Molecular and Cellular Endocrinology xxx (2017) 1e8

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Molecular and Cellular Endocrinology

journal homepage: www.elsevier.com/locate/mce

Effects of arsenic on adipocyte metabolism: Is arsenic an obesogen?

nico a, d,
Zeltzin A. Ceja-Galicia a, b, 1, Alberto Daniel a, c, 1, Ana María Salazar a, Pablo Pa
,*
a
Patricia Ostrosky-Wegman , Andrea Díaz-Villasen ~ or a

a
Instituto de Investigaciones Biom

noma de M

edicas, Universidad Nacional Auto exico, Mexico City, 04510, Mexico
b
Maestría en Ciencias de la Produccio
n y Salud Animal, Unidad de Posgrado, Universidad Nacional Auto
noma de M
exico, Mexico City, 04510, Mexico
c
Maestría en Ciencias Biolo
gicas, Unidad de Posgrado, Universidad Nacional Auto
noma de M
exico, Mexico City, 04510, Mexico
d
Doctorado en Ciencias Biom
edicas, Unidad de Posgrado, Universidad Nacional Auto
noma de M
exico, Mexico City, 04510, Mexico

a r t i c l e i n f o a b s t r a c t

Article history: The environmental obesogen model proposes that in addition to a high-calorie diet and diminished
Received 2 February 2017 physical activity, other factors such as environmental pollutants and chemicals are involved in the
Received in revised form development of obesity. Although arsenic has been recognized as a risk factor for Type 2 Diabetes with a
5 May 2017
specific mechanism, it is still uncertain whether arsenic is also an obesogen. The impairment of white
Accepted 5 May 2017
adipose tissue (WAT) metabolism is crucial in the onset of obesity, and distinct studies have evaluated
Available online xxx
the effects of arsenic on it, however only in some of them for obesity-related purposes. Thus, the known
effects of arsenic on WAT/adipocytes were integrated based on the diverse metabolic and physiological
Keywords:
Arsenic
processes that occur in WAT and are altered in obesity, specifically: adipocyte growth, adipokine
Adipose tissue secretion, lipid metabolism, and glucose metabolism. The currently available information suggests that
Obesity arsenic can negatively affect WAT metabolism, resulting in arsenic being a potential obesogen.
Obesogen © 2017 Elsevier B.V. All rights reserved.
Adipogenesis
Lipolysis
Adipokines
Glucose uptake

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Effects of arsenic on adipocyte growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Effects of arsenic on adipokine secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Effects of arsenic on lipid metabolism of adipocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Effects of arsenic on glucose metabolism of adipocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction

High body-mass index (BMI) is an important risk factor for type

dicas, Departamento
2 diabetes (T2D), as well as other metabolic diseases and some
* Corresponding author. Instituto de Investigaciones Biome
de Medicina Geno
mica y Toxicología Ambiental, Universidad Nacional Auto
noma de types of cancers. From 1975 to 2014, the global age-standardized
Me
xico, Mexico City, 04510, Mexico. BMI has increased from 21.9 kg/m2 to 24.2 kg/m2 (Collaboration,
~ or).
E-mail address: diaz.villasenor@iibiomedicas.unam.mx (A. Díaz-Villasen 2016), and between 1980 and 2008, the prevalence of worldwide
1
These authors contributed equally to this work, listed alphabetically by last obesity rose from 4.8% to 9.8% in men and from 7.9% to 13.8% in
names.

http://dx.doi.org/10.1016/j.mce.2017.05.008
0303-7207/© 2017 Elsevier B.V. All rights reserved.

Please cite this article in press as: Ceja-Galicia, Z.A., et al., Effects of arsenic on adipocyte metabolism: Is arsenic an obesogen?, Molecular and
Cellular Endocrinology (2017), http://dx.doi.org/10.1016/j.mce.2017.05.008
2 Z.A. Ceja-Galicia et al. / Molecular and Cellular Endocrinology xxx (2017) 1e8
women (Malik et al., 2013), meaning that obesity affects more than
half a billion people around the world (Bhurosy and Jeewon, 2014).
Over the past 35 years, a four-fold global increase in the prevalence
of T2D has also occurred, with an estimated 422 million adults with
diabetes in 2014, reflecting an increase in associated risk factors
such as overweight or obesity. Furthermore, diabetes prevalence
has risen faster over the past decade in low- and middle-income
countries than in high-income countries (Collaboration, 2016;
WHO, 2016). Thus, diverse economic and health services efforts
have been focused on preventing and managing pre-diabetes and
T2D (Collaboration, 2016).
