Obesity additives

What Are We Putting in Our Food That Is Making Us Fat? Food
Additives, Contaminants, and Other Putative Contributors to Obesity
Amber L. Simmons, PhD1, Jennifer J. Schlezinger, PhD2, and Barbara E. Corkey, PhD1,*
1Department of Medicine, Boston University Medical Center, 650 Albany St., Rm X810, Boston
MA 02118, Tel.: 617-638-7088, Fax.: 617-638-7124, simmons1@bu.edu
2Department of Environmental Health, Boston University School of Public Health, 715 Albany St.,
Rm R405, Boston, MA 02118. Tel.: 617-638-6497 Fax.: 617-638-6463. jschlezi@bu.edu
The “chemical obesogen” hypothesis conjectures that synthetic, environmental contaminants are
contributing to the global epidemic of obesity. In fact, intentional food additives (e.g., artificial
sweeteners and colors, emulsifiers) and unintentional compounds (e.g., bisphenol A, pesticides)
are largely unstudied in regard to their effects on overall metabolic homeostasis. With that said,
many of these contaminants have been found to dysregulate endocrine function, insulin signaling,
and/or adipocyte function. Although momentum for the chemical obesogen hypothesis is growing,
supportive, evidence-based research is lacking. In order to identify noxious synthetic compounds
in the environment out of the thousands of chemicals that are currently in use, tools and models
from toxicology should be adopted (e.g., functional high throughput screening methods, zebrafishbased
assays). Finally, mechanistic insight into obesogen-induced effects will be helpful in
elucidating their role in the obesity epidemic as well as preventing and reversing their effects.
obesity; BPA; bisphenol A; food additives; preservatives; pesticides; plastics; pollutants;
Since the industrial revolution, the goals of food technology have predominately been
maximizing palatability, optimizing process efficiency, increasing shelf life, reducing cost,
and improving food safety (free from harmful viruses, bacteria, and fungi). As such, over
4,000 novel ingredients have entered the food supply, some intentionally (such as
*Corresponding author: bcorkey@bu.edu.
Conflict of Interest
Amber L. Simmons, Jennifer J. Schlezinger, and Barbara E. Corkey declare that they have no conflict of interest.
Compliance with Ethics Guidelines
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
NIH Public Access
Author Manuscript
Curr Obes Rep. Author manuscript; available in PMC 2015 June 01.
Published in final edited form as:
Curr Obes Rep. 2014 June 1; 3(2): 273–285. doi:10.1007/s13679-014-0094-y.
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preservatives) and some inadvertently (such as bisphenol A, BPA), and there are 1,500 new
compounds that enter the market every year [52]. While food processing techniques are also
constantly being optimized to minimize toxic compounds and toxicants such as lead,
melamine, and aflatoxin, other “non-toxic” additives are not thoroughly tested for their
chronic, additive, and/or cumulative effects on human physiology.
Obesity and related chronic disorders are increasing at alarming rates and it is estimated that
86% of Americans will be overweight by 2030 [53]. This trend continues despite increases
in awareness, nutritional and behavioral research, the amount of diet foods available, and
even gym memberships [54]. Unfortunately, the etiology of obesity and diabetes in regard to
biochemical mechanisms is still largely not understood. Treatment and prevention of obesity
hinges on our ability to 1) characterize the biochemical pathways that promote obesity, 2)
identify what changes in our environment are promoting obesity, and 3) avoid and reverse
the effects of the offensive agents and practices. It is crucial that clinicians understand and
communicate that most novel food ingredients have not been evaluated for metabolic safety.
In this review, we outline what agents have been identified that may be contributing to
obesity, describe current methods being used to identify offensive compounds, and identify
critical gaps in our methods and body of knowledge.
The importance of identifying agents that contribute to obesity
There is an abundance of research related to obesity etiology and prevention in regard to
decreasing caloric intake and increasing energy expenditure. However, “non-traditional” risk
factors are under increased scrutiny for their contributions to the obesity epidemic:
emotional stress, sleep deprivation, disruption of normal circadian rhythm, composition of
the gut microbiome, oxidative stress, medications such as antidepressants and oral
contraceptives, average home temperature, and environmental toxicants [24••,36•,55].
Agents in our food supply have immense potential to affect metabolism due to continuous
exposure and potential interactions among multiple compounds. A recently hypothesized
factor contributing to the obesity epidemic is our exposure to obesogens, chemicals in our
environment that can disrupt metabolism and lead to accumulation of excess fat mass
(coined by Grün and Blumberg in 2006 [27]). It is critical that we identify these obesogens
in our food supply in order to facilitate obesity prevention and treatment [34].
Unfortunately, many of the obesogenic compounds in our food supply were added
deliberately to enhance production instead of being added to enhance nutrition. For
example, pesticides are added to ward off insects during farming; BPA is a strong, clear
plastic that has ideal properties for making bottles and coating cans; and mono- and
diglycerides are added to emulsify the fat and water in foods to achieve a favorable texture.
