.53 Many years ago, Hales and Barker suggested that the fetal origin of this “thrifty phenotype,” a physical condition programed by poor nutritional conditions in early life, leads to insulin resistance in later life.54 Mitochondrial dysfunction may represent a link between malnutrition during early life and chronic diseases in adult life.55 A contrasting concept, the “thrifty genotype” hypothesis,56 was originally proposed to explain the very high prevalence of obesity and diabetes in American Indians such as the Pima. Neel suggested that American Indians might have accumulated genes that are beneficial for survival under famine conditions but are detrimental in an affluent society. Interestingly, Hattersley and his co-workers suggested that altered fetal growth may be a phenotype of a genotype in other words, the thrifty phenotype is the result of a thrifty genotype.57 Thus, there is still a controversy about these concepts. However, a predisposition to insulin resistance is likely to be the result of both genetic and fetal environmental factors.

Environmental factors Over the past few decades, the Western lifestyle, including unhealthy eating and activity patterns, has spread over many countries. People are increasingly exposed to highly palatable, energy-dense foods consume increasing amounts of energy in the

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form of animal fats, protein, and sugar, and consume less energy in the form of vegetables, fruit, and complex carbohydrates. Moreover, people have become accustomed to labor-saving devices, such as cars, elevators, escalators, and television remote controls. These changes in lifestyle have resulted in the accumulation of fat in blood, liver, muscle, and other major organs. In particular, the accumulation of lipid in skeletal muscle is associated with the development of insulin resistance.58 The skeletal muscle of obese individuals is characterized by a profound reduction in mitochondrial function, which interferes with insulin signaling and GLUT4 translocation to the cell membrane, causing insulin resistance and, eventually, T2DM.59 A recent report also showed that a diet high in fat reduces the level of mitochondrial respiratory enzymes, relative mtDNA copy number, and PGC-1␣ expression in adipose tissue.60 Aging has been reported to be accompanied by reduced mitochondrial function and insulin sensitivity. Age-related changes in mitochondrial function are secondary to an age-associated decrease in physical activity in humans.61 Laufs et al. found that physical inactivity increased oxidative stress and endothelial dysfunction.62 These results suggest that a sedentary lifestyle and aging are associated with enhanced oxidative stress, which in turn propagates mitochondrial dysfunction. Environmental toxins affecting mitochondrial function Although lifestyle changes have contributed to the increase in the prevalence of chronic diseases in developing countries, obesity, T2DM, and other diseases associated with insulin resistance are increasing in developed countries where there have been no recent changes in diet or physical activity. It should also be noted that people who consume low-calorie diets and exercise actively may develop diseases associated with insulin resistance. Considering that the gene pool has not changed over the past few centuries, and that food consumption and physical activity have reached a plateau, causes other than genetic and environmental factors must have contributed to the increase in obesity, T2DM, and cancers of the breast, colon, and prostate. In the local context, several intrinsic environmental factors could induce insulin resistance or obesity.

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A report from Mexico showed that irrespective of smoking status, diabetic subjects had high-arsenic concentrations in their hair, blood, and urine.63 A recent report showed that arsenic exposure is closely associated with the prevalence of T2DM in the United States of America.64 There are two kinds of arsenic in the environment, the inorganic and the organic forms. Both inorganic and organic arsenic enter the body via the consumption of contaminated water or food. Inorganic forms of arsenic such as arsenate or arsenite accumulate in adipose tissue. In contrast, organic forms of arsenic such as arsenobetaine are excreted in urine. Therefore, the inorganic form of arsenic may cause T2DM. It is noteworthy that the aforementioned population had low-to-moderate exposure to arsenic. A few years ago, a report was published on the association between serum concentrations of persistent organic pollutants (POPs) and insulin resistance among nondiabetic adults.65 The authors measured the concentration of 19 POPs and the insulin resistance indexes of subjects enrolled in the American National Health and Nutrition Examination Survey. Surprisingly, it was found that of the various POPs, organochlorine pesticides were associated with insulin resistance after adjustment for BMI and waist circumference. As POPs are widespread environmental contaminants and persist in the environment for a very

long time, they have the potential to accumulate in adipose tissue. There are various kinds of POPs in the environment: polychlorinated dibenzo-pdioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), and several organochlorines that are used as pesticides. Some POPs have recently been associated with an increased risk of diabetes. Prospective cohort studies have reported that subjects exposed to 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD), the most potent dioxin congener of the POPs, and to other POPs in occupational or accidental settings have developed insulin resistance. An important finding was that POPs have a greater effect on people who are obese.66 People who had less exposure to POPs were less likely to develop insulin resistance irrespective of their abdominal obesity. Therefore, it is possible that POPs and obesity have synergistic effects that increase the likelihood of developing T2DM. Pelletier et al. proved that a large adipose tissue depot such as that present in obese individuals is associated with an elevated level of circulating organochlorines, whereas leaner sedentary and fit persons had lower plasma concentrations of these compounds.67 Moreover, there was a negative correlation between the concentration of organochlorines and basal metabolic rate (Fig. 2). Thus, mitochondria seem to be a major target of POPs in the development of obesity or insulin