Improved access to food intake with high caloric content and
decreased physical activity levels have been identified as the prime
risk factors for the increasing prevalence of overweight, obesity and
chronic metabolic diseases, such as T2D (Bhurosy and Jeewon,
2014), in the last 30 years. However, these factors by themselves
do not fully explain this phenomenon, and have failed in the pre-
vention and/or treatment of these metabolic diseases. Thus, other
risk factors could be involved in obesity and T2D etiologies.
Environmental pollutants and chemicals, most of them cata-
logued as endocrine-disrupting chemicals because they interfere
with hormone actions, have been proposed to act as obesogens
and/or diabetogens (Gore et al., 2015; Grun and Blumberg, 2009;
Holtcamp, 2012; Kuo et al., 2013; Neel and Sargis, 2011). Chem-
icals that promote obesity have been functionally defined as
obesogens because they increase the number of adipocytes (hy-
perplasia) and/or the storage of fat into existing adipocytes
(hypertrophia). Obesogens can also act indirectly to promote
obesity by changing basal metabolic rates, shifting energy balance
to favor calorie intake and storage and altering hormonal or
neuronal control of appetite and satiety, among others (Heindel
et al., 2015).
The obesogen hypothesis is less than 10 years old, and approx-
imately 20 environmental chemicals are already known to have
obesogenic properties (Heindel et al., 2015). In animals, pharma-
ceutical drugs such as diethylstilbestrol, chemicals used for the
polymerization of plastics and resins such as bisphenol A and
phthalates, pesticides (particularly DDT) organotins such as fungi-
cides, disinfectants used for marine paints such as tributyltin and
the nonstick coating perfluorooctanoic acid are obesogenic (Gore
et al., 2015; Heindel et al., 2015; Janesick et al., 2014; Karoutsou
and Polymeris, 2012). Diverse compounds have shown to alter
adipocyte differentiation, and several endocrine-disrupting chem-
icals modulate adipocyte physiology (Regnier and Sargis, 2014).
However, arsenic has not been defined as an obesogen, even though
it is a considerable risk factor for the development of T2D and
available data exit in relation to its diverse effects on white adipose
tissue (WAT).
Arsenic in drinking water obtained from underground occurs
naturally in many countries worldwide, and from 2001 to 2009, it
has been estimated that 140 million people were exposed to con-
centrations above 50 mg/L, which is five-fold higher than the upper
limit established by the World Health Organization (WHO) (Pilsner
et al., 2009; van Halem et al., 2009; WHO, 2012).
The epidemiologic relationship between high chronic arsenic
exposure and obesity development has not been evaluated directly.
Based on epidemiological studies from the mid-90s, arsenic has
been associated with an increased risk of developing T2D in
humans, more evident in areas with high exposure levels (Kile and
Christiani, 2008; Maull et al., 2012; Thayer et al., 2012; Wang et al.,
2014). In particular, a prospective study in Taiwan carried out in
people with and without arsenic exposure through drinking water,
shows that the multivariate-adjusted relative risk for T2D was 2.3
(1.2e4.3) for a BMI
25 vs < 25 kg/m2 (Tseng et al., 2000). Although
obesity and T2D are not completely equitable, obesity is one of the
Please cite this article in press as: Ceja-Galicia, Z.A., et al., Effects of arsenic on adipocyte metabolism: Is arsenic an obesogen?, Molecular and
Cellular Endocrinology (2017), http://dx.doi.org/10.1016/j.mce.2017.05.008
major risk factors for T2D development (Boles et al., 2017).
The mechanisms by which arsenic increases the risk for T2D
involves the impairment of glucose-stimulated insulin secretion in
pancreatic beta-cells, the induction of pancreatic oxidative damage
and insulin resistance in skeletal muscle, increment of gluconeo-
genesis in liver, and modulation of other hepatic insulin signaling
(Diaz-Villasenor et al., 2006, 2008; Douillet et al., 2013; Hamann
et al., 2014; Izquierdo-Vega et al., 2006; Liu et al., 2014; Padmaja
Divya et al., 2015). Interestingly, in an integrated computational
systems biology approach that examines possible pathogenetic
linkages between environmental chemicals to genes and proteins
involved in T2D through genome-wide associations, disease simi-
larities, and published epidemiologic and experimental evidence,
arsenic was found in the top 10 potentially environmental chem-
icals linked to T2D, and moreover arsenic also showed literature-
based association with obesity (Audouze et al., 2013). Thus,
arsenic has been considered an important risk factor for T2D,
though its obesogenic effects are uncertain because the effects of
arsenic on WAT have been explored non-specifically and with
diverse objectives. Therefore, we believe it is relevant to review the
findings from these studies with the purpose of better under-
standing the mechanism of action and the role arsenic plays as an
obesogen, as well as to identify the knowledge gaps in the area.
