Persistent organic pollutants in adipose tissue should be considered in obesity research

Authors


Summary

Although low doses of persistent organic pollutants (POPs), strong lipophilic chemicals with long half-lives, have been linked to various endocrine, immune, nervous and reproductive system diseases, few obesity studies have considered adipose tissue as an important POPs exposure source. Because the toxicodynamics of POPs relate directly to the dynamics of adiposity, POPs might explain puzzling findings in obesity research. In two people exposed to the same amounts of environmental POPs, the one having more adipose tissue may be advantaged because POPs storage in adipose tissue can reduce burden on other critical organs. Therefore, adipose tissue can play a protective role against the POPs effects. However, two situations increase the POPs release from adipose tissue into the circulation, thereby increasing the risk that they will reach critical organs: (i) weight loss and (ii) insulin resistance. In contrast, weight gain reduces this possibility. Therefore, avoiding harmful health effects of POPs may mostly contradict conventional judgments about obesity and weight change. These contradictory situations can explain the obesity paradox, the adverse effects of intensive intentional weight loss and the protective effects of obesity against dementia. Future studies should consider that adipose tissue is widely contaminated with POPs in modern society.

Persistent organic pollutants contaminate adipose tissue

Although many researchers consider adipose tissue as a pure organ consisting of adipocytes, blood vessels and endogenous molecules, the contemporary view of adipose tissue suggests that it is widely contaminated with various man-made lipophilic chemicals, including the by-products of a wide range of manufacturing processes. The most well-known class of these chemicals is persistent organic pollutants (POPs). POPs include several hundred halogenated compounds with common features such as resistance to biodegradation, environmental persistence, bioaccumulation in the food chain, strong lipophilicity and storage in the adipose tissue of living organisms [1]. Typical examples of POPs include chlorinated compounds such as organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs) and dioxins [1].

Most OCPs and PCBs were banned several decades ago in many countries, and dioxin emission is strictly regulated in most countries. However, humans are still exposed to these chemicals through several routes [1]. The major source of external exposure to these chemicals is POP-contaminated food, especially fatty animal products such as fish, meat and milk (including breast milk) [1, 2]. An important source of internal exposure to these chemicals is POP-contaminated adipose tissue in the body [3, 4]. When these chemicals enter the body through breast milk, food or other sources, they are primarily stored in adipose tissue and slowly released into the circulation to be eliminated over several years [5].

Although early toxicological studies indicated that exposure to high levels of POPs is harmful to human health, it was recently observed that chronic exposure to low levels of POPs can also adversely affect the endocrine, immune, nervous and reproductive systems [6]. In particular, substantial epidemiological and experimental evidence has linked low-dose POP exposure to obesity-related metabolic dysfunctions such as type 2 diabetes and metabolic syndrome [1, 7].

Traditional toxicity studies argued that dioxin is the most toxic compound among various compounds classified as POPs because of its affinity for the aryl hydrocarbon receptor [8]. However, findings from recent human studies have suggested that the harmful effects of low-dose POPs might be the result of chronic exposure to mixtures of POPs rather than to independent effects of several individual compounds [1, 7]. Although many in vitro and in vivo toxicological studies have been conducted on the effects of exposure to high levels of individual POP compounds, only a few experimental studies have explored the effects of chronic exposure to low levels of POP mixtures, especially in terms of the dose and duration of exposure in humans [9, 10]. Many individual compounds classified as POPs are well-established endocrine disrupting chemicals (EDCs), and chronic glutathione depletion and mitochondrial dysfunction are also possible consequences of chronic exposure to low-dose POP mixtures [1, 9, 11].

In addition to strong lipophilic POPs with long half-lives, less lipophilic chemicals with brief half-lives, such as polycyclic aromatic hydrocarbons, bisphenol A, synthetic musk compounds, triclosan and nonylphenol, have been detected in adipose tissue [12, 13]. Therefore, adipose tissue can be considered as an organ storing various exogenous chemicals that are not easily metabolized and excreted from the body.

