Adipose Tissue Pollutants And Obesity

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Author(s):

	Robert Barouki
	Robert Barouki is a biochemist and molecular biologist whose main research focus during the last fifteen years has been understanding the mechanisms of toxicity of environmental pollutants such as dioxin.
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	Jean-Philippe Antignac
	Dr. Jean-Philippe Antignac is engineer and PhD graduated in analytical chemistry, and a scientist belonging to the National Institute of Agronomic Research (INRA).
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	Claude Emond
	Clinical Assistant Professor in the Department of Environmental and Occupational Health at the University of Montreal, Canada, and Associate Professor at the ISE at the UQAM.
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	Karine Clément
	Prof Karine Clément is full professor of Nutrition, Division of Cardiometabolism, Pitié-Salpêtrière university hospital, Paris 6 Pierre et Marie Curie university, Paris.
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	Linda Birnbaum
	Linda S. Birnbaum, Ph.D., is director of the National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health, and the National Toxicology Program (NTP).
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	Michele La Merrill
	Michele La Merrill conducts integrated toxicological and epidemiological studies to understand susceptibility to environmental diseases.
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	Min Ji Kim
	Min Ji Kim studied, during her PhD, the adipose tissue dysfunctions in obesity and antiretroviral therapy-induced lipodystrophies at the University of Paris 6 and at INSERM.
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	Bruno Le Bizec
	Prof. Dr. Bruno Le Bizec, is graduated from Nantes University as a Doctor in Analytical Chemistry (PhD, 1995).
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Summary

During the last decades there has been a dramatic increase in obesity world-wide. There are several reasons for such an increase, including diet and lifestyle. Recently toxicological and epidemiological evidence pointed to a likely contribution of environmental pollutants which has led to the obesogen concept. Perinatal exposure to several endocrine disruptors leads to increased body weight later in life as well as to several metabolic disorders, which may partially contribute to the obesity epidemics and interact with other risk factors. Additionally, there is evidence that pollutants such as persistent organic pollutants (POPs) trigger an inflammatory phenotype in the adipose tissue (AT) thereby enhancing the pathological consequences of obesity. The AT also plays a role in the toxicokinetics of POPs since it can store these chemicals for a long time and, in that sense, may be protective during acute exposure. However growing evidence suggests that these chemicals can be released from the AT at a low level. Thus, this tissue constitutes an endogenous source of chronic exposure to POPs.

Introduction

Non-communicable diseases have considerably increased worldwide during the last decades (1). The increase in obesity prevalence is particularly relevant since it is a commonly known risk factor for disorders such as impaired glucose tolerance, metabolic syndrome, diabetes mellitus, liver and cardiovascular diseases (CVD), as well as some cancers (2). The adipose tissue (AT) of obese individuals is quantitatively much larger and includes more pathological features, than that of lean individuals. Much of our understanding of the interaction between obesity and environmental pollutants is largely focused on the AT. Historically, the AT was considered as a simple storage tissue. However, its physiological functions have been considerably reassessed over the last decade (3). Evidence for metabolic, endocrine and immune functions of the AT including stroma has accumulated. Greater attention is now given to the pathological contribution of the AT to obesity and metabolic disorders such as type 2 diabetes. Lately, various interactions between the AT and certain pollutants such as the persistent organic pollutants (POPs) have been established suggesting that this tissue plays a significant role in the kinetics and the toxicity of POPs.

This review will summarize recent observations on the interaction of POPs with AT and obesity (for more details, refer to 4, 5). POPs cannot be metabolized by the xenobiotic metabolizing system and therefore tend to accumulate in ecosystems and in living organisms. The best studied are those which were listed in the Stockholm convention to limit their production and dissemination because of their possible long term toxicity (5, 6). POPs include certain organochlorine pesticides, dioxins, furans, polychlorobiphenyls and polybrominated flame retardants. They do not readily undergo degradation by xenobiotic metabolizing enzymes (XMEs), because of their bulk and halogenation. However, they do activate certain xenobiotic receptors, and some bind to certain XMEs such as CYP1A2 without undergoing catalytic transformation. Because of their hydrophobicity, POPs tend to distribute into lipid rich tissues such as the AT and milk.

