65© Springer International Publishing Switzerland 2016
S.I. Ahmad, S.K. Imam (eds.), Obesity: A Practical Guide, DOI 10.1007/978-3-319-19821-7_6
Oxidative Stress and Obesity
Isabella Savini , Valeria Gasperi ,
and Maria Valeria Catani
Obesity is a nutritional disorder, characterized by
abnormal or excessive fat accumulation, as a result
of adipocyte hypertrophy (increase in size) and/or
hyperplasia (increase in cell number). It represents
a serious risk to health, as it increases the likelihood
of several pathologies (including metabolic syn-
drome, Type 2 diabetes, cardiovascular diseases,
non-alcoholic fatty liver disease, cancer, sleep
apnoea and gynaecological pathologies), thus
reducing quality of life and life expectancy [
A lot of evidence has shown that obesity is a
state of chronic oxidative stress, although it is not
completely understood if alteration in redox bal-
ance is a trigger rather than a result of obesity
2 – 19 ]. Overfeeding, high-fat (especially rich in
saturated and trans-fatty acids) and high-
carbohydrate meals stimulate speciﬁ c signalling
pathways, promoting oxidative stress and inﬂ am-
mation in different cell types [
20 – 23 ]. On the
other hand, oxidative unbalance alters food intake
[ 24 , 25 ] and stimulates adipocyte proliferation
and differentiation, thus playing a crucial role in
controlling body weight [ 26 – 28 ].
Systemic oxidative stress is achieved through
multiple biochemical mechanisms, including
superoxide generation, endoplasmic reticulum
stress, glyceraldehyde autoxidation, enhanced
ﬂ ux in the polyol and hexosamine pathways, and
activation of redox-sensitive kinases and tran-
scription factors [
29 , 30 ]. Noticeably, in obese
individuals, oxidative stress is so closely inter-
linked with inﬂ ammation as to trigger a vicious
circle: oxidants activate speciﬁ c redox-sensitive
transcription factors [including nuclear factor-kB
(NF-kB) and activator protein-1 (AP-1)], which
drive the expression of pro-inﬂ ammatory cyto-
kines; these mediators, in turn, enhance produc-
tion of reactive oxygen species (ROS), thus
contributing to the onset and maintenance of oxi-
dative stress [
Besides pharmacological approach, several
strategies (weight reduction, physical activity
and antioxidant-rich diet) may be taken to lower
oxidative stress in obesity. Firstly, weight loss
and/or physical activity increase antioxidant
defences, thus decreasing oxidative markers and
risks for obesity co-morbidities [
32 – 36 ].
Secondly, diet rich in fruits, vegetables, ﬁ sh and
olive oil helps to maintain the right weight and
reduce the risk of metabolic diseases [ 37 – 39 ].
Certain nutrients (including monounsaturated
fatty acids, ω-3 polyunsaturated fatty acids, vita-
mins C and E, phytochemicals and probiotics)
contained in such food may account for reduced
oxidative stress and inﬂ ammation observed in
obese subjects [
40 – 44 ]. Although underlining
healthy effects, nonetheless observational and
human intervention studies failed to demonstrate
I. Savini (*) • V. Gasperi • M. V. Catani
Department of Experimental Medicine and Surgery ,
University of Rome Tor Vergata ,
Via Montpellier 1 , Rome 00133 , Italy
the efﬁ cacy of a single dietary component [ 45 ];
rather, it is likely that the beneﬁ cial effects on
reduction of oxidative stress observed in obese
subjects have to be ascribed to cumulative effects
of multiple nutrients.
Oxidative Stress: An Overview
In the last 40 years, vast array of data have tried
to elucidate the mechanisms involved in the
maintenance of redox state in humans; however,
some critical issues, related to interpretation of
data obtained on in vitro experimental models,
have been raised as well [
46 – 48 ]. In addition, this
research ﬁ eld often experiences confusion about
the correct meaning of some terms. Below, a
brief description of concepts commonly used in
studies on redox balance is given.
Any molecule that contains one or more unpaired
electrons, with a half-life varying from a few
nanoseconds (very reactive radicals) to seconds
and hours (rather stable radicals).
A molecule with the ability to scavenge free radi-
cals and hence able to protect biological targets
(DNA, proteins, and lipids) against oxidative
Reactive Oxygen Species (ROS)
A collective term that includes radical (hydroxyl
. OH, or superoxide O
2 −. ) and non-radical
(hydrogen peroxide H
2 O 2 ) derivatives of oxygen.
Reactive Nitrogen Species (RNS)
A term including derivatives of nitrogen, such as
nitric oxide (NO), nitrogen dioxide (NO 2 . ), dinitrogen
2 O 3 ) and peroxynitrite (ONOO
Injury caused by RO(N)S to cells and tissues.
A term formulated by Sies in 1985, referring to a
signiﬁ cant imbalance between RO(N)S genera-
tion and antioxidant protection (in favour of the
former), causing excessive oxidative damage
48 ], depending on the cellular source and/or the
major ROS produced. It can be sub-classiﬁ ed in
metabolic, environmental, drug-dependent or
nutritional oxidative stress [
20 ]. Main ROS and
RNS, together with their biochemical character-
istics, are summarized in Table 6.1 .
All these reactive species, RO(N)S, are con-
tinuously produced through cellular metabolism
and also act as signalling molecules. Indeed these
reactive species, if maintained below a critical
threshold value, may play regulatory roles in a
range of biological phenomena [
49 , 50 ].
Mitochondria are the major site of intracellular
ROS production, due to electron leakage along
the respiratory chain; other sources include
plasma membrane systems, endoplasmic reticu-
lum (ER), lysosomes, peroxisomes and cytosolic
At low concentrations, RO(N)S act as sec-
ondary messengers, modulating speciﬁ c signal
transduction pathways that, in turn, regulate cell
homeostasis, proliferation, differentiation and
cell death. Moreover, RO(N)S can directly or
indirectly be involved in immune-mediated
defence against pathogenic microorganisms
46 ]. These physiological effects are mainly
mediated by changes in the redox state of crucial
intracellular and/or surface thiols. Indeed, the
RO(N)S-triggered reversible modiﬁ cation of
sulphur- containing amino acids represents a
common post-translational mechanism for regu-
lating the activity of enzymes, transporters,
receptors and transcription factors. Spatial and
temporal regulation includes covalent modiﬁ ca-
tion of cysteine thiols within the active and allo-
steric sites of enzymes, oxidation of iron-sulphur
clusters, S-glutathionylation (disulﬁ de link
between protein thiols and glutathione),
I. Savini et al.
S-nitrosylation (reaction between NO and thiol
radical), and S-nitrosation (reaction between
nitrosonium ion and protein thiolates).