Adipose tissue is an important protective organ against persistent organic pollutants

Once POPs enter the body, they are readily distributed through the lymph and blood to their primary deposition site, adipocyte lipid droplets in adipose tissue, although we note that the liver is another major storage site for certain types of POPs like dioxins, particularly at high doses [5, 14]. Compared with other critical organs, adipose tissue is a relatively safe organ for POP accumulation because it is a natural location for lipid storage. Therefore, the storage of POPs in adipose tissue can reduce their burden on other critical organs. Because the half-lives of POPs range from several months to years, storing POPs safely before they are finally eliminated is important to human health.

Several animal experiments have demonstrated the possible protective effects of adipose tissue against POPs. For example, treatment with PCBs results in impaired glucose homeostasis in lean mice but not in obese mice; however, glucose homeostasis was impaired after weight loss in obese mice [15]. Diet-induced obesity in rats after exposure to a lethal dose of dioxin increased survival time [16]. A recent review article expertly discussed the role of adipose tissue as a protective organ against POPs [17].

Situations associated with the increased release of persistent organic pollutants from adipose tissue

The POPs stored in adipose tissue are slowly released as they are eliminated from the blood to maintain equilibrium [18]. The ratio of the concentration of POPs in adipose tissue to blood may remain relatively constant. In certain situations, however, the amount of POPs released from adipose tissue into the circulation increases. Under these conditions, if the body cannot efficiently metabolize and eliminate these chemicals, then the circulating POPs have a higher chance of reaching critical organs.

Two common situations occur in which POPs are released at a higher rate than normal from adipose tissue into the circulation: (1) weight loss and (2) insulin resistance. The reduction of fat mass during weight loss leads to the release of POPs from adipocytes into the circulation [19]. As the primary physiological function of insulin in adipose tissue is the suppression of lipolysis, elevated lipolysis in people with insulin resistance can also enhance the release of POPs from adipose tissue into the circulation with increased release of free fatty acids [20]. However, weight gain can decrease this effect by sequestering POPs from the circulation into adipose tissue [21]. An experimental animal study clearly demonstrated that weight loss redistributed hexachlorobenzene (a POP) from adipose tissue to critical organs such as the brain and kidneys; however, weight gain reversed this effect [22]. Hexachlorobenzene in the liver increased after weight cycling (i.e. weight regain following weight loss) [22]. These findings suggest that changes in weight affect the concentration of POPs in adipose tissue and critical organs.

In fact, the two situations that cause the increased release of POPs from adipose tissue seem to be contradictory from the viewpoint of fat mass because weight loss makes people less obese, while obesity is the most common cause of insulin resistance. Nevertheless, both situations increase the release of POPs from adipose tissue, although their patterns of release can differ. We suspect that the release of POPs due to obesity-related insulin resistance is more subtle and chronic than the release that occurs during weight loss. The potential health effects of POPs during weight change also contradict the conventional wisdom of weight change; typically, weight loss is considered beneficial, whereas weight gain is considered harmful.

It is important to emphasize that greater adipose tissue as the primary storage site for POPs can be more advantageous than less adipose tissue only if uncontrolled lipolysis does not develop. In addition, more subcutaneous adipose tissue is better than more visceral adipose tissue because the latter is a less stable storage site for POPs [23]. It may be related to the higher lipolytic activity in visceral adipose tissue in comparison with subcutaneous adipose tissue [24]. This difference might partially explain why subcutaneous fat plays a protective role according to human and animal studies in contrast with the detrimental effects of visceral adipose tissue [25].