We can now consider that, in addition to its other metabolic and endocrine functions, the AT has an identified and diverse toxicological function. First, the AT is a target of several chemicals which alters its functions, increase inflammation, and/or modulate the differentiation of precursor cells. For instance, obesogens are exogenous chemicals (food contaminants, pharmaceuticals, personal care products, or environmental toxicants) that directly or indirectly increase obesity through disruption of metabolic, hormonal, or developmental processes (7,8). Second, the AT can store a variety of hydrophobic xenobiotic chemicals, in particular POPs. Third, AT also constitutes a low-grade internal source of stored POPs leading to continuous exposure of other tissues. In this review, we discuss the interaction between pollutants and obesity with a focus on the complex, previously unsuspected, role of AT in toxicology.

The Obesogen Concept

Exposure to certain pollutants during particular windows of vulnerability has been shown to increase AT mass and contribute to obesity later in life. Development, e.g. prenatal, postnatal, and pubertal, is likely a critical window of susceptibility to obesogen effects of toxic exposures (9) (figure 1). Programming mechanisms are still unclear (see below), but are believed to involve epigenetic regulation of critical genes that lead to adiposity later in life (10, 11). Evidence suggests that developmental exposures to chemicals that increase risk of obesity sometimes operate in a non-monotonic dose-response manner; cachexia may occur at high doses whereas body and/or adipose mass gain occurs at low doses of the same chemical. Further, there may be gender specific effects of developmental toxic exposures that increase the risk of obesity (12). Developmental exposures to these same POPs are positively associated with obesity in humans (4, 5).

Figure 1: Model representing the effect of pollutants on AT. Exposure to several chemicals called obesogens during the perinatal period leads to the development of obesity later in life. The mechanisms of this programing effect have not been delineated, however, it is believed that epigenetic regulations are involved. Pollutants, particularly POPs, can also interfere with AT biology either by increasing inflammation or through metabolic disruption and thereby contribute to the appearance of pathological side effects of obesity. Such mechanisms may also take place at the adult stage and are therefore distinct from the obesogen effects.

Obesogens are frequently endocrine disruptors and belong to several chemical families. Several studies have been carried on POPs which are either dioxin-like (DL), ie they mimick the effect of dioxin on the dioxin receptor, AhR, or non DL. Rodent models indicate that DL chemicals may be obesogens. Exposure to TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), 100 µg /kg b.w. once every 2 weeks for 8 weeks, increased body weights of adult mice over 40% higher than control-treated C3H/HeN mice (13). This body weight change was only seen when mice were fed a high fat diet. In a one-month study, chronic developmental exposure to the PCB mixture Aroclor 1254 was associated with increased body weights of mouse pups on postnatal days (PND) 16-20 (14). Further, exposure of adult mice PCB-77 led to an AhR dependent increase in body mass (15). This PCB-77 exposure also increased fatty liver in CVD model mice (16). Fatty liver, attributed to increased hepatic triglycerides and cholesterol, was also caused by 50 mg of PCB-169/kg body weight (17).

There is limited evidence of increased adiposity in animal studies of POPs that are not DL, however body fat is seldom assessed in studies reporting no increased body mass after POP exposure (9). Prenatal exposure to a major polybrominated- diphenyl ether (PBDE-99, 2,2’,4,4’,5-penta-BDE) increased mouse birth weight (18), and pre- and postnatal exposure to BDE-47 (2,2’,4,4’-tetra-BDE) increased rat body weights from birth to puberty (when the study ended) (19). In the longest study of developmental PBDE exposure to examine body weights, male mice exposed to BDE47 10 days after birth had increased body weights from PND 47 until the end of the study, at 4 months of age (20). These studies indicate significant body composition effects of perinatal exposure to PBDEs, however the mechanisms remain unclear and the data should be interpreted with caution as certain preparations of BDEs could be contaminated with DL chemicals. In perinatal exposure to perfluorooctanoic acid (PFOA) which is not a traditional POP, obesogenic effects do not appear until later in life. Mice exposed to low levels of PFOA in utero had increased body mass once mature, with an inverted U shape dose response curve (21). By 18 months of age, there was no longer an effect on mouse weight, however, there was a positive dose response relationship between in utero PFOA exposure levels and abdominal brown AT mass in the aged mice, whereas a negative relationship was found with white AT mass. Consistent with experimental findings, a recent prospective human study demonstrated that maternal PFOA levels during pregnancy were associated with obesity in the daughters 20 years later (22). Organochlorine pesticides may also increase adiposity. For instance, oral DDT exposure increased the body weights and/or adiposity of both mouse and rat offspring in several multi-generational studies (11, 23, 24).