Simple exclusion of these compounds may not be possible until alternatives are developed,
but then these novel compounds must be tested. Like pharmaceuticals, thorough testing is
time-consuming and expensive.
Obesogen identification and characterization is in its infancy, and much of the scientific
evidence supporting the relationship between synthetic compounds and the obesity epidemic
is currently weak. Strong, evidence-based scientific support is derived from randomized,
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controlled trials, ideally cross-over design, that comprise four steps: 1) addition of the
compound of interest, 2) observation of an effect, 3) removal of the compound of interest,
and 4) disappearance of the effect. However, the bulk of evidence relating environmental
contaminants and obesity is derived from epidemiological studies which are correlational by
nature. While correlations are important, they are limited in that conclusions about causal
relationships are impossible. Well-designed animal studies provide strong evidence within
the animal model, but must be confirmed in humans. Cell studies are important for deriving
mechanisms that may link certain compounds to obesity, yet provide only weak evidence for
the global phenomenon (the obesity epidemic). Thus, we currently do not have any strong
evidence that any contaminant, food additive, or ingredient that is “generally recognized as
safe” (GRAS) causes obesity, which is essential for making confident recommendations and
changes in public policy.
It is important to note that in evaluating foods for their contribution to obesity, we may
identify ingredients that prevent obesity. For example, some hydrocolloids including guar
gum and β-glucan may be able to increase satiety and reduce caloric intake with their
bulking properties [56]. Also, anthocyanins (potent color compounds from grapes, purple
corn, blueberries, and other plants) may reduce oxidative stress, prevent obesity, and help
control diabetes in cell culture, animal models, and humans [57]. Again, not all compounds
in a class are equal; for example, although the hydrocolloid guar gum may prevent obesity
(mentioned above), another hydrocolloid called carrageenan, found commonly in chocolate
milk and ice cream, may contribute to insulin resistance in mice [58].
What in our food is making us fat?
There are many aspects of the average Western diet that may promote obesity. The
macronutrient ratio (fat:carbohydrate:protein), the characteristics of the fat (e.g., diets rich in
palmitic acid vs. eicosapentaenoic acid), the characteristics of the carbohydrates (refined vs.
whole grain carbohydrates) [2,59], and form of the protein [60] are major concerns and
reviewed elsewhere [2,59-63]. In addition, advances in food processing have facilitated
consumption of high caloric food that is low in other nutrients (e.g., edible oils, refined
grains) [61] as well as increased the glycemic load of common meals [62]. Increased
consumption of nutrient-poor added fat, added sugar, added salt, and refined grains may also
underlie obesity and co-morbidities in ways that extend beyond energy balance [63]. Baillie-
Hamilton announced a well-received hypothesis in 2002 highlighting the potential for
environmental compounds in our food to contribute to the obesity epidemic [55]. While the
relationship between obesity and food structure is reviewed elsewhere [59-63], herein, we
will focus on potential obesogens and obesity-promoting food additives in our foods supply

Fat: Saturated fat and trans-fat
The negative social stigma around saturated fat stems from studies correlating high intake of
saturated fat, often from meat and cheese, with elevated risk of unhealthy weight gain,
cardiovascular disease, insulin resistance and type 2 diabetes [2]. However, more
comprehensive studies have revealed that this nutritional advice is oversimplified and
misleading; lauric acid (C12:0) and stearic acid (C18:0) may not be as harmful as myristic
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acid (C14:0) and palmitic acid (C16:0) in regard to cardiovascular health [2]. Moreover,
saturated medium chain fatty acids such as caproic acid (C6:0), caprylic acid (C8:0), and
capric acid (C10:0) may even promote fat oxidation [64]. The science of macronutrient
intake is very complex; replacement of saturated fat with other nutrient categories (e.g.,
monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), high vs. low
glycemic index carbohydrates,) often yields disparate results due to a variety of confounding
factors (e.g., age, lifestyle factors) [2]. Thus, although we know that there are some aspects
and some types of saturated fat that promote obesity, particularly in rodents, it is not
appropriate to view all saturated fat as metabolically similar in humans.
Trans-fat, although inherent in bovine milk at about 0.85 g/kg and other natural foods, is
consumed in much larger quantities from partially hydrogenated vegetable oil [3]. Partial
hydrogenation of oil yields a solid (often soft and spreadable) fat at room temperature. It is a
common ingredient in fried foods, high-fat bakery products (especially packaged cookies
and cakes), and packaged frozen foods such as pizza and breaded chicken nuggets. Based on
a meta-analysis of four prospective cohort studies, an increase of 2% energy from trans-fats
(i.e. 5 g in a 2000 kcal diet) is associated with an increase in the risk of coronary heart
disease by 23% [3]. In the same vein, there is strong evidence that trans-fat consumption is
associated with increased adiposity in monkeys [4] yet randomized, controlled clinical trials
in humans have not been performed.
Food additives and ingredients “generally recognized as safe” (GRAS)
The FDA maintains a database with “Everything added to food in the U.S.” (EAFUS) [52].