A recent human study reporting that the plasma levels of POPs were higher in the metabolically abnormal obese phenotype than in the metabolically healthy but obese phenotype supports this hypothesis [26]. One relevant finding is that type 2 diabetes was rare among individuals with very low serum concentrations of POPs in the general US population, even if these people were obese, which suggests the possibility that POPs play a more critical role than adipose tissue in the pathogenesis of type 2 diabetes [27, 28]. Therefore, the efficacy of adipose tissue as a stable storage site for lipophilic chemicals such as POPs may be a crucial factor that determines metabolic health regardless of adiposity.

A more fundamental possibility can be proposed. Under the current paradigm, chronic low-grade inflammation of adipose tissue is a key mechanism of obesity-related diseases; the enlarged adipocytes of obese individuals recruit pro-inflammatory cells and release a range of cytokines, which predispose toward insulin resistance through ectopic fat accumulation in non-adipose tissue [29, 30]. However, the uncontrolled leakage of poorly biodegradable POPs from enlarged or necrotic adipocytes of obese individuals to interstitial spaces between adipocytes can be an underlying cause of inflammatory changes in adipose tissue because the presence of foreign bodies is an important cause of inflammation. In fact, chronic treatment with low-dose POP mixtures in mice led to a chronic state of low-grade inflammation in adipose tissue, including macrophage infiltration and up-regulation of pro-inflammatory cytokines [10]. On the other hand, when weight loss happens, POPs in the interstitial spaces of adipose tissue might be more easily drained to blood and lymph, leading to the immediate reduction of pro-inflammatory reaction in adipose tissue. In this scenario, POPs may explain even the possible health effects from the viewpoint of fat mass.

Several conditions related to adiposity (obesity without insulin resistance, obesity with insulin resistance, weight loss and weight gain) commonly occur in modern societies, and many people experience some of these events more than once during their lifetime. Therefore, the toxicodynamics and health-related effects of POPs are directly related to the health effects of obesity and weight change. The following sections present three examples of puzzling findings from the obesity literature and the role that POPs play in these findings.

Three examples of puzzling findings from obesity research

The obesity paradox

Although obesity is an important risk factor for many chronic diseases, overweight and obese patients with these diseases show a better survival rate than patients with ideal body weights, suggesting that obesity has a protective effect [31]. This phenomenon is called the ‘obesity paradox’. The obesity paradox is also observed among the elderly [32]. The inaccurate assessment of body fat using the conventional BMI, selective survival bias, better nutritional reservation and/or aggressive treatment among obese patients might explain this phenomenon [31]. In contrast to the current paradigm of obesity, however, adipose tissue is likely the first line of defence, and it protects critical organs from the possible harmful effects of POPs as stated previously. If this specific role of adipose tissue becomes more significant among patients with chronic diseases or the elderly, then the obesity paradox can be explained.

In general, chronic diseases and old age are considered to be conditions featuring a disturbance of homeostasis that affects various cellular functions at the molecular level. The detrimental effects of POPs could be more serious among individuals with functionally impaired cells because of homeostatic imbalance than those without chronic diseases or those who are younger. It is worth noting that glutathione depletion and mitochondrial dysfunction (which are suspected to be possible molecular mechanisms linking chronic exposure to low-dose POP mixtures to many diseases [1, 9, 11]) are commonly found in a myriad of diseases and the elderly [33, 34]. In addition, patients with chronic diseases or the elderly might not metabolize and eliminate POPs as efficiently as healthy or young people [35]. Therefore, the role that adipose tissue plays as a protective organ might be more critical when the obesity paradox is observed.

Interestingly, one study reported that the association between fat mass and mortality among elderly people differed depending on the serum concentrations of POPs [36]. The obesity paradox was clearly observed among elderly people with high-serum POP concentrations but not those with relatively low-serum POP concentrations. For example, in elderly subjects that had high-serum POP concentrations, the risk of mortality in subjects with high fat mass was only one-fifth that of subjects with low fat mass. However, in elderly subjects that had low-serum POP concentrations, the risk of mortality in subjects with high-fat mass was two to three times higher than that of subjects with low-fat mass. Compared with elderly people with low-serum POP concentrations, those with high-serum POP concentrations already have a higher burden of POP metabolism and a higher chance that these chemicals would reach critical organs. Under this condition, a large and relatively safe reserve for storing POPs and other lipophilic chemicals can improve survival.