Conversely, RO(N)S over- production (often cou-
pled with impaired antioxidant defences) can
damage DNA, lipids and proteins; thus poten-
tially being harmful to living organisms and
being causative of several pathologies, including
metabolic alterations, cardiovascular and neuro-
degenerative diseases, and cancer [
To keep RO(N)S at correct levels, tissues pos-
sess antioxidant molecules working in synergy to
minimize free radical cytotoxicity. The main
endogenous antioxidant compounds include: (i)
enzymes, such as superoxide dismutase (SOD),
glutathione peroxidase (GPx), glutathione
reductase, glutathione S-transferase, catalase,
thioredoxin reductase, peroxiredoxins (Prx),
NAD(P)H:ubiquinone oxidoreductase (NQO1),
heme oxygenase-1 (HO-1) and paraoxonase-1
(PON- 1); (ii) low molecular weight molecules,
such as urate, glutathione, ubiquinone and thiore-
doxin; and (iii) some proteins (ferritin, transfer-
rin, lactoferrin, caeruloplasmin) able to bind and
sequester transition metals that may trigger oxi-
dative reactions. Exogenous antioxidants, com-
ing from diet, include: vitamin C, vitamin E and
a broad spectra of bioactive compounds (such as
phytochemicals); other important nutrients are
certain minerals (zinc, manganese, copper and
selenium) that are crucial for the activity of anti-
oxidant enzymes [
Table 6.1 Main reactive oxygen/nitrogen species and relative features
RO(N)S Reaction Description
O 2 • − ( superoxide ) O 2 + e − → O 2 • − Oxygen with an extra electron.
Produced by: mitochondrial electron
transport chain; NADPH oxidases;
xanthine oxidase; LOX; COX;
H 2 O 2 ( hydrogen peroxide ) 2O 2 • − + 2H + → 2H 2 O 2 + O 2 Formed by the action of SOD.
Intracellular signalling. Low intrinsic
HOCl ( hypochlorous acid ) H + + Cl
− + H 2 O 2 → HOCl + H 2 O Formed by the action of MPO.
It inhibits bacterial DNA replication by
destroying anchorage at the membrane.
HO• ( hydroxyl radical ) HOCl + O 2 • − → HO• + O 2 + Cl −
HOCl + Fe 2+ → HO• + Fe 3+ + Cl
HOCl + Cu + → HO• + Cu 2+ + Cl
H 2 O 2 + Fe 2+ → HO• + Fe 3+ + OH
H 2 O 2 + Cu + → HO• + Cu 2+ + OH
H 2 O 2 + O 2 • − → HO• + O 2 + Cl −
Produced spontaneously by HOCl with
2 • − or metal ions and by H
2 O 2 through
ROO• ( peroxy radicals )
ROOH ( organic hydroperoxide )
RO• ( alkoxy radicals )
RH + O 2 → R• + •OH
R• + O 2 → ROO•
ROO• + RH → R• + ROOH
ROOH → RO• + HO −
Produced by the attack of oxygen
radicals on unsaturated lipids (RH).
NO ( nitric oxide ) L-arginine + O 2 + NADPH →
L-citrulline + NO + NADP + + e −
Formed by the action of NOS. Free
At physiological concentrations, it acts
as intracellular messenger. It conjugates
ONOO − ( peroxynitrite ) NO + O 2 • − → ONOO − Formed through the action of SOD.
It reacts directly with proteins
containing transition metal centres.
N 2 O 3 ( dinitrogen trioxide ) •NO + ·NO 2 ⇆ N
2 O 3 Strongly oxidizing agent.
It causes nitrosylation of phenols.
RO(N)S reactive oxygen/nitrogen species, COX cyclooxygenase, GSH reduced glutathione, LOX lipoxygenase, NOS
nitric oxide synthase, SOD superoxide dismutase, MPO myeloperoxidase
6 Oxidative Stress and Obesity
Biomarkers of Redox State
Oxidative stress can be evaluated by direct
assessment of free radical production or by indi-
rect methods that assess end-products of oxida-
tive damage to proteins, lipids and nucleic acids
in blood and urine (Table
Direct measures of free radicals, carried out by
electron spin resonance (ESR) or by immuno spin-
trapping methods are difﬁ cult and expensive;
therefore, even if promising, they mostly are inap-
plicable in human research [
52 ]. Oxidative damage
to proteins is normally assessed by measuring
plasma protein carbonyls, 3-nitrotyrosine,
advanced glycosylation end products (AGEs) and
advanced oxidation protein products (AOPPs).
Indicators of lipid peroxidation are F2-isoprostanes,
malondialdehyde (MDA), oxidized LDL (oxLDL),
thiobarbituric acid reactive substances (TBARs)
and 4-hydroxynonenal (4-HNE). Some biomarkers
(such as F2-isoprostanes) are highly sensitive,
while others (such as TBARs) are much less sensi-
tive and speciﬁ c. Furthermore, F2-isoprostanes
reﬂ ect both acute and chronic oxidative stress.
DNA oxidative damage is usually evaluated by
measuring urinary 8-hydroxy-2′-deoxyguaine [
56 ]. Several studies also employed NADPH oxi-
dase or myeloperoxidase activities in neutrophils.