Figure 2. (A) Relationship between fat mass and total plasma organochlorine concentration, adjusted for age. Adapted from Pelletier et al.77 (B) Correlations between changes in plasma organochlorine concentrations and changes in resting metabolic rate (RMR), adjusted for weight loss, during a 15-week weight-loss program in 18 obese men. HCB, hexachlorobenzene; PCB, polychlorinated biphenyl.

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resistance. When fatty acids are released from adipose tissue, POPs are released simultaneously. This can damage mitochondria in endocrinologically active tissues such as the liver and muscle. Thus, POPs may decrease mitochondrial oxidative capacity in various organs. We have also found that there is an apparent overlap between areas in the United States of America where the herbicide atrazine, a POP, has been used extensively and obesity-prevalence maps of people with BMIs greater than 30. Given that herbicides act on photosystem II of the thylakoid membrane of chloroplasts, which have a functional structure similar to that of mitochondria, we investigated whether chronic exposure to low concentrations of atrazine might cause obesity or insulin resistance by impairing mitochondrial function. Chronic administration of atrazine decreased basal metabolic rate, and increased body weight, intra-abdominal fat, and insulin resistance without changing food intake or physical activity level.68 A high-fat diet further exacerbated insulin resistance and obesity. Mitochondria in skeletal muscle and liver of atrazine-treated rats were swollen with disrupted cristae. Atrazine blocked the activities of oxidative phosphorylation complexes I and III, resulting in decreased oxygen consumption. These results suggest that long-term exposure to the herbicide atrazine may contribute to the development of insulin resistance and obesity, particularly when a high-fat diet is consumed.68 A recent report also provides evidence that exposure to POPs commonly present in food chains causes insulin resistance and associated metabolic disorders.69 Mitochondrial paradigm for the etiology of metabolic syndrome We developed a model based on mitochondria and the mitochondrial genome55 by expanding the aforementioned hypotheses and taking into account observations showing that (1) a mtDNA polymorphism is associated with insulin resistance, (2) mtDNA density is associated with insulin sensitivity and predictive of the development of diabetes at population level, (3) mtDNA density is low in the offspring of diabetic parents, and (4) mitochondrial structure and mtDNA density are altered in the offspring of dams exposed to malnutrition during gestation. In this model, various environmental toxins induce mitochondrial dys-

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function and insulin resistance, which reduce metabolic rate and prevent weight loss. Under these conditions, a lack of exercise and overeating aggravate metabolic abnormalities and finally lead to an increase in the prevalence of obesity, metabolic syndrome, chronic neuromuscular diseases, and some cancers. The mitochondrial theory is a new paradigm for understanding the current epidemic of obesity. Because the eukaryotes are of symbiotic origin, the mitochondrion is an essential component of this life form. When the genes that encode mitochondrial components malfunction, diseases involving energy utilization result. Obesity and insulin resistance are prototypes of these diseases. The processes responsible for development in early life, particularly nutrition and placental sufficiency, are important determinants of the basic body plan, which persists throughout life. The effects of malnutrition and placental ischemia are most apparent in the mitochondria. After birth, the mitochondria must fulfill the needs of the body plan as determined by the nuclear genes. Mitochondria must generate ATP and heat simultaneously. If the set-point of a mitochondrion is low, it must work harder, which will produce more ROS and result in insulin resistance and obesity. The environmental toxin-mitochondrial dysfunction concept is useful for understanding metabolic syndrome. The dominant features of metabolic syndrome can be accommodated by this approach. According to Lee et al., dioxins and furan are associated with hypertension and PCBs, and organochlorines are associated with hyperglycemia, a high triglyceride level, and abdominal obesity. Based on this concept, the clinical features of metabolic syndrome may be of toxicologic origin.66,70 Weight reduction is sometimes associated with an unfavorable rapid rate of weight regain. It has been suggested that weight loss induces a significant increase in plasma organochlorine levels in humans.71 This rise in plasma organochlorine concentration has also been associated with a decrease in T3 concentration, resting metabolic rate67 and skeletal muscle capacity for fat oxidation.72 These observations are of clinical importance as they raise concerns about the potentially adverse effects of weight loss. These physiological changes may prevent further weight loss or even favor weight