As of January 2014, the database includes 3,968 additives with varying regulatory statuses.
Some of these ingredients are food additives approved by the FDA and others are GRAS
(i.e. they have demonstrated safety through long-term use in the food supply and/or
published studies). While many ingredients have undergone an extensive literature search
for toxicology information, most of the items on this list have not been evaluated for effects
on metabolic regulation. Artificial sweeteners, preservatives, monosodium glutamate
(MSG), mono-oleoylglycerol (MOG) and others have demonstrated potential lipid
accumulation effects (see Table 1). There are scores of other compounds that are used
generously in our food but have not been evaluated for effects on key metabolic pathways
(Table 2).
High intensity sweeteners are studied most often when comparing consumption of sugarsweetened
beverages to consumption of beverages with calorie-free (or low calorie) artificial
sugars with the assumption that artificial sugars are inert. However, Kyriazis et al.
demonstrated that saccharin can potentiate glucose-stimulated insulin release from isolated
pancreatic β-cells via direct binding to the sweet taste receptor [65]. Additionally,
aspartame, in combination with MSG, promoted fat accumulation and other pre-diabetic
symptoms in C57BL/6 mice [66]. On the other hand, the high intensity sweetener stevia has
the potential to treat insulin resistance in mice [67]. Recently, artificial sweeteners have been
shown to resist breakdown during sewage treatment, thus persisting in the water system
[68]. Formidably, irradiation of acesulfame (sold as acesulfame potassium, AceK) by
sunlight can cause a persistent by-product that is greater than 500 times more toxic than
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AceK per se [68]. Taken together, prudent analyses of the effects of artificial sweeteners in
humans and in the environment are crucial in light of their wide-spread use and potential
hazard to health.
Artificial colors (dyes) are used in many foods including candy, fruit-flavored drinks, many
breakfast cereals marketed to children and, not as obviously, in packaged foods containing
fruit (e.g., blueberries in blueberry muffins), vitamin supplements, and even white
marshmallows. There are nine artificial colors approved for use in the U.S. (see Table 2),
plus Citrus Red #2, permissible for citrus rinds, and Orange B, allowed in hot dogs and
sausage casings. In fact, use of artificial food colors per capita has increased almost five-fold
between 1950 and 2010 [69]. This may be important because research has suggested that
consumption of artificial colors can reduce attention and increase hyperactivity in sensitive
children [69]. However, research correlating artificial color consumption with obesity is
scarcer. Amin et al. did not observe an increase in weight gain in rats consuming “low” (15
mg/kg body weight) or “high” (500 mg/kg) concentrations of tartrazine for 30 days [70],
though they did observe alterations in the circulating redox state, which could affect weight
gain later in life [71]. Axon et al. discovered that tartrazine and sunset yellow bind the
estrogen receptor, thus exhibiting potential to disrupt endocrine function [72]. More
investigation into the molecular effects of these compounds, particularly in human cells, is
crucial in light of their ubiquity in the food supply, increased consumption, and potential for
adverse metabolic effects.
Plastics interact with our food supply via numerous points of production, packaging, or
transporting. Plastic components (e.g., BPA, phthalates, organotins) leach into food and
beverages, especially at high temperatures. Plastic components, along with many pesticides
and other persistent organic pollutants (POPs), share a similar mode of action in the etiology
of obesity in that they disrupt endocrine communication. Endocrine disrupting compounds
(EDCs), by definition, mimic hormones and/or interfere with the production, release,
metabolism, or elimination of endogenous hormones. Because many EDCs are lipid soluble,
they can accumulate in tissue and thus biomagnify as they traverse the food chain (e.g.,
humans consume and accumulate compounds that were consumed and accumulated by fish),
thereby having enduring effects. Moreover, because of their liberal use, understanding
interactions among EDCs is of vital importance in assessing their physiological effects. A
recent discussion by Elobeid & Allison concluded that although there is not yet strong
evidence in humans that EDCs are contributing to the overweight phenotype, studies in cell
culture, animal models, and wildlife as well as epidemiological studies are highly suggestive
Organotins, organic derivatives of tin, are used liberally for stabilization of plastics [27].
Due to its strong biological effects, the organotin tributyltin inspired the coining of the term
“environmental obesogen” [27]. Butyltin compounds have been detected in food containers
and parchment paper and are transferred to foods baked in/on these products [73].
Assessment of human exposure to organotins is limited, but significant human exposure is
indicated by the presence of organotins in liver, blood, and breast milk ([27,73,74] and
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references within). Tributyltin, triphenyltin, and, to a lesser extent, dibutyltin, are PPARγ
ligands that can induce adipocyte differentiation ([27] (review) and more recent primary
literature [28,75-77]). Prenatal exposure to tributyltin induces increased adiposity in
adulthood in mice [27] that results from reprogramming of the differentiation capacity of
multipotent mesenchymal stromal cells (MSCs) [79]. The enhanced propensity of MSCs to
differentiate into adipocytes induced by tributyltin is inherited transgenerationally in a
mouse model [80].