The ﬁ rst enzyme is a plasma membrane enzyme
catalysing the mono-electronic reduction of exog-
enous oxygen using NADPH as an internal elec-
tron donor (thus producing O
2 −. ), while the second
enzyme is heme-containing protein catalysing the
reaction between chloride and H
2 O 2 (thus generat-
ing the potent oxidant hypochlorous acid) [
Another method, widely used to investigate
oxidative stress in various diseases and in post-
prandial responses, is ROS generation by isolated
mononuclear cells [ 22 ]. Other promising bio-
markers of oxidative stress include urinary levels
of allantoin (produced by the oxidative break-
down of urate), acrolein-lysine and dityrosine
56 ]. Finally, a stable, sensitive and inexpensive
method to assess changes in oxidant levels is the
measurement of total oxidant status (TOS),
which is based on the oxidation of ferrous ion to
ferric ion in the presence of oxidative species in
the acidic medium. By this method, additive
effects exerted by different oxidant molecules
can easily be determined at the same time [ 58 ].
Plasma antioxidant proﬁ les may be useful in
conjunction with other biomarkers to measure the
levels of oxidative stress. The most widely used
biomarkers of the antioxidant state are serum con-
centrations of antioxidant molecules (retinol,
carotenoids, vitamin E, vitamin C, glutathione,
uric acid), minerals (selenium and zinc), as well
as antioxidant enzyme (SOD, catalase, glutathi-
one reductase, PON1). Another useful biomarker
is the total antioxidant capacity (TAC), which
evaluates the integrated action of some plasma
antioxidants (uric acid, protein thiols and vitamin
20 ]. Finally, quantitative proteomic is emerg-
ing as an additional approach to simultaneously
evaluate any change taking place in different
members of the antioxidant enzyme network [
Evidence for Obesity-Related
Oxidative Stress in Humans
Substantial cross-sectional studies have outlined
the presence of altered redox state in obese sub-
jects and redox imbalance has been demonstrated
by the way of increased oxidative stress biomark-
ers and/or decreased antioxidant defences, both
in obese children and adults.
Impairment of body defences in obese sub-
jects may arise either from inadequate intake of
antioxidant micronutrients and phytochemicals,
from metabolic alterations leading to modiﬁ ca-
tions in the endogenous antioxidant machinery,
or from enhanced requirements due to RO(N)S
over-production. Currently, the relationship
between body mass index (BMI), body fat, and
antioxidant defences is still an open question,
especially concerning the expression and activity
of antioxidant enzymes [ 34 , 60 – 63 ]. Controversial
data, however, may be explained in terms of
time-window, as tissues, at the onset of obesity,
increase the activity of antioxidant enzymes in
order to counteract oxidative stress, but, as obe-
sity goes on, the antioxidant apparatus is progres-
In recent years, particular attention has been
given to the assessment of redox state in obese
I. Savini et al.
Table 6.2 Common markers used to measure oxidative stress in tissue and/or body ﬂ uids
Oxidative effects Biomarker Characteristics
Lipid peroxidation F2-IsoPs Speciﬁ c and stable products of arachidonic acid peroxidation.
MDA End product of the polyunsaturated lipid peroxidation pathway.
Capable of binding to proteins and forming stable adducts, also
termed advanced lipid peroxidation end products.
TBARs By-product of lipid peroxidation, estimated by using
thiobarbituric acid as a reagent. Assay product estimate of MDA
4-HNE Primary α, β-unsaturated hydroxyalkenal produced by lipid
peroxidation. 4-HNE protein adducts are typically more stable
than MDA protein adducts.
Ox-LDL LDL is the major transport protein for cholesterol in human
plasma. Its oxidation is catalysed by transition metal ions, free
radicals, and some oxidizing enzymes. When oxidized, it is
speciﬁ cally recognized by macrophages, leading to foam cell
Protein carbonyls Derived from oxidative cleavage of the protein backbone, direct
oxidation of amino acids (such as lysine, arginine, histidine,
proline, glutamic acid, and threonine), or binding of aldehydes
produced from lipid peroxidation.
3-nitrotyrosine Product of nitration of tyrosine by reactive nitrogen species.
AGEs Products derived from the reaction between carbohydrates and
free amino group of proteins. The most common are the very
unstable, reactive pentosidine and carboxyl methyl lysine.
AOPPs Uremic toxins formed during oxidative stress through the reaction
of chlorinated oxidants (such as chloramines and HOCl) with
plasma proteins. Indicators of nitrosative stress.
Acrolein-lysine Derived from the attack of acrolein (the most reactive aldehyde
produced from lipid peroxidation) with lysine.
Dityrosine Formed by free-radical attack on tyrosine residues, resulting in
generation of tyrosyl radical, which in turn yield the stable
cross-linked product dityrosine.
8-OHdG Oxidized derivative of deoxyguanosine of nuclear and
8-OHG Oxidative derivative of guanosine.
NADPH oxidases NADPH oxidase family of ROS- generating enzymes with
different subcellular localizations. They are differentially
expressed and regulated in various tissues.
MPO Heme-containing enzyme that generates the potent oxidant HOCl
in activated neutrophils.
Others GSSG/GSH ratio It evaluates the increased oxidation of glutathione. Under normal
conditions, reduced GSH constitutes up to 98 % of cellular
TOS It evaluates overall oxidant molecules. It is based on oxidation of
2+ to Fe
3+ in the presence of various oxidative species.
Allantoin Produced by the oxidative breakdown of urate, the terminal
product of purine metabolism.
4-HNE 4-hydroxynonenal, 8-OHdG 8-hydroxy-2′-deoxyguanosine, 8-OHG 8-hydroxyguanosine, AGEs advanced gly-
cosylation end products, AOPPs advanced oxidation protein products, F2-IsoPs F2-isoprostanes, GSSG/GSH ratio
reduced/oxidized glutathione, MDA malondialdehyde, MPO myeloperoxidase, Ox-LDL oxidized low-density lipopro-
teins, TBARs thiobarbituric acid reactive substances, TOS total oxidant status
6 Oxidative Stress and Obesity
children and adolescents, with or without the
simultaneous presence of metabolic alterations
(insulin resistance and steatosis), since these
patients show higher risk to early develop
obesity- associated chronic diseases. Moreover,
children and adolescents often have poor intakes
of vegetables and fruit, as well as micronutrient
deﬁ ciencies (iron, zinc, vitamins A, E and C),
that may contribute to oxidative stress [
A signiﬁ cant inverse relation has been found
between adiposity and serum concentrations of
carotenoids and vitamin E, in Mexican-American
children (8–15 years of age), included in the
2001–2004 U.S. National Health And Nutrition
Examination Survey (NHANES). The ﬁ nding has
been conﬁ rmed in NHANES III (as well as in
separate studies carried out in the United States,
Brazil, France, and Italy) that pointed out lower
serum levels of lipophilic vitamins in overweight
or obese children and adolescents with respect to
normal-weight counterparts(despite similar daily
intakes of fruit and/or vegetables) [
11 , 64 ]. These
differences seem to be not gender-speciﬁ c, since
similar results have been obtained in boys and
girls [ 11 ]. Also vitamin E and C levels appear to
be inversely proportional with body fat, abdomi-
nal fat and waist/height ratio, in 197 Mexican
school-aged children. In addition, low
concentrations of zinc, vitamins A and E appear
to be positively correlated with insulin resistance
and inﬂ ammation in overweight or obese children
8 ]. Deﬁ ciencies in selenium and zinc have also
been reported in children with central adiposity
65 , 66 ]. Finally, a relationship between glutathi-
one homeostasis and obesity has been proven: a
signiﬁ cant reduction in total, reduced and oxi-
dized glutathione as well as in glutathionylated
proteins has been found in 30 obese children [
As mentioned before, less clear are investiga-
tions carried on antioxidant enzymatic activities.