Although this observation [36] must be replicated, the different associations between obesity and mortality based on serum levels of POPs might not always be observed in other populations. If most people have concentrations of POPs above certain levels, then the protective role of obesity would be observed in all study subjects, even if participants are stratified based on POP levels.

The adverse effects of intensive intentional weight loss

It is well known that weight loss intervention studies have shown improvements in the cardiovascular risk profiles of many obese people. However, if POPs are not eliminated from the body, then the increased release of POPs from adipose tissue into the circulation during weight loss can lead to undesirable outcomes, especially in the long term. Despite the immediate release of POPs from adipose tissue during weight loss and possible negative effects on resting metabolic rate, thyroid hormone levels and liver function tests [37-39], the net effect of weight loss in the short term would be revealed as favourable because of the significant benefits of decreased fat mass. However, the early beneficial net effect of weight loss can be reversed over time, especially when the POPs released from adipose tissue are not efficiently eliminated from the body.

Findings in a recent large randomized controlled study of overweight or obese patients with type 2 diabetes (the Look AHEAD study) [40] are consistent with this speculation. This study evaluated the effects of an intensive lifestyle intervention focusing on weight loss on the development of cardiovascular disease over 10 years. As expected, significant weight loss and improvements in traditional cardiovascular risk factors were observed, especially during an earlier follow-up period. However, no difference was found in the rate of cardiovascular events between the intensive lifestyle intervention group and control group at the 10-year follow-up assessment.

The authors stated that this finding was unexpected. Several possible explanations were suggested with regard to the methodology, including the use of lower doses of cardioprotective drugs in the intervention group, the characteristics of the participants (i.e. whether they belonged to a subgroup that was healthier than the general population with type 2 diabetes or an unhealthier subgroup) and an insufficient follow-up period [40, 41]. However, we point out that the delayed adverse effects of POPs released from adipose tissue might have counteracted the improvements in the traditional cardiovascular risk factors observed earlier during the study. The increase in serum POP concentrations after weight loss is proportional to the magnitude of weight loss [42]. Therefore, to protect critical organs, it is essential to increase the metabolism and elimination of POPs based on the rate at which they are released from adipose tissue. However, because the body's capacity to metabolize POPs is limited, intensive weight loss might negatively affect various organs.

Importantly, the release of POPs into the circulation during weight loss can lead to repeated cycles of weight gain/loss known as ‘the yo-yo phenomenon’ [22]. In many human studies, weight cycling has been associated with an increased risk of cardiovascular and total mortality [43]. However, given that weight cycling is commonly the result of intentional weight loss, which is considered a healthy behaviour, the validity of the epidemiological findings concerning weight cycling has often been questioned [44]. However, POPs released from adipose tissue during intensive weight loss might explain the findings regarding weight cycling in humans.

In fact, the pattern of weight loss of the intensive lifestyle intervention group in the Look AHEAD study [40] was consistent with inadequate excretion of POPs and weight cycling. For example, the intervention group experienced a mean weight loss of 8.6% after 1 year, weight regain during years 2–5 and then gradual weight loss over the last 5 years of the follow-up period. Compared with the intervention group, the mean weight loss in the control group at the 1-year follow-up assessment was only 0.7%; however, the weight loss occurred gradually and without weight regain. At the end of the study, the weight loss was 6.0% in the intervention group and 3.5% in the control group. Therefore, although the absolute weight loss was lower, the pattern of weight loss in the control group was less harmful than that in the intervention group with regard to POPs. This finding might explain why the rate of cardiovascular events was similar between the two groups despite the remarkable improvements in traditional cardiovascular risk factors observed in the intervention group.