BPA is one of the highest produced chemicals by volume ([18,21] and references within)
and is used to make plastic water bottles, line tin cans, and coat production pipes. In
humans, it was detected in 95% of adult urine samples at greater than 0.1 g/L from an
American population ([19] and references within). Strong positive correlations were
revealed between urine BPA concentration and BMI, waist circumference, and high density
lipoprotein cholesterol [21]. In vitro and in vivo studies have shown that BPA accelerates
adipocyte differentiation and promotes lipid accumulation via alteration of glucose
homeostasis as well as by activating the glucocorticoid receptor (review: [19] and
publications since then: [81-85]). However, not all studies agree that BPA promotes weight
gain and adiposity. For example, mouse studies have shown no effect of BPA on weight
gain or reduced weight gain following perinatal exposure [19,84,86,87]. Discrepancies
among studies may be attributable to differences in sex, estrogen status, species/strain of
mouse, dosing timing/regime, and diet. BPA is known to induce non-monotonic dose
responses, thus low dose exposures may be the most relevant to obesogenic endpoints [84].
Phthalates are used in the pharmaceutical industry, in food production, and in packaging as
plasticizing agents. They can be found in the enteric coatings of nutritional and
pharmaceutical capsules; polyvinylchloride (PVC) tubing used in food production;
packaging of plastic milk cartons, cheese, and meat; and PVC-based plastic wrap [88].
Phthalates, unlike BPA, are not covalently bound to the plastic and thus can readily diffuse
into food, especially foods high in fat such as meat due to their high lipophilicity. Urine
samples from the 2009-2010 U.S. National Health and Nutrition Examination Study
(NHANES) from 2,749 Americans presented an average of 64.4 g/L of mono-(2-ethylhexyl)
phthalate, a metabolite of di-(2-ethylhexyl) phthalate [89•]. Monoester metabolites of
phthalates are ligands of PPARα and PPARγ and can induce adipocyte differentiation, yet at
concentrations 100-1000 times greater than what is present in urine (M concentrations vs.
nM concentrations) [90,91]. Phthalates have been associated with dysregulated sex
hormones, obesity, and insulin resistance at a large range of concentrations [23,24••].
Analysis of data from males in the NHANES study from 1999-2002 revealed significant
correlations between four phthalate metabolites and waist circumference and three phthalate
metabolites and insulin resistance (review [25]). Additionally, Trasande et al. reported an
association between low molecular weight metabolites of phthalates and increases in being
overweight or obese in non-Hispanic black children between the ages of 6-19 years who
participated in the NHANES study between 2002-2008 [92].
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Persistent organic pollutants (POPs) and pesticides
POPs are a category of compounds that resist typical chemical, biological, or photolytic
degradation. POPs, some of which are used as pesticides, introduce danger because of their
stability in the environment; they tend to be hydrophobic and bioaccumulate in the food
chain. Some also undergo transformation by natural sunlight irradiation, increasing their
toxicity [68]. The 12 POPs of greatest concern, all organochlorides, were addressed in the
Stockholm Convention in 2001 and included aldrin, chlordane,
dichlorodiphenyltrichloroethane (DDT), dieldrin, dioxins, endrin, furans, heptachlor,
hexachlorobenzene, mirex, polychlorinated biphenyls (PCBs), and toxaphene. More
recently, chemicals such as perfluorooctanoic acid, organobromines, polybrominated
diphenyl ethers, and organotins have been considered POPs as well. Systematic review of
the epidemiological data supports an association between POP exposure and type 2 diabetes
[20••,34••]. Also, animal studies with PCBs support the role of these chemicals in
modulating glucose/insulin homeostasis. PCB exposure has been shown to impair glucose
homeostasis, exacerbate high fat diet-induced insulin resistance, and disrupt lipid
metabolism in mice (36 mg Aroclor-1254/kg/wk for 20 wks [30], 4 × 50 mg PCB-153/kg
over 10 wks [32], 50 mg PCB-77/kg/wk for 2 wks [33], or 1.6 mg PCB-126/kg/wk for 2 wks
[33]). These few studies likely mark the beginning of a large initiative to document the
effects of man-made compounds on the environment and on human health.
Heavy metals
Inorganic arsenic from natural mineral deposits contaminates drinking water worldwide
[93]. As many as 25 million Americas are exposed to concentrations of arsenic in drinking
water greater than the Environmental Protection Agency (EPA) drinking water standard of
100 ppb [94], while people in parts of Bangladesh and Taiwan are exposed to arsenic
concentrations >150 ppm [34]. In addition, because rice is grown in arsenic-contaminated
fields, people can be exposed to levels greater than the recommended intake of arsenic by
consuming only about 1/2 cup of rice per day [40]. Inorganic arsenic has been shown to
elevate basal glucose and insulin concentrations in rats (1.7 mg arsenite/kg for 90 days),
reduce insulin sensitivity in insulin-sensitive cells in cell culture, and, in vitro, interfere with
insulin signaling pathways ([93,95] and references within). Furthermore, 25 and 50 ppm
inorganic arsenic in drinking water for 20 weeks has been shown to exacerbate high-fat,
diet-induced glucose intolerance in mice [96]. While arsenic exposure has not been linked
with accretion of fat mass per se, arsenic indeed impairs adipocyte metabolism in vivo [97]
and total arsenic concentration in the urine has been associated with metabolic
complications such as type 2 diabetes [34••,93].