Adipose tissue is a central metabolic organ in the regulation of
whole-body energy homeostasis, thus adipose dysfunction is a
critical step in obesity. Particularly, WAT functions as a key energy
reservoir for other organs and secretes various hormones, cyto-
kines, and metabolites (termed as adipokines), as well as free fatty
acids that control systemic energy balance by regulating appetite
signals in the central nervous system and metabolic activity in
peripheral tissues (Choe et al., 2016).
Moreover, a number of studies suggest that overnutrition during
pregnancy is a major risk factor for obesity in offspring in adult-
hood, in part, due to epigenetic mechanisms (Elshenawy and
Simmons, 2016). Similarly, exposure to various substances during
critical periods, such as the embryonic stage, can cause health ef-
fects. Thus, prenatal exposure to substances can have lasting and
potentially permanent effects on offspring, including changes on
adipogenesis, lipid imbalance and obesity (Janesick et al., 2014). In
fact, the consequences of ancestral exposure to obesogenic chem-
icals can result in the transmission of obesity-related phenotypes
even through three generations via epigenetic mechanisms
(Boekelheide et al., 2012; Chamorro-Garcia and Blumberg, 2014).
Blood concentrations of arsenic and its metabolites in newborns
have been found to be similar to those of their mothers because the
placenta is not a barrier to arsenic (Hall et al., 2007). Literature
about prenatal arsenic exposure on experimental animal models
and its changes on adipocyte metabolism are limited. However,
some studies have shown evidence that arsenic may act on
adipocyte function across generations.
Thus, the aim of this review is to compile the available infor-
mation about the direct and transgenerational effects of arsenic on
adipocytes to understand how arsenic exposure can contribute as a
risk factor to obesity and the onset of T2D by specifically focusing
on roles that do not lead to pancreas, skeletal muscle and liver
impairment. Based on the diverse metabolic and physiological
processes that occur in WAT, the review is divided into the
following topics: (1) adipocyte growth, (2) adipokine secretion, (3)
lipid metabolism (particularly lipogenesis and lipolysis), and (4)
glucose metabolism (mainly glucose uptake).
2. Effects of arsenic on adipocyte growth
The increase in adipose mass is the result of an increase in size of
adipocytes (hypertrophy) and number of adipocytes (hyperplasia)
 Z.A. Ceja-Galicia et al. / Molecular and Cellular Endocrinology xxx (2017) 1e8
through adipogenesis. Adipogenesis is the cell differentiation pro-
cess by which preadipocytes become adipocytes and begin to
storage lipids, particularly as triglycerides (TG) and has been
extensively studied for the last 25 years. Adipogenesis involves a
complex and highly orchestrated program of transcription factors,
cofactors and signaling intermediates from numerous pathways
(Lowe et al., 2011; Moreno-Navarrete, 2012).
One of the main concerns regarding chronic arsenic exposure is
related to its carcinogenic effects. A considerable amount of evi-
dence suggests that arsenite (and perhaps some of its metabolites)
acts as a co-carcinogen in humans, in part by activating signal
transduction pathways that enhance cell proliferation, reduce
antiproliferative signaling, override checkpoints that control cell
division after genotoxic insults, and induce cell transformations
into more malignant phenotypes (Rossman, 2003).
In the last 15 years, different types of in vitro experimental
models have been utilized to study the effect of different arsenic
species on adipogenesis in diverse preadipocyte cell lines that are
already committed to the adipocyte lineage (3T3-L1, 3T3-F442A
and C3H 10T1/2) (Hou et al., 2013; Salazard et al., 2004; Trouba
et al., 2000; Wang et al., 2005; Wauson et al., 2002), in human
mesenchymal stem cells (hMSC) derived from bone marrow (Cheng
et al., 2011) or adipose tissue (Klei et al., 2013) and in mouse stromal
vascular cells (SVC) isolated from adipose tissue (Hou et al., 2013;
Klei et al., 2013).
Trouba et al were interested in the effects of arsenic on adipo-
cyte differentiation, proposing that arsenic blocks differentiation
and shunts cells into an enhanced proliferative state that leads to
cellular morphological transformation (Trouba et al., 2000). Based
on lipid accumulation and morphological characteristics, sodium
arsenite (trivalent) exposure (3e6 mM) eight weeks prior to dexa-
methasone/insulin (DMI)-induced differentiation or from the
beginning of the differentiation process reduces the capacity of
C3H-10T1/2 cells to differentiate into adipocytes (Trouba et al.,
2000).
Some evidence also suggests that the ability of arsenic to inhibit
DMI-induced adipogenesis is through the peroxisome proliferator-
activated receptor-gamma (PPARg) pathway. The transcriptional
increase in CCAAT-enhancer binding protein (C/EBP)-b is consid-
ered one of the initial steps for adipoge
nesis that also induces the
expression of PPARg and C/EBPa. This generates a positive feedback
loop by activating one another's expression to induce and maintain
the expression of adipocyte-specific genes at later stages (Hou et al.,
2013).