Sfar and colleagues reported increased SOD activ-
ity in 54 obese healthy children (aged 6–12 years),
while GPx and CAT activities appeared unaffected
9 ]. Conversely, Sun’s group documented a
decrease in SOD activity, associated with increased
MDA levels and NADPH oxidase activity, in 93
overweight adolescents [ 10 ]. Similarly, lower thiol
content and SOD activity (paralleled by enhanced
GPx1 and catalase activities) have been found to
be related to central obesity, in 156 children and
adolescents (47 lean, 27 overweight and 82 obese
subjects). This cohort also showed inverse relation
between PON1 activity and central obesity. All
these associations were gender dependent: PON1
catalytic activity appeared to be sensitive to oxida-
tive stress in girls, while being modulated by
inﬂ ammation in boys [
16 ]. Accordingly, Agirbasli
reported a negative correlation between BMI and
PON1 catalytic activity, while Torun found that
PON1 activity signiﬁ cantly increased in 109 obese
children and adolescents (either with or without
12 , 17 ].
Juvenile overweight and obesity is also linked
to high levels of oxidative stress and inﬂ amma-
tion markers [
67 , 68 ]. Pirgon and co-workers
found decreased TAC values in obese adoles-
cents (either with or without steatosis), increased
oxidative stress index (TOS/TAC ratio) and insu-
lin resistance [
69 ]. Decreased TAC and increased
oxidative stress was also found in 25 Caucasian
obese children [
70 ]. Conversely, Torun’s group
reported comparable oxidative stress indexes in
obese and lean children, and increased TAC mea-
surements in obese children with non-alcoholic
fatty liver disease (NAFLD) [
Central obesity, triglycerides and insulin corre-
lated also with oxidative stress markers. A positive
correlation between AOPPs and obesity has been
found in children and adolescent; this marker also
correlated with glucose/insulin ratio and HDL-
cholesterol [ 71 , 72 ]. In 112 overweight and obese
children (7–11 years old), F2-isoprostane concen-
trations were positively linked to body mass index
(BMI), waist circumference, insulin resistance,
and dyslipidemia, while being inversely associated
with ﬁ tness (peak of oxygen consumption:
2 max) [ 73 ]. Similar results have been obtained
in a study enrolling 82 African American and 76
White American youth (8–17 years old) [
68 ]. In a
cross- sectional study, severely obese Caucasian
children (7–14 years old) showed enhanced levels
of AOPPs and inﬂ ammatory markers [ 72 ].
Mineral and vitamin deﬁ ciencies are often
detected in obese adults [
74 – 76 ]. Studies on
Coronary Artery Risk Development in Young
Adults (CARDIA) showed a strong inverse rela-
tionship between BMI and serum carotenoids
(α-carotene, β-carotene, β-cryptoxanthin, zeaxan-
I. Savini et al.
thin/lutein) [ 77 ]. The multicentre prospective pop-
ulation study of diet and cancer in Europe (EPIC)
reported inverse correlation between plasma vita-
min C concentrations and central fat distribution
[ 78 ]. As obesity goes on, a linear rate of deﬁ ciency
of vitamins A, B
6 , C, D and E has been noted [ 79 ].
Several experimental and clinical trials have
shown that the catalytic activity of antioxidant
enzymes is often reduced in adult obese subjects,
although available data remain ambiguous and
unconﬁ rmed. Indeed, obese individuals with insu-
lin resistance appear to have lower plasma SOD
activity and higher GPx activity than healthy, lean
80 ]. In addition, serum GPx activity
seems to be positively correlated with weight
reduction [ 63 ]. Accordingly, several studies under-
lined an inverse relationship between BMI and
antioxidant enzyme activities (especially SOD,
catalase, PON1 and GPx) [
13 , 61 , 62 , 81 , 82 ].
In a population-based (3042 Greek adults)
study, an inverse relationship was found between
waist circumference and TAC, regardless of vari-
ations in, sex, age, physical activity, smoking,
and dietary habits [
83 ] Comparable reduction in
TAC measurements (together with low levels of
vitamins C and E and high levels of hydroperox-
ides and carbonyl proteins) was observed in
young and old obese patients, and signs of oxida-
tive stress were aggravated in older adults [
Concerning biomarkers of oxidative stress,
levels of F2-isoprostane, protein carbonyl, TOS,
oxLDL and TBARs have been shown to be posi-
tively associated with BMI and waist circumfer-
ence in adults [
2 , 3 , 14 , 82 , 85 , 86 ]. In addition,
endothelial dysfunction and endothelial NADPH
oxidase activity were found to be associated with
central adiposity markers (waist circumference
or waist-to-hip ratio) [
87 ]. Interestingly, associa-
tion of central adiposity markers with oxLDL and
TAC is more evident in women, thus suggesting
that changing the gynoid to android phenotype
may lead to an unfavourable redox state in young
women rather than in men [
Recently, several studies have focused on the
relationship between obesity and redox state dur-
ing pregnancy. In a prospective case-control study,
obese pregnant women showed increased inﬂ am-
mation and oxidative stress (low levels of vitamins
6 , C, E, and folate, high levels of GSSG/GSH
ratio, C-reactive protein and IL-6), with respect to
lean pregnant women. Newborns from these obese
mothers, however, did not show signiﬁ cant
changes in oxidative stress and inﬂ ammation [ 89 ].