Cadmium is found in high concentrations in shellfish since it biomagnifies in the aquatic
food chain, as well as in the livers of other meat animals. Cadmium can accumulate in other
foods, too, as it is present in industrial processes for making plastics. In murine adipocytes,
cadmium mimicked the effects of insulin, thus promoting glucose metabolism and
lipogenesis [43]. In their review, Edwards and Prozialeck elegantly illustrate a mechanism
by which cadmium exposure can lead to elevated blood glucose, diabetes, and diabetic
nephropathy [43]. Similar to arsenic, cadmium may not promote adiposity (it may even
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reduce the size of adipocytes), but it may promote insulin resistance and type 2 diabetes
Animal hormones and milk
Recombinant bovine growth hormone (rbGH; also known as recombinant bovine
somatotropin, rbST) was introduced in the 1990’s and has increased milk production in
cows about 15% [48]. Despite the amount of press regarding rbGH in relation to obesity and
early onset of puberty, the compositions of conventional milk, organic milk, and milk
labeled “rbST-free” are very similar in regard to macronutrient composition and hormone
content [49]. In fact, bovine growth hormone is not active in humans, even when injected
directly into the bloodstream ([48] and references within). Thus, it is unlikely that rbGH is
contributing to the obesity epidemic directly, but there may be an elusive intermediate factor
that has yet to be discovered.
Methods for identifying obesogens
The mechanisms by which obesogens can cause weight gain are extremely diverse.
Biochemical pathways involving estrogen, testosterone, catecholamines, thyroid hormones,
steroids, growth hormone, and endocrine hormones (e.g., insulin, ghrelin, leptin) all
influence anabolic and catabolic pathways [55]. In addition, the sympathetic and
parasympathetic nervous systems regulate energy metabolism from the level of the brain
(e.g., appetite) to the level of the cells (e.g., mobilization of fat stores). The reductionist
approach of analyzing individual constituents of the biological system has been successful in
identifying molecular targets for several obesogens. However, models developed with this
approach are limited in that they cannot accommodate redundant pathways, they do not
accurately represent multifarious interactions with a variety of receptors in different tissues,
nor do they account for effects that require time to present. Holistic approaches are
necessary to complement the reductionist approach in order to observe and understand
effects on the entire system.
With the enormous number of potential obesogens that require study, high throughput
screening (HTS) methods are necessary. Functional HTS methods are valuable for
identifying compounds and also understanding the mechanisms by which the compounds
interfere with normal metabolism. Examples of functional HTS screening methods include
analysis of glucose output from hepatocytes, insulin secretion from β-cells, and lipid storage/
lipolysis in adipocytes. Integrative models that utilize tools from genetics and epigenetics,
transcriptomics, proteomics, metabolomics, systems biology, computational biology, and
developmental biology are useful to best describe the effects of these compounds on humans
without human studies themselves. The establishment of a database will allow pattern
recognition and predictions of properties of novel chemicals.
The field of toxicology has been paramount in developing HTS methods and can currently
analyze compounds at unprecedented rates. For example, the Tox21 initiative, funded by the
United States’ EPA, FDA, National Institute of Environmental Health Sciences, and
National Institutes of Health Chemical Genomics Center uses a robotic HTS system to
evaluate approximately 8,000 unique compounds daily for various biological effects.
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ToxCast™ is an initiative from the EPA to collaborate with Tox21 [98]. Using HTS
techniques, compounds can be tested for at least 650 biological effects, and then prioritized
for further analysis by other laboratories, including the Endocrine Disruption Screening
Program (EDSP) and the drinking water Candidate Contaminant List [99]. The EDSP has
been evaluating compounds since 2009 for effects ranging from binding to the estrogen
receptor (in silico and in vitro) to the effects on male and female puberty (in vivo, rats). In
order to direct efforts towards obesogen identification, the National Toxicology Program
enlists experts to identify relevant ToxCast targets for biological processes related to
diabetes and obesity (e.g., insulin signaling, islet cell function, adipocyte differentiation, and
feeding behavior in Caenorhabditis elegans). Positives and negatives were identified for
each pathway from the Phase I ToxCast set using the ToxPi analytical prioritization tool
[100]. Targeted testing of these putative obesogens is being carried out in relevant biological
systems [34••].
As a new and rigorous in vivo model, zebrafish are an increasingly valuable screening model
for the ability of compounds to cause obesity. Zebrafish hold an advantage over cell culture
in that they are a complete biological system. Compared to mice, zebrafish experiments can
be done more rapidly (11 days vs. about 3 months) and in a much smaller space. Protocols
are available for use in screening compounds for their effects on adiposity specifically
([101•] and references within). For example, Lyche et al. introduced female zebrafish to
POP mixtures extracted directly from fish in a Norwegian freshwater system [102]. They
observed differences in weight gain, age of maturity, and a large spectrum of changes in the
transcriptional profile.