Several studies assessing obesogenic effects were devoted to other pollutants which are not persistent, particularly endocrine disruptors. Much effort was devoted to Bisphenol A (BPA), and, in many cases, perinatal exposure to BPA was shown to lead to increased body weight later in life (reviewed in 25 and 26). Non monotonic curves were sometimes observed. However, the effect of BPA was not always consistent, suggesting that specific experimental conditions were required to unravel the obesogenic effects of BPA. This could be interpreted as suggesting that the interaction of this chemical with other environmental factors such as diet is critical for the obesogenic effect to be observed. Human studies recently demonstrated that fetal exposure to BPA was associated with increased BMI in 4 years old children (27). Another well studied obesogen is tributyltin (TBT). Perinatal exposure to TBT leads to increased adipose mass transgenerationally (28, 29). These effects have been related to the activation by TBT of the PPARg/RXRa heterodimer and with a possible involvement of epigenetic effects. The effects of more complex exposures such as maternal smoking and air pollution, which also correlate with offspring obesity, will not be discussed here.

Are metabolic consequences of obesity induced by pollutants?

Obesity causes predisposition for other metabolic diseases such as type 2 diabetes and and metabolic risk features such as moderate elevation of glycemia, hypertriglyceridemia or low HDL. Several epidemiological studies carried following industrial exposure of workers or accidental contamination by POPs indicated a relationship between serum concentration of certain POPs and markers of diabetes or of a prediabetic state. This is the case of the Seveso cohort in which increased metabolic syndrome (but not obesity) was observed in women exposed to dioxin before the age of 12 (30). Such a correlation was also found in a large study carried in the general population (31). Prospective studies in the elderly have also indicated a possible role of certain POPs in the pathogenesis of type 2 diabetes (32). There are also some experimental studies clearly correlating POP mixtures with metabolic syndrome occurrence in the rat (33). A National Toxicology Program workshop concluded that POPs were associated with type 2 diabetes but that no causal relationship could be established at this stage (34). A recent study indicated that metabolically healthy but obese individuals had lower plasma levels of several classes of POPs than obese individuals with metabolic abnormalities (35). Other pollutants were also associated with metabolic diseases but only POPs have been discussed here.

The interactions between obesity, POPs and metabolic disruption were unraveled in several mechanistic studies. Because of the implication of the AT in metabolic diseases, it was hypothesized that this tissue could be a target of POPs and indeed, several effects were found. Its vulnerability may be due to its ability to accumulate POPs as we will see later. Most of the studies were in vitro or ex vivo, but recently the effect of POPs on the AT of rodents was also assessed. POPs were shown to display anti-insulin effects in cellular models of adipocytes. For example, dioxin repressed the glucose transporter Glut4 expression and lipoprotein lipase in 3T3-F442a cells (36). This anti-insulin effect is not general and consistent for all genes. Indeed, whereas dioxin was found to antagonize insulin action on certain genes such as the IGFBP1 gene in hepatocytes (37), it displayed a different effect on other genes such as the liver PEPCK gene, since it tended to inhibit gluconeogenesis in this tissue, similarly to insulin (38).