On the other hand, dysregulation of redox balance
in the mother-placenta-fetus axis has been reported
by Malti’s group; maternal, foetal and placental
tissues coming from obese women (pre-pregnancy
BMI > 30 kg/m 2 ) showed higher oxidative stress
(MDA, carbonyl proteins, O
2 − , NO) and lower
antioxidant defences (GSH and SOD activities), if
compared to control pregnant women, and varia-
tions of redox balance were also observed in new-
borns from these obese mothers [
In obese women, oxidative stress may also be
associated with gynaecological disorders. A sys-
tematic meta-analysis showed increased SOD
activity, decreased GSH levels and decreased
PON1 activity in patients with polycystic ovary
91 ]. Also localised oxidative stress
and insulin resistance (in abdominal adipose tis-
sue) seem to play a crucial role in the pathogen-
esis of this syndrome [
In conclusion, conﬂ icting results emerging
from cross-sectional and intervention studies in
obesity ﬁ eld are difﬁ cult to interpret. However,
they could be explained in terms of the use, in
each investigation, of single or only few, insensi-
tive, non-speciﬁ c markers of redox state [
53 ]. The
best and unambiguous results demonstrating the
relationship between oxidative stress and obesity
have been obtained when several oxidant and
antioxidant molecules were considered together
or when urinary isoprostanes (the best available
biomarker of lipid peroxidation) were measured.
Mechanisms Underlying Oxidative
Stress in Obesity and Oxidative
Mechanisms Underlying Oxidative
Oxidative stress is clearly connected with obesity,
although it is not fully understood the real cause-
effect relationship. Nutritional overload (espe-
cially after consumption of high-fat
high- carbohydrate meals, as well as of high
6 Oxidative Stress and Obesity
dietary saturated fatty acids and trans-fatty acids)
leads to oxidative stress by different mechanisms
23 ]. On the other hand, oxidative stress could
play a causative role in the development of obe-
sity, by altering food intake and stimulating adi-
pocyte proliferation and differentiation [
24 – 28 ].
Several factors contribute to obesity-associated
oxidative stress, including abnormal post-prandial
ROS generation, low antioxidant defences, hyper-
leptinemia, tissue dysfunction and chronic
inﬂ ammation [
2 – 22 , 92 , 93 ]. In this context, it
should be recalled that a vicious circle can be
established: ROS activate redox sensitive tran-
scription factors [including nuclear factor-kB
(NF-kB) and activator protein-1 (AP-1)], which in
turn promote over-expression of inﬂ ammatory
cytokines that lead to exacerbation of ROS pro-
31 ] (Table 6.3 ).
In obese subjects, the adipocytes surpass to
non-physiological limits and become unable to
Table 6.3 Potential mechanisms accounting for oxidative stress in obesity
Obesity-associated conditions Metabolic changes
Effects on redox/inﬂ ammatory
Hyperlypidemia ATP accumulation in mitochondria.
Mitochondrial DNA damage
Pro-inﬂ ammatory cytokine
increase. Endoplasmic reticulum
Adipose tissue dysfunction Adipose tissue macrophage inﬁ ltration ROS overproduction.
Pro-inﬂ ammatory cytokine
Antioxidant enzymes decrease.
Endoplasmic reticulum stress.
Hyperglycemia Increased glycolysis and tricarboxylic acid
Increased polyol pathway NADPH depletion
Increased AGEs Stimulation of NF-kB, NADPH
oxidases and iNOS
Activation of PKC Stimulation of NF-kB and iNOS.
Aberrant expression of speciﬁ c
Increased hexosamine pathway Thioredoxin inhibition.
Endoplasmic reticulum stress.
Pro-inﬂ ammatory cytokine
Endothelial dysfunction Chronic inﬂ ammation and monocyte
Activation of NADPH oxidases,
xanthine oxidase and iNOS.
Pro-inﬂ ammatory cytokine
Hyperleptinemia Increased mitochondrial and peroxisomal
fatty acid oxidation. Monocytes/
Pro-inﬂ ammatory cytokine
Genetic variants (SNPs) Altered activity of GPx, PON1, catalase,
peroxiredoxins, SOD, NADPH oxidases,
PPARγ, PGC1α, Nrf2
Antioxidant enzymes decrease.
AGEs advanced glycosylation end products, iNOS inducible nitric oxide synthase, PKC protein kinase C, ROS reactive
oxygen species, SOD superoxide dismutase, GPx glutathione peroxidase, PON1 paraxonase 1, PPARγ peroxisome
proliferator activated receptor γ, PGC1α PPARγ co-activator 1α, Nrf2 nuclear factor E2-related factor 2, SNPs single
I. Savini et al.
function as an energy storage organ; therefore, fat
is improperly accumulated in heart, muscle, liver
and pancreas, where it can trigger these organs’
dysfunction. In particular, adipose tissue dys-
function contributes to the onset of oxidative
stress, by increasing expression of adipokines
(MCP-1, -2, -4, and macrophage inﬂ ammatory
protein (MIP) -1α, -1β, -2α) that trigger macro-
phage inﬁ ltration and subsequent overproduction
of ROS and inﬂ ammatory cytokines [
94 , 95 ].
Simultaneously, the activity of the redox- sensitive
transcription factor, nuclear factor E2-related
factor 2 (Nrf2) becomes impaired. As a result, the
expression of Nrf2 downstream targets (antioxi-
dant and phase II detoxifying enzymes) is inhib-
ited, leading to the weakening of the body
antioxidant defences [
96 ]. Also bioavailability of
antioxidant molecules may be impaired, as is the
case with vitamin C. Also, sodium-dependent
vitamin C transporters expression has been
shown to be modulated by metabolic and/or oxi-
dative stress, thus affecting cellular uptake and
the overall homeostasis of this vitamin [
Additionally, intracellular triglyceride accu-
mulation triggers lipotoxicity, by inhibiting the
adenosine nucleotide translocator (ANT) leading
to ATP accumulation into mitochondria.