In addition to assessing compounds on fat accumulation and metabolism in adults, it is also
important to describe the effects of these compounds at sensitive stages in development.
Metabolic effects of these compounds have the potential to invoke irreversible damage to
prenatal organisms and infants [24••,103•].
For identifying avenues of future research, epidemiological correlations are extremely
valuable [92]. Samples from the U.S. NHANES study have highlighted correlations between
various obesogens and increased waist circumference, insulin resistance, low/high birth
weights, and other potential association with exposure ([6,7,18,19,20••,24••,34••,36•,89•,
103•] and references within). However, we must keep in mind the limitations of
correlational studies; increased microwave dinners, canned pasta meals, and soda from
plastic bottles could increase intake of environmental plastics but the development of the
person’s obesity may be entirely unrelated to the plastic exposure. In addition, moving
forward, a shift from food frequency questionnaires to metabolomics approaches for
quantifying food intake will allow a more accurate assessment. Subsequently, additional
testing is always essential to differentiate causation from correlation.
What we can do as scientists with identified obesogens
Once obesogens are identified, we have both responsibilities and opportunities. We have
responsibility to inform public policy in order to minimize usage of offensive compounds.
Scientists also must develop healthy alternatives to fit the needs of industry and/or antidotes
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for the offensive compounds. Knowledge of obesogens and their mechanisms will
undoubtedly allow a more thorough understanding of the etiology of obesity, which can
inform prevention and treatment tactics, including anti-obesity pharmaceuticals. Focusing on
these issues will lead to improved efficiency identifying obesogenic compounds and a more
streamlined process for safely introducing novel compounds into our food supply. Finally, to
prevent unnecessary redundant initiatives, a database should be developed for the tested
compounds that do and do not contribute to obesity.
Identification of obesogens is akin to identification of carcinogens in that scientists and
clinicians will drive change to provide solutions. In response to the identification of
carcinogens, the 1958 Delaney Clause was established to prevent FDA approval of any
chemical compound found to cause cancer in animals or humans. Thus, many compounds
are already tested for long-term carcinogenic and toxic effects. An additional FDA
requirement for reporting body weight increases could help prevent the introduction of
future obesogens.
From farm to fork, our food carries thousands of compounds that we consume (Figure 1),
some of which are harmful and some of which are helpful depending on quantity and
context. Photolytic degradation products of compounds [68] as well as bioaccumulation of
obesogens from water to crops (e.g., rice), fish, and farm animals [24••] demonstrate that
toxicologists and environmental scientists in addition to nutrition and metabolic scientists
are crucial in the endeavor to minimize the effects of environmental obesogens. Both
holistic and reductionist approaches are needed while heeding physiologically relevant
concentrations; zebrafish offer a new, promising model to help reach these goals. In the light
of the current obesity epidemic, it is prudent to evaluate everything that is added to our food
for potential contributions to obesity.
This work was supported by the Superfund Research Program grant P42ES007381 (J.J.S), DK35914 (B.E.C), and
DK56690 (B.E.C). A.L.S. is supported by the USDA AFRI/NIFA post-doctoral fellowship program, grant no.
2012-67012-20658. We would like to thank Albert R. Jones IV, Kalypso Karastergiou, Ian Kleckner, and Tova
Meshulam, for helpful discussions while preparing the manuscript.
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Figure 1.
Compounds are introduced into our food at many stages of the food production process.
Waste from factories including persistent organic pollutants (POPs) and heavy metals (e.g.,
arsenic (As), cadmium (Cd), and lead (Pb)) contaminate the water supply. These compounds
can be consumed by fish and then be ingested by humans directly or after further processing.
At the farm, these chemicals leach into the crops in the soil, and farmers introduce pesticides
to increase crop yield. Animals are fed with antibiotics and hormones (e.g., recombinant
bovine growth hormone, rbGH), which have the potential to be transferred to animal
products for human consumption. Crops are then refined in order to produce the raw
ingredient: insects are removed, organic waste is removed, some products are washed and/or
cooked, and solvents are added to wash away chemicals or isolate desired components. At
the processing plant, ingredients are combined to produce the final product. Many of the
ingredients used in our food supply have not been tested for their effects on key metabolic
pathways (see Table 2). During processing and packaging, food is exposed to plastic-coated
pipes and is packaged into plastic containers or plastic-coated cans. Bisphenol A (BPA) is an
example of a compound in plastic that can diffuse into food, especially at high temperatures
(e.g., during retorting). Next, preparation of the food, especially during heating, can
mobilize chemicals in the packaging (e.g., BPA from baby bottle into milk during
microwaving) or the cookware (e.g., perfluorocarbons (PFCs) from non-stick pans [1]),
which can subsequently contaminate the food. Thus, the final food product often contains
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much more than simply the ingredients added in the large mixer. (Figure courtesy of Ian
Robert Kleckner).