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ing the pathogenesis of complex diseases such as obesity. Future works

Figure 3. General outline of the mitochondrial hypothesis. Networks of genotypes and phenotypes are expressed in accordance with various environmental factors.

regain in obese individuals. In effect, the storage of a toxin in a tissue where it is inactive is a protective process, because it decreases the concentration of the toxin in the plasma and hence the concentration in the target organ. It should be borne in mind that moderate weight loss may normalize the metabolic profile and decrease the risk of developing obesity-related health problems, such as diabetes, hypertension, and cardiovascular disease even if a theoretically normal BMI is not attained.73 Moderate body weight loss could thus avoid the release of high levels of organochlorines into the blood, which would otherwise have caused weight-loss resistance or perhaps even health problems. In conclusion, mitochondrial dysfunction affects a range of functions, from metabolic pathways to signaling pathways that regulate hormone action. When perturbed, the mitochondrial system alters the output of matter and energy; depending on the environmental context, this may result in a pathological or a normal phenotype. Figure 3 shows a general outline of the mitochondrial hypothesis, which includes various manifestations of mitochondrial dysfunction. Environmental factors, including POPs, affect genetic components (nuclear genes, epigenetic state, and the mitochondrial genome). These two factors simultaneously determine the initial whole-body mitochondrial status or the total ATP-generating capacity. Subsequently, mitochondrial dysfunction from the molecular to the tissue levels results in phenotypes, such as obesity, dyslipidemia, metabolic syndrome, high blood pressure, and cancers of the breast, prostate, or colon. This concept affords a new way of understand-

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Diagnostic methods for detecting mitochondrial dysfunction and POP levels in humans An accurate and inexpensive method for detecting mitochondrial dysfunction is needed. Nuclear MRS can be used to evaluate mitochondrial activity in muscle or liver, but it is a complicated technique.37,74 mtDNA density is an indirect measure of mitochondrial function.29 Although various methods have been used to measure POP levels in humans, most are very expensive and labor intensive. A chemical-activated luciferase GENE expression (CALUX) assay was recently introduced. It is easier to perform than previous methods and can be used to test for mitochondrial toxicity. The CALUX assay is a reporter gene assay that detects dioxin-like compounds based on their ability to activate the aryl hydrocarbon receptor, and thus expression of the reporter gene.75 Lessons from studies conducted by environmental toxicologists There is increasing interest in the concept that exposure to environmental pollutants is associated with insulin resistance and obesity. Importantly, exposure in early life seems to program the individual toward an increased risk of developing diabetes or becoming obese. Thus, the association between environmental pollutants and diabetes or obesity is an emerging topic in the field of environmental health sciences. Most studies on the health effects of environmental pollutants involve substances to which humans are often exposed (PCBs, bisphenol-A, arsenic, and other heavy metals). Knowledge on this topic is rapidly accumulating and includes a large number of human studies on exposure to certain chemicals as well as a diverse range of animal and in vitro studies. Several agents and toxins affect mitochondria, energy metabolism, and glucose homeostasis. Table 1 lists toxins that affect mitochondrial function, their targets, and their associated phenotypes. Although further studies on the relationship between mitochondrial toxins and obesity, diabetes, metabolic syndrome, and other diseases are needed, environmental toxins that affect mitochondrial function

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Table 1. Possible mitochondrial toxins and their targets and phenotypes

Toxin

Category

Target mtDNA density78

Antiretroviral agents

Medicine

Atrazine

POP (herbicide) Respiratory complexes I and III68 POP Adiponectin,81 TNF␣, IL6,82 Estrogen-related receptor-␥ 83

Bisphenol-A

2,3,7,8-Tetrachloro-dibenzop-dioxin (TCDD) Organochlorine

POP

3-Nitropropionic acid (3-NPA) Arsenic

POP

POP

Heavy metal

Gene encoding insulin receptor substrate-185 Basal metabolic rate, oxidative capacity67 Succinate dehydrogenase87 Insulin signal transduction, adipocyte differentiation, insulin sensitivity88,89

Phenotype Insulin resistance, metabolic syndrome79 Insulin resistance, obesity,68 gestational diabetes80 Metabolic syndrome, obesity,82 cardiovascular disease, diabetes84 Diabetes, atherosclerosis, hypertension86 Obesity67 Neurodegenerative disorders87 Type 2 diabetes64

POP, persistent organic pollutant; IL6, interleukin 6.

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