PPARg, C/EBPa, and fatty acid binding protein 4 (also known as
ap2) mRNA levels are decreased in arsenic-treated C3H-10T1/
2 cells by sodium arsenite (6 mM) when preadipocytes are exposed
at least 2 months prior to differentiation (Wauson et al., 2002). The
differentiating effects of pioglitazone, which induces adipogenesis
by activating PPARg, is inhibited by arsenite, demonstrating more
forcefully that arsenic interferes with adipogenic signaling at or
below PPARg (Wauson et al., 2002).
Some other studies support that the transcription factors PPARg
and C/EBPa are involved in arsenic-inhibited adipocyte differenti-
ation (Cheng et al., 2011; Hou et al., 2013; Klei et al., 2013; Wang
et al., 2005). In particular, the mRNA or protein expression levels
of C/EBPb, PPARg or C/EBPa are decreased in response to different
arsenic species, with a wide range of doses, diverse cellular
adipocyte models, and different exposure times, starting before or
at the beginning of the differentiation: (1) 3T3-L1 adipocytes
exposed to 3 mM arsenic trioxide 2 days before differentiation and
10 days after its induction (Wang et al., 2005); (2) adipocytes
differentiated from hMSC derived from bone marrow treated with
1 mM arsenic trioxide for 48 h (Cheng et al., 2011); (3) adipocytes
differentiated from hMSC derived from adipose tissue and mouse
Please cite this article in press as: Ceja-Galicia, Z.A., et al., Effects of arsenic on adipocyte metabolism: Is arsenic an obesogen?, Molecular and
Cellular Endocrinology (2017), http://dx.doi.org/10.1016/j.mce.2017.05.008
3
SVC exposed to 0.1e2.5 mM sodium arsenite for 6e12 days (Klei
et al., 2013); and (4) 3T3-L1 adipocytes exposed to 5 mM sodium
arsenite, adipocytes differentiated from mouse SVC treated with to
0.1e1 mM trivalent monomethylated arsenic (MMA), specifically
methylarsine oxide, and human adipose tissue-derived stem cells
exposed to 2 mM trivalent dimethylarsinic acid (DMA) as dime-
thylthioarsenite, all treated for a period of 48 h (Hou et al., 2013).
One mechanism by which arsenic suppresses adipogenesis is
through endoplasmic reticulum stress. Arsenic up-regulates the
expression of C/EBP homologous protein (also known as CHOP10)
at mRNA and protein levels, which in turn inhibits C/EBPb tran-
scriptional activity and PPARg and C/EBPa gene expression. Thus,
early exposure to arsenic (in the first 48 h after DMI-induced dif-
ferentiation) shows the most critical effect on adipogenesis since
cells express genes and proteins involved in the adipogenic differ-
entiation process during this period (Hou et al., 2013).
Moreover, the activation of cell-signaling cascades that recruit
repressive complexes to the promoters of regulatory adipogenic
genes, such as C/EBPa, are also induced by 0.1e1 mM sodium
arsenite in hMSC undergoing DMI-induced adipogenesis (Klei et al.,
2013). Authors have established that this inhibition of adipogenesis
by sodium arsenite occurs through Gi protein-coupled endothelin-
1 receptor particularly type B (ENDRB) (Klei et al., 2013). In fact, a
study conducted in the Spanish population shows a positive asso-
ciation between two SNPs located in the ENDRB gene (rs5251 and
rs3759475) with obesity risk in individuals exposed to higher
arsenic levels (Martinez-Barquero et al., 2015).
Another proposed mechanism by which arsenic inhibits adi-
pogenesis via PPARg is through the disruption of the interaction
between PPARg and its co-activator Retinoic-X-Receptor (RXR),
inhibiting the heterodimer assembly that is required for
PPARgemediated adipogenic gene expression (Wang et al., 2005).
Arsenic also inhibits the interaction between PPARg and Akt, as
well as Akt phosphorylation (Wang et al., 2005). In line with this
finding, it has been reported that Akt signaling is required for the
transcriptional activation of PPARg, however the downstream
mechanism is still not well established. For example, Akt phos-
phorylates transcriptional co-activators such as CBP/p300 to
enhance its acetyl transferase activity, implying that the acetyla-
tion/deacetylation processes are involved in the modulation of the
PPARg responsive element activation (Kim et al., 2010).
Contrary to the previous studies mentioned, the transcriptional
expression of PPARg and C/EBPa in response to 0.5 mM arsenic
trioxide exposure for 72 h during differentiation in 3T3-F442A
adipocytes was shown to increase. This induction was exacerbated
in the presence of insulin, though pre-adipocyte differentiation was
not evaluated directly (Salazard et al., 2004).