Mitochondrial ADP fall reduces the speed of oxi-
dative phosphorylation and mitochondrial uncou-
pling promotes electron leakage and ROS
generation. High fat diet-induced mitochondrial
dysfunction also triggers the endoplasmic reticu-
lum (ER) stress. The ER is a cytosolic organelle
that participates in the regulation of lipid, glucose
and protein metabolism, apart from being at the
site where protein folding occurs. ER stress
observed in obesity basically results in impair-
ment of protein folding leading to production of
misfolded proteins which activate abnormal
“unfolded protein response” (UPR). In turn this
stimulates ROS production, with subsequent sys-
temic release of free fatty acids and inﬂ ammatory
mediators, lipid droplet creation and hepatic cho-
lesterol accumulation [
98 , 99 ].
Ectopic-fat deposition also inhibits glucose
transport and insulin signalling in skeletal mus-
cle, thus promoting insulin resistance [ 62 , 100 ].
Hyperglycaemia is another condition promoting
oxidative stress, by enhancing oxidative degrada-
tion of glucose; the resulting increase in proton
gradient across the mitochondrial inner mem-
brane leads to electron leakage and O
2 −. produc-
tion. As a result, glycolytic metabolites are
shifted to four alternative pathways: (i) glucose is
redirected into the polyol pathway; (ii) fructose-
6- phosphate is redirected into the hexosamine
pathway; (iii) triose phosphates produce methyl-
glyoxal, the main precursor of advanced glyco-
sylation end products (AGEs), and (iv)
dihydroxyacetone phosphate is converted to dia-
cylglycerol, thus activating protein kinase C
101 ]. These four pathways induce oxida-
tive/nitrosative stress, by different mechanism.
Activation of the polyol pathway leads to NADPH
depletion, glucosamine-6-phosphate derived
from the hexosamine pathway induces oxidative
and ER stress, and AGEs and PKC stimulate
ROS/RNS production by activating NADPH oxi-
dases and NF-kB [
102 , 103 ]. In particular, NF-kB
is a transcription factor whose downstream tar-
gets are pro-inﬂ ammatory cytokines (TNF-α and
IL-6), inducible nitric oxide synthase (iNOS),
adhesion molecules (E-selectin, intercellular
adhesion molecule-1 and endothelin- 1), and
some microRNAs (miR). Aberrant expression of
these NF-kB-responsive genes may account for
increased oxidative/nitrosative stress and inﬂ am-
mation, as well as for enhanced adipogenesis
(for example, modulation of miR-103, miR-143,
miR-27a and miR-27b has been recognized as
condition leading to adipose hypertrophy and
hyperplasia) observed in obese individuals [
106 ]. Finally, oxidative stress is exacerbated by
inﬂ ammatory mediators that worsen insulin sig-
nalling, thus intensifying hyperglycaemia [ 6 ].
A relevant source of ROS can also be repre-
sented by endothelial dysfunction, commonly
found in obesity, due to chronic inﬂ ammation
and dysregulation of adipocyte-derived factors.
Activation of endothelial NADPH oxidase (trig-
gered by cytokines, hormones, elevated intralu-
minal pressure and hypertension) increases ROS
levels, thus aggravating vascular injury [
Among adipocyte-derived factors, the hor-
mone leptin plays a crucial role in obesity-
associated oxidative stress. Hyperleptinemia
6 Oxidative Stress and Obesity
increases mitochondrial and peroxisomal fatty
acid oxidation, with subsequent stimulation of
ROS production via the mitochondrial respira-
tory chain [ 92 , 108 ]. In addition, it stimulates
activation of monocytes/macrophages, with pro-
duction of pro-inﬂ ammatory cytokines (IL-6 and
TNF-α) that intensify oxidative stress [
Genetic variants, such as single nucleotide
polymorphisms (SNPs) in genes encoding for
mediators of redox balance, represent an emerg-
ing research ﬁ eld in obesity. Recently, Rupérez
and colleagues reviewed the current knowledge
about the impact of speciﬁ c SNPs on the risk of
obesity or obesity-associated co-morbidities
110 ]. In particular, they focused on SNPs of
antioxidant enzymes (GPx, PON1, catalase, per-
oxiredoxins, SOD), ROS-producing enzymes
(NADPH oxidases) and transcription factors
involved in ROS response mechanisms (PPARγ,
PGC1α, Nrf2). Other genetic loci relevant for
body weight regulation and oxidative stress have
also been identiﬁ ed, including protective and sus-
ceptible SNPs in the mitochondrial control region
111 ], in fat mass and obesity associated (FTO)
gene [ 112 ], and in the gene encoding for uncou-
pling protein 2 (UCP2) that leads to heat dissipa-
tion (without synthesis of ATP) and controls
mitochondrial free radical production [
However, the expression of metabolic pheno-
types is markedly affected also by environmental
and epigenetic factors, thus making difﬁ cult to
assess the real impact of genetically controlled
heritability in human obesity.
Oxidative Stress-Induced Diseases
All the above mentioned ROS-generating condi-
tions may play a causative role in obesity-related
114 ]. In Non-alcoholic Fatty
Liver Disease (NAFLD) and Non-alcoholic
Steatohepatitis (NASH), mitochondrial dysfunc-
tion, ER stress and hyperglycaemia cause exces-
sive electron ﬂ ux in the electron transport chain
and ROS overproduction. As a result, fatty acid
catabolism is impaired, while lipogenesis is
stimulated, and, therefore, lipids abnormally accu-
mulate in hepatocytes [
115 ]. ROS accumulation
also plays a key role in the development of meta-
bolic syndrome, characterized by central obesity
associated with two or more complications (hyper-
glycaemia, hypertension, dyslipidaemia), repre-
senting elevated risk factors for cardiovascular
pathologies. Subsequently redox- inﬂ ammatory
processes, together with visceral adiposity, dis-
rupts downstream events of the insulin signalling
pathway, thus triggering insulin resistance, which
in turn promotes endothelial dysfunction,
decreased vasodilatation and increased blood pres-
116 ]. Type 2 diabetes develops in obese indi-
viduals as a result of insulin- resistance. Impaired
glucose tolerance is achieved through multiple
mechanisms, all involving oxidative stress: (i)
β-cells (possessing low scavenging ability) die
because of chronic oxidative stress and adipokine
secretion, (ii) adipocyte oxidative stress leads to
production of glutathionylated products of lipid
peroxidation that results in insulin resistance and
inﬂ ammation, and (iii) protein oxidation and/or
misfolding, resulting in proteasomal dysfunction,
contribute to the onset of insulin-resistant and
obese phenotype [
117 – 119 ].