POPs-related problems due to weight loss are more serious in older adults than in younger adults. First, adipose tissue is more contaminated with POPs and other chemicals in the elderly than in younger people because chemicals such as POPs that are poorly metabolized tend to accrue with age [45]. Therefore, more POPs are released from adipose tissue into the circulation when elderly people lose body weight than when younger people lose the same amount of weight. Second, the physiological ability to metabolize and excrete xenobiotics decreases with age [35]. We presume that the amount of POPs released from adipose tissue into the circulation and the likelihood that these chemicals will reach critical organs are higher among the elderly than younger people. Therefore, the net benefits of weight loss decrease with age, and the health benefits of weight loss among the elderly are unclear even if it is intentional.

Obesity and dementia

One of the most puzzling findings regarding obesity has been observed with regard to dementia. Conventionally, obesity is linked to dementia as a direct effect of adiposity or through obesity-related disorders such as type 2 diabetes and hypertension [46]. However, findings are conflicting with regard to the possible links between obesity in middle age and older age individuals and the subsequent development of dementia. In a review of epidemiological studies from 2003 to 2013 [47], midlife obesity was positively associated with the risk of dementia, whereas obesity later in life decreased the risk of dementia. In a recent large cohort study of nearly 2 million people [48], however, both midlife and late-life body mass index were inversely related to the incidence of dementia, suggesting that obesity during midlife is also protective. Again, several methodological issues were suggested to explain these diverse findings [49].

One important finding that dementia researchers have overlooked is that serum concentrations of OCPs, a class of POPs, were recently linked to the risk of dementia and cognitive impairment in the general population [50-52]. Although high doses of OCPs are well known to act as neurotoxins [53], these findings were surprising because their current human body burden is very low after their production and use was banned during the 1970s and 1980s. Therefore, the recent link between OCPs and dementia suggests that chronic exposure to low doses of OCPs can be much more harmful to neuronal function than researchers previously thought. Indeed, the current elderly population is the first generation to have been exposed to these chemicals throughout their lifetimes.

Serum concentrations of OCPs are highly correlated with brain concentrations of OCPs because of the direct transport of OCPs across the blood–brain barrier [52]. Accordingly, the toxicodynamics of OCPs in relation to adiposity and weight change may also explain the confusing results regarding the relationship between obesity and dementia. For example, body weight among the elderly is determined by body weight during middle age and the subsequent changes that occur before late life. Groups of obese elderly might include more individuals who have experienced weight gain than groups of lean elderly, whereas the reverse might be true regarding weight loss. Therefore, with regard to OCPs, a history of weight change may create more favourable conditions for the brains of the obese elderly, an advantage not experienced by the lean elderly. These situations suggest that late-life obesity protects against the risk of dementia.

In fact, even the positive association between midlife obesity and dementia may be explained by the release of OCPs from adipose tissue due to obesity-related insulin resistance rather than adiposity itself. The protective role that midlife obesity plays with regard to the risk of dementia, which was observed in the recent large cohort study [54], supports this speculation. Unless OCPs are significantly released into the bloodstream through insulin resistance, even midlife obesity may not be a risk factor for dementia. Figure 1 presents four scenarios that demonstrate how midlife obesity and weight change after midlife can lead to a positive association with midlife obesity but an inverse association with late life obesity regarding the risk of dementia.

Figure 1.

Four hypothetical scenarios regarding the relationship between obesity and dementia in terms of persistent organic pollutants (POPs). An obese group in middle age (risk score: ‘+’) might have a higher risk of dementia than a lean group (risk score: ‘0’) due to the release of POPs through insulin resistance. However, this association differs in the elderly because the body weights of these individuals are determined by their body weights in middle age and the subsequent changes that occur up to late life. Weight loss (risk score: ‘+’) increases the release of POPs from adipose tissue to the circulation; however, weight gain (risk score: ‘−’) decreases this release. A risk score of ‘0’ is assigned to people with no weight change. Therefore, the risk score for the elderly is the sum of the risk score during middle life and the risk score throughout the weight change. As a result, the mean risk score for two obese elderly individuals is ‘0’ (i.e. the mean of ‘+’ and ‘−’), whereas the mean risk score for two lean elderly individuals is ‘+’ (i.e. the mean of ‘++’ and ‘0’). Therefore, the positive association between midlife obesity and dementia can change into an inverse association between late-life obesity and dementia.