Transgenerational studies have also provided evidence that
arsenic can affect weight gain and body fat content. A study con-
ducted in the offspring of pregnant CD-1 mice exposed to 10 mg/L or
42.5 mg/L sodium arsenite in drinking water from gestational day
10 to birth showed that body weight at 3-weeks-old was greater in
mice exposed to arsenite in utero than in the controls. Moreover,
body weight gain was also significantly greater in these groups
(10 mg/L and 42.4 mg/L), at least until the mice were 15 weeks old.
This was accompanied by higher body fat percentage at 5 months
old. One month later (6 months old), body weight was only
significantly higher in the mice exposed to 10 mg/L in utero
compared with the controls (Rodriguez et al., 2016). Swiss Webster
mice exposed to 100 mg/L sodium arsenite in utero until 13 weeks
after birth, demonstrated significantly higher body weights than
controls starting at 5 weeks of age. However, animals exposed to
arsenite only in utero displayed no differences compared with
controls (Ditzel et al., 2016).
In contrast, maternal arsenic exposure early in pregnancy has
4 Z.A. Ceja-Galicia et al. / Molecular and Cellular Endocrinology xxx (2017) 1e8
been associated with low birth weight in populations from
Bangladesh and Chile (Hopenhayn et al., 2003; Huyck et al., 2007).
Similarly, studies in mice exposed to low levels of sodium arsenite
(10 mg/L) in utero were also found to have decreased body weights
during the first postnatal month (Kozul-Horvath et al., 2012). Tak-
ing into account that low birth weight is an important risk factor for
the development of obesity and other metabolic diseases in
adulthood (Saggese et al., 2013), this effect of arsenic could be
related to the induction of obesity.
3. Effects of arsenic on adipokine secretion
Adipose tissue is an endocrine organ that secretes diverse hor-
mones and inflammatory cytokines called adipokines that play an
important role in metabolism. Among the many varieties of adi-
pokines that adipose tissue secretes, adiponectin and leptin were
both discovered in the mid-90s and are the best known (Fantuzzi,
2014). One of the principal effects of adiponectin is primarily
related to improved insulin sensitivity in the liver and skeletal
muscle, though other functions include reducing hepatic gluco-
neogenesis, inducing glucose uptake and lipid oxidation in muscle,
or decreasing macrophage transformation into foam cells (Leal and
Mafra, 2013; Li et al., 2011). Leptin is principally involved in con-
trolling satiety, suppressing appetite and increasing energy
expenditure (Xu and Xie, 2016), as well as in starvation. During a
negative energy balance, a rapid decrease in serum leptin levels
occurs prior to the depletion of adipose tissue mass (Gautron and
Elmquist, 2011).
Some studies have shown that sodium arsenite can affect the
synthesis of adiponectin or the circulating levels of leptin. In fully
differentiated adipocytes from adipose tissue-derived primary
hMSC exposed to 1 mM arsenite, the amount of adiponectin mRNA
was not affected after 24 h of exposure. However, there was a 72%
decrease in adiponectin transcripts after a 72 h-exposure compared
to control conditions (Garciafigueroa et al., 2013). Adiponectin
mRNA levels decreased in a dose-dependent manner in hMSC
exposed to low-doses of arsenite (0.1e2.5 mM) for 12 days starting
at the beginning of the differentiation process (Klei et al., 2013).
Moreover, knocking down the ENDRB in hMSC was partially pro-
tective in reducing arsenite-inhibited adiponectin transcript levels
(Klei et al., 2013).
Additionally, in diverse studies conducted in pregnant rodents
or women exposed to arsenic through drinking water, leptin levels
are increased either in the serum of the offspring (Rodriguez et al.,
2016), in the placental tissue (Ahmed et al., 2011) or in the cord
blood (Gossai et al., 2015).
Elevated levels of leptin in umbilical cord blood correlate with
high birth weight and may provide insights into the future risk of
childhood obesity (Karakosta et al., 2011). In a cohort study con-
ducted with 156 pregnant women from New Hampshire, cord
blood leptin levels were positively associated with maternal second
trimester urinary arsenic concentrations, particularly inorganic
arsenic and its main metabolites, which include pentavalent MMA
and pentavalent DMA. Thus, urinary arsenic concentration is pre-
dictive and influences infant cord blood leptin levels, after adjust-
ment by diverse variables. Furthermore, when comparing the 3rd
tertile of maternal total urinary arsenic to the 1st tertile in adjusted
models, cord blood leptin concentration tended to increase (37.7%)
(Gossai et al., 2015).
Arsenic exposure during pregnancy was also found to be posi-
tively associated with the presence of leptin in placental tissue at
birth (Ahmed et al., 2011). This study was conducted with 130
women located in rural areas of Bangladesh, where 70% of water
from wells exceed WHO guideline arsenic levels (10 mg/L), evalu-
ating maternal urinary arsenic collected at 30 weeks of gestation.