Inflammation of the AT is one of the hallmarks of obesity and inflammatory phenotype is critical in metabolic diseases. POPs have been shown to induce proinflammatory genes in rodent adipose cells (36). We found similar effects in human adipocytes (39). Importantly, in mice treated with dioxin, not only the gene expression of proinflammatory genes was increased, but also invasion of this tissue by macrophages and lymphocytes was observed (39). Finally, dioxin was shown to inhibit the differentiation of adipocyte precursor cells in certain model systems and to antagonize the effects of PPARg. However the actual mechanisms remain elusive (40). In conclusion, preadipocytes and adipocytes are targeted by POPs which appear to disrupt certain signaling and differentiation pathways and to induce inflammation.

Is there a protective role of AT and obesity?

As mentioned earlier, the AT is a compartment which contains a high amount of POPs, particularly in organisms that are at the top of the food chain. Such a bioaccumulation leads to the age-dependent increase in POP content (41). POPs are taken up by adipocytes and localize within lipid droplets (42). However their precise location and their actual effects at the subcellular level are poorly understood. It is nevertheless believed that their accumulation within the AT decreases their availability for other cells and tissues thereby limiting their toxicity. Experimental evidence supports such a protective function for the AT. Indeed, studies carried in the 80s and the 90s showed that there was an inverse correlation between toxicity of POPs and fat mass of different animal species. Authors compared the 30-day toxicity of TCDD in approximately twenty terrestrial animal species and found a positive correlation between the BMI of these species and the LD50 (the dose that leads to 50% death in the animal population) of dioxin (43). They concluded that the species with the highest fat mass tended to display better resistance to dioxin in this particular acute exposure test. These conclusions were in line with studies showing that resistance of aquatic species to dioxin was also related to their fat mass leading to the paradoxical notion of “survival of the fattest” (44). However, these observations should not be taken as evidence suggesting that the BMI is the only factor discriminating sensitive and resistant species. There is indeed strong evidence for a major contribution of the genetically determined arylhydrocarbon receptor affinity for dioxin.

It should be stressed that this protective function of the AT was revealed in acute or subacute exposure tests. These high dose treatments may allow the distribution of the pollutants to all tissues unless an efficient “filter” or a buffer system can capture them, thereby decreasing exposure of the most sensitive tissues. This role is played by the partitioning of POPs into lipid-rich tissues. This kinetic protective system does not only include the AT. Indeed, it has been established that proteins such as the dioxin-inducible liver CYP1A2 can bind this pollutant particularly during acute or subacute exposures and play an important role in its toxicokinetics (45). It is now believed that POPs are first distributed throughout the body and then captured by the liver inducible protein compartment, with excess then redistributed to the AT. Obviously, these kinetic distribution mechanisms depend heavily on the treatment dose and the body burden (46). Furthermore, in several metabolic disorders, lipid droplets are found in other tissues such as liver, muscle, heart, etc. with possible consequences related to POP storage.

AT could also be involved in the higher blood half-life of POPs in children. Indeed, newborns have a high body burden due to placental transfer during pregnancy and to breast-feeding. A higher blood elimination rate observed for the children compared to the adults might be explained by the dilution of the POPs across tissues like the AT rather than a higher metabolic rate.

There is some indirect evidence for a protective role of AT from human studies. The association between fat mass and mortality depends on the serum concentration of POPs. Indeed, in those individuals with low POP concentration, mortality increased with fat mass, whereas in those with high POP concentrations, mortality tended to paradoxically decrease with fat mass (47). These observations can be accounted for by a protective function of the AT which becomes significant at high levels of POP contamination.

Is the AT a source of endogenous exposure?

As mentioned earlier, POPs and other lipophilic contaminants distribute according to their affinity for proteins and lipids and are stored primarily in the liver and the AT. They are also found in blood from which they can contaminate other tissues. Blood POP content can be either related to their release from storage tissues or to recently absorbed pollutants. Several observations in both human and animals suggest that the release of pollutants from the AT is an important source of blood POPs.