Relatedly, a 25-year longitudinal study [55] showed that mortality was highest among men who were previously overweight and lost weight later in life (scenario 2). This rate was higher than the risk of mortality in consistently overweight men (scenario 1). In contrast, weight gain after middle age (scenario 4) showed no notable effect on the risk of mortality compared with the risk among people who had a normal body weight throughout their lives (scenario 3).

Importantly, unintentional weight loss is commonly observed before the diagnosis of dementia [56], and it predicts the progression from mild cognitive impairment to dementia [57]. This is currently interpreted to be caused by a declining ability for self-care or appetite loss, which usually co-exists with the subclinical progressive loss of cognitive function, rather than a risk factor that contributes to the development of dementia [46]. However, weight loss can directly increase the risk of dementia by releasing OCPs into the bloodstream. In fact, unintentional weight loss is common among patients with various chronic diseases, although it is simply regarded as a marker of poor prognosis. However, regardless of the cause of the weight loss in patients, the release of POPs through unintentional weight loss can worsen their prognosis. Proper nutritional interventions to prevent unintentional weight loss among patients are required.

Possible interventions to increase the elimination of POPs

Notwithstanding the release of POPs from adipose tissue to the circulation during weight loss or insulin resistance, their harmful effects can be minimized if they are more efficiently eliminated from the body. Although a variety of chemicals are excreted through urine, lipophilic chemicals including POPs are primarily excreted in faeces through bile; however, transluminal passive diffusion has also been reported with regard to certain POPs [5, 58]. The reabsorption of excreted POPs through enterohepatic recirculation is one mechanism that can increase the half-lives of POPs [59]. Despite limited direct evidence in humans, several interventions to facilitate the excretion of POPs in faeces can be suggested.

First, bile formation and secretion from hepatocytes is the first step to eliminate POPs from the body. Most of the major transporters and enzymes that determine the mechanisms of bile formation and secretion in hepatocytes have been characterized at the molecular level, offering the opportunity to regulate this process therapeutically [60]. Phytochemicals in some herb or plant food have been reported to increase bile secretion through the synthesis of bile salts, changes in transporter expression/activity and the evocation of signalling pathways [61-64]. A diet rich in phospholipids can also increase bile formation and bile acid transport [65].

Second, bile flow in the intrahepatic and extrahepatic biliary tracts should not be stagnant. Bile stasis for any reason hinders the excretion of POPs from the liver to the intestine. The most common reasons for this phenomenon are gallstone or biliary sludge. Symptomatic gallstones are generally removed, and medications such as ursodeoxychloic acid are used for patients with serious bile stasis [66]. However, chronic mild cholestasis without any symptoms or signs can still disturb the excretion of POPs. Some health behaviour-based approaches have been reported to increase bile flow. For example, time-restricted feeding with intermittent fasting was reported to increase bile flow [67] because the distinct cycle of gallbladder filling and emptying is important to control bile flow [68]. Exercise is another efficient intervention. Chronic physical activity substantially increased the hepatobiliary clearance of endogenous and exogenous chemicals according to animal experiments [69, 70].