Please cite this article in press as: Ceja-Galicia, Z.A., et al., Effects of arsenic on adipocyte metabolism: Is arsenic an obesogen?, Molecular and
Cellular Endocrinology (2017), http://dx.doi.org/10.1016/j.mce.2017.05.008
However, urinary arsenic levels at gestational week 8 did not show
any association (Ahmed et al., 2011). In regard to postnatal serum
leptin levels, a significant increase occurred in the 6-month-old
offspring of pregnant CD-1 mice exposed to 42.5 mg/L sodium
arsenite in drinking water from gestational day 10 to birth; the
leptin values reached approximately 30 ng/ml compared to 10 ng/
ml in the controls (Rodriguez et al., 2016). With lower arsenite
doses (10 mg/L), serum leptin levels in the offspring only showed a
tendency to increase in comparison to the controls, with values
approximately 20 ng/ml (Rodriguez et al., 2016).
In contrast, maternal blood arsenic concentrations (around
1.14 mg/L) during the 1st and 3rd gestational trimesters in 1363
women from a Canadian cohort exposed to different metals in well
water, were not associated with cord blood adiponectin or leptin
levels (Ashley-Martin et al., 2015).
4. Effects of arsenic on lipid metabolism of adipocytes
In higher eukaryotes, TG depots in WAT represent the major
energy reserve. During energy surplus, adipocytes accumulate
excess fuel as TG for periods of negative energy balance, such as
fasting, starvation or long-term exercise (Fruhbeck et al., 2014). The
main mechanism by which WAT accumulates TG is lipogenesis,
which encompasses both de novo fatty acid synthesis (also referred
as de novo lipogenesis) and the esterification of fatty acids for TG
synthesis (Saponaro et al., 2015). The two main organs where de
novo lipogenesis takes place are the liver and the adipose tissue.
This mostly occurs after high-carbohydrate meals, where only some
of the carbohydrates are stored as hepatic glycogen, and the excess
carbohydrates are converted to fatty acids and TG (Ameer et al.,
2014; Saponaro et al., 2015; Solinas et al., 2015).
In contrast, one of the main actions of WAT is lipolysis, which is
TG hydrolysis to release glycerol and free fatty acids into the cir-
culation so they can be used as energy substrates by other organs.
Thus, under normal conditions, balance energy is achieved through
lipid storage and lipolysis (Maeda et al., 2009; Sethi and Vidal-Puig,
2007), however its dysregulation is key in the etiology of obesity
and other metabolic diseases (Fruhbeck et al., 2014; Saponaro et al.,
2015).
Aside from what is known about lipid metabolism in WAT,
scarce data related to the effects of arsenic on lipogenesis (Adebayo
et al., 2015; Garciafigueroa et al., 2013) and lipolysis in WAT (Ditzel
et al., 2016; Garciafigueroa et al., 2013; Liu et al., 2014) are available.
Changes in WAT weight and in the expression of genes involved
in lipid synthesis between the fed and the fasting states are
impaired by oral sodium arsenite exposure (100 mg/L or ppb in
drinking water for 5 weeks) in C57BL/6 mice (Adebayo et al., 2015).
As expected, refeeding doubles the amount of WAT in control mice,
accompanied by a significantly increment in the expression of
genes involved in fatty acid and TG synthesis, such as the tran-
scription factor sterol regulatory element-binding protein 1-c
(SREBP-1c) and the diglyceride acyltransferase-2 (DGAT-2). In
contrast, WAT weight during fasting in mice exposed to arsenic is
higher than in controls despite similar levels of SREBP-1c and
DGAT-2 mRNA. Additionally, no differences in WAT amounts were
observed in arsenite-exposed mice between those that were fed
and fasted for 6 h. Thus, the expression of DGAT-2 mildly increased
between fed and 6-h fasted mice, whereas the expression of SREBP-
1c remained unchanged (Adebayo et al., 2015). In accordance, ad-
ipocytes from the epididymal fat depot in C57BL/6 mice exposed to
100 mg/L sodium arsenite in drinking water for 5 weeks are
significantly hypertrophic (Garciafigueroa et al., 2013).
Arsenic induces insulin resistance in mouse myotubes (Padmaja
Divya et al., 2015), and in addition it also induces muscle wasting,
particularly muscle weakness, atrophy and sensorimotor
 Z.A. Ceja-Galicia et al. / Molecular and Cellular Endocrinology xxx (2017) 1e8
impairment through impairment mitochondrial myopathy and
altered oxygen consumption (Ambrosio et al., 2014). Arsenic also
inhibits myotubes differentiation (Yen et al., 2010) and regenera-
tion (Zhang et al., 2016). In fact, alterations in muscle fiber
composition and size may precede whole-body insulin resistance
in individuals with low birth weight, contributing to the develop-
ment of T2D (Jensen et al., 2007). Thus, all these myopathies may
increase the risk for T2D, as obesity also does. However, structurally
and metabolically altered muscle by arsenic that promotes skeletal
muscle insulin resistance and contributes to serum glucose eleva-
tion could result on an increase of de novo lipogenesis by adipose
tissue. In fact, Swiss Webster mice exposed to 100 mg/L sodium
arsenite in utero until 13 weeks after birth, demonstrated signifi-
cantly higher plasma TG than controls starting at 5 weeks of age, in
addition to elevated insulin resistance (Ditzel et al., 2016).