Circulating free fatty acids, insulin resistance,
oxidative stress, mitochondrial and endothelial
dysfunction are also key pathogenic factors of
obesity-associated cardiovascular pathologies
(including coronary and peripheral artery dis-
ease, stroke, cardiomyopathy and congestive
heart failure) [
95 ]. Elderly subjects appear to be
more susceptible to obesity-associated vascular
complications than younger individuals, may be
because aging worsens obesity-triggered inﬂ am-
mation in perivascular adipose tissue, thus
increasing oxidative stress and inﬂ ammation in a
paracrine manner [
120 ]. A signiﬁ cant correlation
has been found between BMI and tumour suscep-
tibility: obesity accounts for 14–20 % of deaths
due to gastrointestinal, breast, prostate, endome-
trium, uterus and ovary tumours in both males
and females [
It is now well recognized that ROS overpro-
duction triggers DNA damage, thus leading to
I. Savini et al.
genomic instability associated with activation of
oncogenes and/or inactivation of tumour sup-
pressor genes [ 122 – 124 ]. A recent systematic
meta-analysis documented that oxidative stress,
together with visceral adipose tissue, is one of the
pathogenic mechanisms accounting for polycys-
tic ovary syndrome. Indeed, abdominal adipo-
cytes coming from patients affected by polycystic
ovary syndrome show enhanced oxidative stress
and impaired insulin signalling [
15 , 91 ]. Finally,
oxidative stress and inﬂ ammation are involved in
the pathogenesis of obstructive sleep apnea, a
breathing disorder often associated with central
obesity. In this disorder repeated breathing arrests
lead to an ischemia/reperfusion condition, result-
ing in ROS overproduction that is enhanced by
high levels of pro-inﬂ ammatory cytokines found
in neutrophils and monocytes of sleep apnea
Lifestyle and Nutritional
Intervention to Reduce Oxidative
Stress in Obesity
Natural strategies designed to increase antioxidant
defences in obese subjects could be useful to pre-
vent and treat obesity and co-morbidities. Herein,
we will report recent experimental evidences con-
cerning the effects of physical activity and diet on
modulation of redox state; we will also describe
potential mechanisms through which weight loss,
overall diet composition and single diet compo-
nents (macronutrients, micronutrients, and phyto-
chemicals) modulate redox homeostasis.
Independent of weight reduction, physical
activity exerts positive effects on oxidant/anti-
oxidant balance. For example exercise reduces
NADPH oxidase activity and ROS generation,
while increasing blood levels of anti-
inﬂ ammatory cytokines (interleukins 1 and 10)
126 , 127 ]. In a retrospective analysis enrolling
108 obese, middle-aged men, exercise training
without dietary restriction has been shown to
improve hepatic inﬂ ammation and related oxida-
tive stress [
128 ]. A cross-sectional study carried
out on overweight/obese postmenopausal women
(45–64 years old) showed that active lifestyle
(aerobic exercise for at least 30 min, three times
per week) was associated with increased antioxi-
dant enzyme activities (catalase and SOD) in
peripheral blood mononuclear cells [
36 ]. Krause
and colleagues reported that aerobic exercise (at
moderate intensity, three times per week) did not
change body composition or aerobic ﬁ tness, but
ameliorated oxidative markers in obese subjects
with or without Type 2 diabetes [
129 ]. A retro-
spective analysis have been conducted to deter-
mine whether exercise without dietary restriction
can inﬂ uence the pathophysiology of abnormal
liver function in obese, middle-age men. Results
showed that physical activity beneﬁ ts the man-
agement of obesity-related liver diseases regard-
less of detectable weight reduction; in particular,
these effects seem to be acquired through an
improvement in hepatic oxidative stress levels
and related inﬂ ammatory conditions [
Besides direct effects on oxidative stress, exer-
cise is also able to reduce abnormal conditions
such as inﬂ ammation and insulin resistance that
underpin obesity-associated diseases. Aerobic
and resistance exercise (Nordic walking) for
12 weeks without dietary intervention does not
inﬂ uence oxidative stress, but decreases athero-
genic index in overweight or obese males (40–
65 years) with impaired glucose regulation [
Therefore, regular exercise acts as a natural anti-
oxidant and anti-inﬂ ammatory strategy for pre-
venting obesity-associated complications.
Combination of regular exercise with caloric
restriction potentiates the beneﬁ cial effects on
redox balance. Physical activity associated with
weight loss has been found to be the most efﬁ ca-
cious approach to prevent dyslipidemia, hyper-
tension, Type 2 diabetes, cardiovascular diseases,
NAFLD and colorectal cancer, even though it is
difﬁ cult to determine if the observed effects are
due to exercise, weight loss or speciﬁ c diet com-
131 , 132 ]. Gutierrez-Lopez et al.
showed that regular and moderate aerobic exer-
cise plus hypocaloric diet was more effective
than hypocaloric diet alone in decreasing
6 Oxidative Stress and Obesity
oxidative stress markers and insulin polymeriza-
tion, in 32 obese subjects [ 34 ]. Lifestyle interven-
tion (including both exercise and diet) has been
shown to be a successful approach for ameliorat-
ing endothelial dysfunction, inﬂ ammation and
oxidative stress, in obese children [ 133 ].