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Simmons et al. Page 19
Table 1
What in our food is making us fat? Putative contributors to obesity
Compound Where it is found and concentration in food
(if available)
Comments Key
Saturated fat animal fat including lard and cream, palm
kernel oil
Not all saturated fats have equivalent biological
activity; compared with carbohydrates and
unsaturated fat, the saturated fats
palmitic acid and myristic acid may have the
most negative effects on circulating lipid
Trans-fat partially hydrogenated vegetable oil (e.g.,
packaged cookies, microwave popcorn, icing,
fried foods); up to 3 g per serving
2% of energy can lead to a 23% increase in
coronary heart disease [3].
The U.S. Food and Drug Administration (FDA)
proposed a ban in Nov. 2013.
High fructose corn
syrup and sucrose
soda, candy, breakfast cereal, granola/nutrition
bars; about 37 g/12 oz. soda
Despite popular reproach, the metabolic fate of
high fructose corn syrup is similar to that of
sucrose, yet the taste, convenience,
and low cost of products with high fructose
corn syrup may encourage excessive intake.
Salt processed foods May be indirectly related to obesity because of
increased fluid consumption, including
consumption of sugar-sweetened
Ingredients that incidentally contain bioactive compounds
Soy vegetarian meat substitutes, tofu; up to 50 mg
soy isoflavones/serving
Although isoflavones bind the estrogen
receptor, they may protect against obesity.
Effects may be gender and age dependent.
Food additives and ingredients “generally recognized as safe” (GRAS; added purposefully)
as an emulsifier in ice cream, whipped
toppings, margarine, shortening, 0.1-1.0%
Can also be formed in the gut from
triglycerides by hydrolysis of fatty acids at sn-1
and sn-3 positions.
Can stimulate GLP-1 secretion from L
intestinal cells [9] and insulin secretion from
rat islets [10].
Sodium benzoate
soda, salad dressing, fruit juices and jams,
margarine; <0.1%
Can decrease leptin release in vitro. [11]
Sodium sulfite
wine; up to 6 mM (750 mg/L) Can reduce leptin release and potentiate
lipopolysaccharide-induced interleukin-6
secretion in vitro.
glutamate (MSG) and
autolyzed yeast/yeast
extract (a natural
source of MSG)
as a flavor enhancer in savory foods including
soups, meat products, Asian sauces, and
savory snacks (e.g., Doritos®); up to about
May increase food consumption due to flavor
enhancement, but elevated caloric intake has
not been shown to be sustained [13].
“Monosodium glutamate-induced obesity” was
an experimental technique used mainly in the
1970’s and 1980’s. The researcher
injected rodents with 2-4 g/kg MSG 5 times
every other day for the first 10 days of life. The
MSG destroyed arcuate nucleus
neurons and disrupted the hypothalamicpituitary-
adrenal axis, thus causing obesity
Food additives (accidentally)
Plastic Components
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Compound Where it is found and concentration in food
(if available)
Comments Key
Bisphenol A (BPA) polycarbonate bottles, canned food
Content: 0.23-65.0 ng/g in foods sold in
or cans [15], 0-5 ppb in water [16]
Bottle-fed infants are exposed to about 0.4-1.7
μg/kg body weight/day, adults, about .01-0.2
μg/kg/day [17]
Environmental Protection Agency limit = 50
μg/kg body weight/day, although this is
controversial. Perinatal exposure leads to
increased weight gain in mouse models,
although there are studies that say the opposite.
BPA modifies adipocyte differentiation and
function in vitro and in animal models, though
detrimental concentrations are not consistent.
Epidemiological studies show positive
correlations between urinary BPA
concentrations and waist circumference.
Phthalates foods and beverages of all types; quantity
varies depending on congener and packaging
(plastic packaging increases phthalate content)
Phthalate monoesters are PPARΥ ligands that
induce adipocyte differentiation and fat
Epidemiological studies have shown a positive
correlation between some phthalate metabolites
and waist circumference.
Organotins seafood, shellfish; quantity in food is
unknown but monobutyltin, dibutyltin, and
tributyltin detected in tens ng/mL in blood
Tributyltin chloride and triphenyltin activate
PPARΥ and RXRα ligands with a binding
constant in the nanomolar range. As these
receptors participate in regulation of gene
expression, activation can afflict a wide range
of consequences in homeostatic
regulation including dysregulation of fatty acid
storage, adipocyte differentiation, and energy
Persistent organic pollutants and pesticides
biphenyls and
pesticides (including
canola and olive oil, butter, salmon, canned
sardines, hard and soft cheeses, whole milk
yogurt, ice cream, peanut butter [29], foods
cooked in non-stick pans, microwave popcorn
[1]; most common: DDT metabolite p,p’-DDE
at up to 9.0 ng/g in catfish fillets
PCB exposure has been shown to impair
glucose homeostasis, exacerbate high-fat-dietinduced
insulin resistance, and disrupt
lipid metabolism in mice. These compounds
accumulate in adipose tissue and exposure can
increase to dangerous levels during diet- and/or
fat loss. Although mechanistic
evidence is currently weak, these compounds
have been associated with dysregulation of
energy metabolism.