In relation to lipolysis, basal (not stimulated) glycerol release
used as a lipolysis marker, is significantly increased in cultured
adipocytes differentiated from hMSC within 24 h of 1 mM sodium
arsenite exposure, and the same effect is maintained within 72 h of
treatment (Garciafigueroa et al., 2013). This also occurs in subjects
with obesity (Langin et al., 2005), although no information
regarding the effects of arsenic upon stimulated-lipolysis is
available.
5. Effects of arsenic on glucose metabolism of adipocytes
One effect of insulin on adipose tissue is glucose uptake stim-
ulation, which is accomplished by the translocation of the glucose
transporter 4 (GLUT4) from intracellular deposits to the plasma
membrane (Bogan, 2012). Although adipose tissue accounts only
for 3e8% of whole-body glucose uptake (Kowalski and Bruce, 2014;
Virtanen et al., 2002), the proper uptake and metabolism of glucose
in adipocytes is crucial for normal tissue functioning (Gustafson
et al., 2015). Moreover, the actions of insulin in the muscle and
liver are also dependent on the proper functioning of glucose up-
take in adipose tissue. This leads to an adequate lipid biosynthesis
through pathways related to the transcription factor carbohydrate-
responsive element-binding protein (CHREBP) (Abel et al., 2001;
Herman et al., 2012). Thus, the impairment of insulin-stimulated
glucose uptake (ISGU) in adipose tissue leads to global glucose
intolerance, insulin resistance, altered lipolysis and lipogenesis
(Abel et al., 2001; Carvalho et al., 2001; Smith, 2002). In this
context, adipose tissue glucose uptake impairment by environ-
mental pollutants, such as arsenic, could prime the entire body for
metabolic alterations.
The first studies addressing the effects of arsenic on glucose
uptake in adipocytes showed that basal glucose uptake (insulin-
independent) significantly decreased in 3T3-L1 adipocytes exposed
to 100, 5 and 1 mM sodium arsenite, trivalent monomethylarsonic
acid (MMA), and sodium arsenate (pentavalent arsenic), respec-
tively, for 4 h (Walton et al., 2004). Additionally, ISGU is signifi-
cantly diminished in a dose-dependent manner with lower doses of
arsenic (20e50 mM sodium arsenite or 1e2 mM trivalent MMA)
(Paul et al., 2007; Walton et al., 2004) and the effects of sodium
arsenite are also time-dependent (Walton et al., 2004). One key
mechanism by which a 4-h exposure to sodium arsenite (50 mM)
and trivalent MMA (2 mM) decreases ISGU is through the inhibition
of the PDK-1/Akt insulin signaling pathway by impairing Akt
phosphorylation at Ser473 and Thr308 and thus reducing the
translocation of GLUT4 from the perinuclear compartment to the
plasma membrane in response to insulin (Paul et al., 2007; Walton
et al., 2004).
Despite the clear suppression effects of acute arsenic on glucose
uptake in adipocytes showed by Walton et al and Paul et al (Paul
et al., 2007; Walton et al., 2004), the doses used in these studies
Please cite this article in press as: Ceja-Galicia, Z.A., et al., Effects of arsenic on adipocyte metabolism: Is arsenic an obesogen?, Molecular and
Cellular Endocrinology (2017), http://dx.doi.org/10.1016/j.mce.2017.05.008
5
are at least five-fold higher compared to the arsenic levels found in
the blood of individuals exposed to arsenic in drinking water
(Lemarie et al., 2006; Pi et al., 2000; Wu et al., 2003). Further works
have also shown that lower doses of arsenite (up to 2 mM) signifi-
cantly reduced ISGU in fully differentiated 3T3-L1 adipocytes in a
dose- and time-dependent manner after 4 and 7 days of exposure
(Xue et al., 2011). Such impairment is thought to be through the
induction of oxidative stress and inflammatory response, particu-
larly though the activation of nuclear factor erythroid 2-related
factor 2 (known as NRF2), which inhibits Akt Ser473 phosphory-
lation and decreases GLUT4 expression (Xue et al., 2011).