In humans, most of the evidence has been gathered from studies on drastic weight loss in obese individuals. Such a weight loss can be achieved voluntarily through diet and bariatric surgery and could lead to a decrease of up to 30 kg of fat mass or even more in some cases. Several independent studies have shown that there was an increase in blood POPs following fat mass loss elicited by either diet alone or diet coupled with bariatric surgery (48, 49). If increased blood POP levels during weight loss is related to their release from AT, one would expect changes in POP content of this tissue. This has been addressed by Kim et al (49) who determined POP concentrations in both blood and AT and who also assessed the total amount of fat in the studied individuals. The data indicate that POP concentration in AT (expressed per gram lipid) increases with weight loss. While this may seem paradoxical, it is not particularly surprising since the total amount of fat mass decreases considerably thereby leading to an increased concentration of pollutants, e.g. released POPs can be taken up readily by the remaining fat. In line with these suggestions, we observed that POP concentrations in the AT of obese individuals is lower that that of lean individuals. However, the total amount of fat-stored POPs is 2- to 3-fold higher in obese individuals as compared to lean controls. Furthermore, this total amount tends to decrease by 15% following weight loss at least for certain POPs. This observation suggests that there is indeed some degree of POP release from AT during weight loss and that this release leads to a moderate decrease in total POP content.

Experimental evidence also suggests redistribution of POPs from their storage sites in the AT. Indeed, a study shows that in rodents pretreated with radiolabeled hexachlorobenzene, weight loss leads to a time-dependent increase in the brain content of this compound (50). The study shows that weight loss alters the distribution of lipophilic pollutants, thus leading to enhanced localization in the brain and other sensitive tissues with possible toxic outcome.

Observational studies were also carried in northern elephant seals. These animals accumulate a large amount of fat in order to cope with extended fasting. Their fat is contaminated with PCBs. During the fasting period which could last several weeks, they lose a large amount of fat. Debier et al (51) have shown that an increase in serum concentration of PCB during fasting which is likely due to their release from fat depots. Interestingly, the concentration of PCBs also increased in some of these depots (blubbers) because of the decreased fat content. However, different fat depots did not undergo similar changes, suggesting differences in the kinetics of POP exchange and release. It is suggested that the release of POPs during fasting may lead to toxic effects.

A critical issue is whether the release of POPs from AT observed during weight loss could lead to toxic outcomes in other organs and tissues. Indirect evidence was obtained in humans from several studies of weight loss triggered by either diet or diet associated with bariatric surgery. We have shown that the dynamic increase in serum POPs following drastic weight loss correlated with a delayed and reduced improvement of blood lipid parameters and liver toxicity biomarkers (49). Correlations between blood POP concentrations and other clinical parameters such as metabolic and muscle parameters, were also observed in humans by the group of Tremblay who conducted seminal studies in this field (52).

Conclusion and Hypothesis

Figure 2: Fate of a persistent organic pollutant (POP). Most xenobiotics are metabolized primarily by the liver and are thus detoxified. The detoxification system tends to render hydrophobic xenobiotics more hydrophilic which leads to their elimination in urine. Several halogenated xenobiotics are not metabolized and therefore tend to bind to liver proteins and to adipose mass. They can thus persist for years in the body and constitute a putative long term threat since they can be released from these compartment at low levels.

The AT appears to play critical roles in the kinetics of POPs and in their pathogenic effects. It has a major role, together with the liver protein compartment in storing POPs and in preventing their distribution into more sensitive tissues. However, the AT storing capacity is constitutive and not inducible. This kinetic system acts as a buffer during acute or subacute exposure conditions. However, it translates an acute exposure into a long term, low-grade internal exposure (see figure 2). It thus transforms an immediate threat into a latent chronic threat. This buffer system perfectly illustrates a previously developed hypothesis (53) which proposes that systems that protect from acute exposure to xenobiotics contribute to their chronic toxicity. In addition to these functions, the AT constitutes a target of POP toxicity. Indeed, the main toxic effect triggered by these compounds is inflammation which is a well known risk factor for metabolic diseases. These observations support the contribution of POPs to metabolic diseases and suggest that AT alteration could at least partially mediate these effects.

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