Third, Dr Jandacek's research group suggested blocking the enterohepatic recirculation of POPs as a possible intervention [59]. Dietary fibre, nonabsorbable lipids such as olestra or bile acid resins such as cholestyramine reportedly have the ability to absorb POPs in the bile and increase their excretion in faeces [22, 71-75]. With the exception of dietary fibre, however, other strategies (e.g. olestra and cholestyramine) can increase the risk of fat-soluble vitamin deficiencies [76, 77]. Although this potentially adverse effect can be offset by vitamin supplementation, their long-term use might not be desirable. Among the various dietary fibres, the binding effects of whole grains seemed to be the most effective because of their high content of lignins [72]. In contrast to common dietary fibres consisting of polysaccharides, lignins are relatively hydrophobic and aromatic organic polymers, which are important for binding lipophilic xenobiotics such as POPs [78]. However, a prerequisite for the successful enterohepatic recirculation intervention is the efficient excretion of bile to the intestine. If POPs cannot properly reach the small intestine for any reason, then the intervention at the site of enterohepatic recirculation might not be effective.

The dilemma is that POPs can directly impair bile secretion from hepatocytes [79] and induce cholestasis [80]. Therefore, although the elimination of POPs can be increased using some of the interventions described previously, the excessive burden of POPs on the liver still remains problematic. Actually, both obesity and rapid weight loss among obese people increase the risk of cholestasis and gallstone disease [81]. These contradictory findings might also be explained by the release of POPs from adipose tissue through obesity-related insulin resistance or weight loss. Importantly, in addition to POPs, a wide range of pharmacological drugs, especially highly lipophilic drugs, can induce cholestasis [82]. These complications should be taken into consideration when planning long-term pharmacological interventions.

Regarding health behaviours, time-restricted feeding combined with intermittent fasting, exercise and a diet enriched with whole grains and phytochemicals are important to increase the elimination of POPs. Avoiding POP-contaminated animal fat, including fish, is another important dietary habit that can reduce the amount of POPs that enter the body from the environment, especially when a substantial amount of POPs are already released from adipose tissue to the circulation. Interestingly, all these behaviours that decrease the body burden of POPs are very similar to well-accepted health-promoting behaviours. As they seem to be effective for weight loss as well, the health behaviours to decrease the body burden of POPs can be adopted as the healthiest method of weight loss for obese persons. One difference is that although fish is generally recommended as a healthy food as the best source of omega-3 fatty acids, it is also a significant source of POPs [83]. The recent contradictory epidemiological findings concerning the health effects of fish consumption can also be explained by the mixed effects of the beneficial nutrients and harmful chemicals contained in fish [84, 85].

Obesity-inducing effects of chemicals (obesogens)

The rise in global obesity rates over the last several decades has been substantial and widespread [86]. The aetiology of the obesity epidemic has been hotly debated [87], but the common belief is that changes in body weight and adiposity are the results of chronic positive energy balance, meaning that energy expenditure is less than energy intake. However, obesity-inducing effects of many EDCs have recently become an important piece of the obesity epidemic puzzle [88].

Exposure to obesogenic chemicals can predispose animals to accumulate more fat, and these effects can be transmitted to their descendants [89]. Obesogens typically act at low, environmentally relevant doses (often below the no-observed-adverse-effect level) during critical windows of prenatal or postnatal development to promote obesity later in life [89]. Different obesogenic compounds may have different mechanisms of action, some of which might affect the number and size of fat cells or the hormones that affect appetite, satiety, food preferences and energy metabolism [90].

In addition to compounds classified as POPs, several dozen EDCs have now been shown to cause weight gain [90]. For example, plasticizers and plastics, organophosphate pesticides, fungicides, flame retardants, and smoking and nicotine have all been linked to obesity in animals [90]. Certainly, however, this figure could be just the tip of the iceberg as there are close to 800 chemicals known or suspected to be capable of acting as EDCs [91]. Moreover, only a small portion of the more than 85,000 chemicals included in the US Toxic Substances Control Act inventory have been evaluated for potential EDC activity [92].