Exposure to the same doses of sodium arsenite for 8 weeks prior
3T3-L1 adipocytes differentiation also reduced ISGU in a dose-
dependent manner by decreasing GLUT4 abundance upon insulin
stimulation as well as reducing GLUT4 in the perinuclear region
(Padmaja Divya et al., 2015). The mechanism proposed also in-
cludes oxidative stress through the generation of reactive oxygen
species due to a dramatic reduction in the expression of the
mitochondrial deacetylase Sirt3 and the decreased binding activity
of its associated transcription factor forkhead box O3 (known as
FOXO3a) to the manganese superoxide dismutase and PPARg
coactivator (PGC)-1a gene promoters (Padmaja Divya et al., 2015).
Thus, these works suggest that one mechanism by which arsenic
impairs insulin signaling and ISGU is by inducing oxidative stress.
In fact, oxidative stress from excessive reactive oxygen species
production and mitochondrial dysfunction are major factors in the
development of insulin resistance in T2D (Padmaja Divya et al.,
2015).
In regard to transgenerational studies, the increase in weight
gain in CD-1 mice exposed to sodium arsenite in utero (10 mg/L and
42.4 mg/L) from gestational day 10 to birth (Rodriguez et al., 2016),
and in Swiss Webster mice exposed to 100 mg/L sodium arsenite in
utero until 13 weeks after birth (Ditzel et al., 2016), was accompa-
nied by glucose intolerance at 5 months old and insulin resistance
observed from 5 weeks after birth, respectively.
6. Concluding remarks
Based on the elevated number of individuals exposed to arsenic
worldwide through drinking water, it is important to precisely
unravel the role arsenic plays in the epidemic of obesity, taking into
account that the obesogen hypothesis is becoming stronger with
each study.
Weight gain impairs the proper function of many organs,
particularly adipose tissue itself. In this sense, the majority of the
effects of arsenic evaluated both in vitro and in vivo on adipose
tissue that are known until now suggest that arsenic can negatively
affect adipocytes/WAT metabolism. While arsenic diminishes adi-
pogenesis in pre-adipocytes, it can concomitantly increase adipo-
cyte size or WAT weight. Arsenic increases basal lipolysis in vitro as
well as lipogenesis at fasting, reduces basal glucose uptake and
ISGU, and down-regulates adiponectin mRNA expression. The
transgenerational effects of arsenic include alterations in birth
weight, higher postnatal weight gain with elevated body fat con-
tent, glucose intolerance, insulin resistance, and increased serum
TG. Transgenerational effects of arsenic also include elevation of
leptin in cord blood, in the placenta as well as on postnatal serum
levels (Fig. 1).
Finally, although there is evidence that arsenic alters various
aspects of adipose tissue metabolism, it is still unknown, as for
many endocrine-disrupting chemicals (Darbre, 2017), if its mech-
anism of action is to promote weight gain by adipocyte hypertrophy
directly or primary. There is also evidence that arsenic can interacts
with other environmental factors, such as high-fat diets (Paul et al.,
2011), or folate-related nutrients (Heck et al., 2007), among others,
6 Z.A. Ceja-Galicia et al. / Molecular and Cellular Endocrinology xxx (2017) 1e8
Fig. 1. Effects of arsenic on white adipocytes upon growth, adipokines, and lipid and glucose metabolism. Postnatal (PN). Studies conducted with direct, transgenerational (Tgn) or
transgenerational and postnatal (Tgn-PN) arsenic exposure.
to modulate positively or negatively its obesogenic effects or
arsenic-related diseases. In addition, the metabolism of arsenic also
plays an important role in its effects. The metabolism of arsenic is
influenced both, by polymorphisms in enzymes involved in arsenic
metabolism, particularly in arsenic (þ3 oxidation state) methyl-
transferase (known as AS3MT) (Agusa et al., 2015; Douillet et al.,
2016; Gomez-Rubio et al., 2011), as well as by BMI, however
there is still controversy related to this last point (Gomez-Rubio
et al., 2011; Gribble et al., 2013; Hudgens et al., 2016; Kuo et al.,
2015; Lindberg et al., 2008; Su et al., 2012).
Thus, based on all the findings presented, arsenic is a potential
obesogen, though more studies are needed to address this issue
accurately.
Conflict of interest
We declare no conflict of interest.
Acknowledgments
This work was supported by DGAPA-UNAM through grant
IA203316 to ADV and Programa Institucional de Estrategias de
Prevencio
n en Obesidad y Diabetes del Instituto de Investigaciones
Biome
dicas.
We acknowledge to the Unidad de Posgrado, UNAM and to
Conacyt Mexico for the postgraduate scholarships to ZACG, AD and
PP.
Please cite this article in press as: Ceja-Galicia, Z.A., et al., Effects of arsenic on adipocyte metabolism: Is arsenic an obesogen?, Molecular and
Cellular Endocrinology (2017), http://dx.doi.org/10.1016/j.mce.2017.05.008
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