Organophosphates blueberries, strawberries, celery These inhibit acetylcholinesterase (AChE),
which is their appreciated mechanism of action
against insects. Prenatal exposure of
chlorpyrifos, diazinon, or parathion have been
associated with development of metabolic
dysfunction resembling prediabetes.
Carbamates fermented foods, especially alcoholic
beverages; up to 12 ppm ethyl carbamate
Albeit via a different mechanism than
organophosphates, carbamates also inhibit
acetylcholinesterase (AChE). Carbamates can
also react with ethanol to form ethyl carbamate
(also known as urethane).
Flame retardants
diphenyl ethers
(PBDEs) and
biphenyls (PBCs)
highest quantity in meat, lower quantities in
animal products; up to 3 ng/g in salmon
The U.S. EPA set a maximum daily dose of 7
μg/kg body weight. Some compounds in this
class are endocrine disrupting compounds,
carcinogens, and disruptors of development
and nerve
Dioxins meat, eggs, milk and milk products, fish;
0.5-1.5 pg toxicity equivalents (TE)/kg
Dioxins are formed during incineration of
waste, production of organochlorine chemicals,
and forest fires. Some congeners may
regulate energy metabolism via the aryl
hydrocarbon receptor (AhR) and/or the
estrogen receptor.
Heavy metals
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Compound Where it is found and concentration in food
(if available)
Comments Key
Arsenic rice, contaminated water, crops grown in
contaminated fields; up to 10 μg/0.56 cups rice
in the U.S. [40], up to 60.8 μg/kg in European
cabbage, up to 257 μg/kg in Arum tuber
in Bangladesh [41]
There is sufficient support for a positive
correlation between arsenic and diabetes when
levels in drinking water are >150 ppb,
such as in regions of Taiwan or Bangladesh.
Cadmium spinach, lettuce, herbs (e.g., dill, parsley) that
were irrigated in contaminated water or soil;
up to 0.51 μg/g [42]
Cadmium may bind the estrogen receptor
and/or mimic the effect of insulin. Cadmium
exposure may elevate blood glucose and
increase risk for diabetes.
[20••, 36• 43,44]
Lead spinach, lettuce, herbs that were irrigated in
contaminated water or soil, up to 3.3 μg/g [42]
Prenatal lead exposure and exposure in
childhood may interfere with signaling in the
hypothalamic-pituitary-adrenal axis.
Alkylphenols (e.g.,
nonylphenol (NP),
butylphenol BP))
bottled water, eggs, milk, up to 465 ng/L
Intakes estimated at about 7.5 μg NP/day in
Germans [46]
Alkylphenols are used as precursors to
detergents, among other uses. They are
endocrine disruptors that perpetuate estrogenic
effects. There are regulated by the European
Union but not yet by the U.S.
Hormones given to
milk; there are no more hormones in milk
cows treated with hormones than cows
treated with hormones
Recombinant bovine growth hormone (GH), or
recombinant bovine somatotropin, increases
the efficiency of milk production.
Substantial evidence shows that bovine GH
does not affect the composition of the milk. In
fact, bovine GH is not active in
humans, even when directly injected into the
Antibiotics given to
unknown Antibiotics are administered to farm animals to
prevent disease and also to promote growth.
Antibiotics can contaminate the
environment and could potentially promote
growth in humans. Additionally, meat and
animal products can possess antibioticresistance
strains of bacteria.
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Table 2
Common food additives and GRAS substances that have not been assessed for their
effects on obesity
Thickening agents
sorbic acid
benzoic acid
EDTA calcium proprionate
sodium nitrate/nitrite
sodium benzoate
sodium sulfite
butylated hydroxyanisole (BHA)
butylated hydroxytoluene (BHT)
tert-butylhydroquinone (tBHQ)
propyl gallate
nisin natamycin dimethyl- and diethyl dicarbonate
medium chain fatty acids and esters
calcium acetate
potassium citrate
sodium/calcium EDTA
glucono delta-lactone
sodium/potassium/ferrous gluconate
sodium tripolyphosphate
High intensity sweeteners
Polyols (including sugar alcohols)
maltitol sorbitol xylitol erythritol isomalt glycerol
lecithin diacetylated tartaric acid with mono- and
diglycerides (DATEM)
hydroxyl citric acid
carbon dioxide
isoamyl acetate
Flavor potentiators
monosodium glutamate (MSG)
FD&C Blue No. 1 (brilliant blue FCF)
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FD&C Blue No. 2 (indigotine)
FD&C Green No. 3 (fast green FCF)
FD&C Red No. 40 (allura red AC)
FD&C Red No. 3 (erythrosine)
FD&C Yellow No. 5 (tartrazine)
FD&C Yellow No. 6 (sunset yellow)
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