However, the obesity-inducing effects of chemicals need to be re-evaluated from the viewpoint of the protective role of adipose tissue against POPs and other lipophilic chemicals. This can represent adaptation of living organisms to secure a relatively safe reservoir for lipophilic chemicals such as POPs. Although the chemicals acting as obesogens can be detrimental to health through a variety of other pathways, their obesogenic effects themselves, especially the adipogenesis-promoting effect, might not be as harmful as researchers are currently speculating. On the contrary, chemicals that suppress adipogenesis might be more harmful than obesogens as they may diminish the safe storage site for unavoidable lipophilic chemicals in chemical-contaminated modern societies.

Conclusions

Realistically, the toxicodynamics of POPs cannot be separated from the dynamics of adipose tissue. Additionally, the possible health effects of obesity and weight change differ with respect to fat mass and POPs. In the context of fat mass, obesity, especially with insulin resistance, and weight gain are found to be harmful. However, in the context of POPs, obesity with insulin resistance and weight loss are found to be harmful, but obesity without insulin resistance and weight gain could be beneficial; most effects of POPs are opposite to those commonly expected in obesity. These observations may help to explain the puzzling findings obtained from epidemiological studies considering only adiposity-related factors. Figure 2 summarizes how POPs, adiposity and weight change interact with each other. Importantly, POPs may explain the possible health effects even from the viewpoint of fat mass through pro-inflammatory changes in adipose tissue, which would be related to the release of POPs from enlarged or necrotic adipocytes to interstitial spaces.

Figure 2.

The relationship between adipose tissue and persistent organic pollutants (POPs). When people are exposed to the same amount of POPs, people with more adipose tissue have an advantage over those with less adipose tissue because the former have a more sufficient and safe reservoir to store harmful chemicals in the absence of insulin resistance (scenario 1: S1). However, when insulin resistance develops (scenario 2: S2) and weight loss occurs (scenario 3: S3), the release of POPs from adipose tissue into the circulation increases, which increases the risk that POPs will reach critical organs. However, weight gain reduces this possibility (scenario 4: S4). The viewpoint of fat mass may also be explained by POPs because the release of POPs from enlarged or necrotic adipocytes to interstitial spaces can induce pro-inflammatory reactions in adipose tissue and related pathological changes in other organs.

Currently, most of the studies on obesity and weight change do not consider the role of POPs. Because chronic exposure to low levels of POPs has emerged as a risk factor of many diseases of the endocrine, immune, nervous and reproductive systems, future epidemiological and experimental studies should consider that, in modern societies, the adipose tissues of both humans and experimental animals are widely contaminated with POPs. Gut microbiome composition, the latest research topic linked to obesity and obesity-related diseases [93], can be also influenced by the presence of various xenobiotics like POPs in faeces [94-96].

Although specific designs differ depending on the purpose of the study, POPs should be measured in future studies that evaluate the health effects of obesity and weight change. If the measurement of POPs is impossible for practical reasons, then POPs should at least be considered in the interpretations of the findings. Well-designed human interventions seeking to increase the elimination of POPs should have a high priority in future research even though it can be technically difficult to measure the elimination of POPs. Even though faeces are the main POPs excretion route, POPs in faeces may not be accurately measured because they would not be homogenously distributed across the total mass of faeces and only a small part of faeces can be practically collected for the measurement of POPs in human studies.

One troublesome issue is that POPs, in addition to contaminating the food consumed by humans, have contaminated laboratory animal diets [97]. The fact that these diets are polluted with low-dose POPs and other toxic environmental chemicals has enormous consequences for current practices in biomedical research [97]. Finally, if weight loss is planned for any reason, then the magnitude and rate of weight loss should be adjusted and the interventions to increase the elimination of POPs should be considered to minimize the potential health hazards caused by their release.

Conflicts of interest statement

No conflict of interest statement.

Acknowledgements

This study was supported by the Korean Health Technology R&D Project (HI13C0715), funded by the Ministry of Health and Welfare; and the Environmental Health Action Program (2016001370002), funded by the Korea Ministry of Environment of the Republic of Korea.

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