Weight reduction obtained via caloric restric-
tion alone has been proven to reduce the levels of
protein carbonylation, AOPPs, lipid peroxida-
tion, oxidized lipoproteins and F2-isoprostanes,
as well as of inﬂ ammatory markers [
33 , 35 , 134 ,
135 ]. In overweight and obese women, a modest
reduction in caloric intake (25 % caloric restric-
tion) is sufﬁ cient to rapidly decrease oxidative
33 ]. This ﬁ nding has been conﬁ rmed by
Chae’s study showing that a daily 100-kcal calo-
rie reduction was able to revert the elevated oxi-
dative stress observed in overweight and obese
individuals (3-year follow-up leading to only
5.4 % weight loss). Noticeably, lifestyle interven-
tion has to be long-lasting, as resuming a habitual
diet brings back the levels of oxidative markers to
the baseline values within 3 months, in ∼80 % of
33 ]. The mechanisms by which lowering
energy supply ameliorates metabolic functions
mainly include activation of sirtuins, NAD
dependent deacetylases that regulate metabolism,
improve antioxidant defences and dampen
inﬂ ammatory activities [ 136 ]. Also the transcrip-
tion factor FoxO (Forkhead box, sub- group O),
which up-modulates the expression of genes
involved in energy homeostasis, induces cell sur-
vival and inﬂ ammatory responses [
Besides weight reduction, diet quality is a key
factor for redox homeostasis. Western diets
(increased intake of artiﬁ cial energy-dense foods
and reduced intake of complex carbohydrates,
ﬁ bres, fruits and vegetables) deeply contribute to
oxidative stress and metabolic alterations pro-
moting lipotoxicity [
20 – 23 , 40 , 138 ]. Conversely,
antioxidant-rich diets are effective in both reduc-
ing oxidative stress and speeding up weight loss.
Indeed, Mediterranean diet (rich in whole-grains,
legumes, nuts, fruit, vegetables, ﬁ sh, low-fat
dairy products, and olive oil as principal source
of fat) and Okinawan diet (rich in unprocessed
foods, vegetables, sweet potatoes with small
amount of ﬁ sh and lean meat) exerts protective
effects against obesity and obesity-related pathol-
37 , 139 – 141 ]. In particular, the
Mediterranean diet (even without weight reduc-
tion) is able to reduce oxidative stress and inﬂ am-
mation, as well as to improve insulin sensitivity.
For example, abdominally overweight men and
women showed lower concentrations of pro-
inﬂ ammatory cytokines after 8 weeks of a
Mediterranean diet [
142 ]. In addition, among
high cardiovascular risk subjects (carrying the
genetic variants rs9939609 for FTO and
rs17782313 for MC4R , conferring genetic sus-
ceptibility to obesity and diabetes), those adher-
ing to Mediterranean diet had lower rate of Type
2 diabetes [
Speciﬁ c food or nutrients also exert positive
effect on redox balance, inﬂ ammatory biomark-
ers and metabolic alterations associated with
obesity. Animal and human studies have high-
lighted the protective role of mono-unsaturated
fatty acids (abundant in olive oil) and ω-3 poly-
unsaturated fatty acids (abundant in ﬁ sh and nuts)
on cardiovascular risk in overweight and obese
subjects, via different mechanisms: (i) reduction
of oxidative stress and inﬂ ammation, (ii) increase
of antioxidant defences via the Nrf2/HO-1 path-
way, (iii) prevention of endothelial dysfunction,
(iv) improvement of hyperglycaemia and hyper-
142 , 144 – 147 ]. Other subsidiary
dietary compounds (such as antioxidant vitamins
and phytochemicals) contribute to a well redox
balance, by directly scavenging ROS or indi-
rectly modulating the activity of redox-sensitive
transcription factors and enzymes, as well as by
exerting anti-inﬂ ammatory actions. A diet con-
taining food with high antioxidant capacity (such
as fruits, vegetables, and legumes) is negatively
associated with adiposity, oxidative stress mark-
ers, and obesity-related co-morbidities (Type 2
diabetes and cardiovascular diseases) [
148 , 149 ].
From the NHANES (2003–2006) studies, it
has emerged that consumption of orange juice
lowers about 21 % the risk of obesity and of about
36 % the risk of metabolic syndrome. On the
other hand mandarin juice consumption up-
modulates antioxidant defences in obese children,
I. Savini et al.
tomato juice consumption improves plasma TAC
and erythrocyte antioxidant enzymes in over-
weight females [ 150 – 152 ]. Daily consumption of
grapefruit (fruit or juice) ameliorates oxidative
stress in overweight and obese adults with meta-
bolic syndrome [ 153 ]. A 24-weeks trial with
unsalted pistachio nuts (20 % of total energy)
leads to beneﬁ cial effects on redox state and
cardio- metabolic proﬁ le of Asian Indians with
metabolic syndrome [
154 ]. The same beneﬁ cial
effects on serum TAC and oxidative stress indexes
have also been obtained with consumption of
broccoli sprouts powder and carrot juice, in over-
weight and Type-2 diabetes patients [
155 , 156 ].
Antioxidant supplements (vitamins C and E,
carotenoids, lipoic acid) may also be useful in pri-
mary and secondary prevention of ROS- induced
health problems. Several short-term studies have
shown that vitamin E supplementation resulted in
signiﬁ cant reduction of oxidative stress and
improvement of lipid state and cardio- metabolic
alterations, in children and adults [
157 – 159 ].
However, adverse effects have been reported as
well, especially in long-term clinical trials, so that
vitamin E supplementation should be carefully
160 , 161 ]. Obese individuals and dia-
betic subjects often experience high rate of vita-
min C deﬁ ciency and, therefore, regular
consumption of vitamin C-rich foods has to be
recommended [ 7 ]. Indeed, observational and
interventional studies have suggested a beneﬁ cial
role of vitamin C on prevention of diabetes,
hypertension, stroke and heart failure, but supple-
mentation data do not allow to univocally estab-
lish the role played by vitamin C on health
162 – 165 ]. Another vitamin deﬁ ciency
commonly found in obese individuals are carot-
enoids (both pro-vitamin A and not pro-vitamin A
carotenoids), so that these individuals may beneﬁ t
from their supplementation [
166 ]. Acting as anti-
oxidant and anti-inﬂ ammatory agents, they mod-
ulate markers of inﬂ ammation, oxidative stress,
and endothelial dysfunction, thus exerting a pro-
tective role against obesity-associated diseases
167 , 168 ]. However, both positive and negative
effects have been reported by in vivo supplemen-
tation studies with β-carotene, astaxanthin,
β-cryptoxanthin and lycopene [
169 ]. Interestingly,
the potential of α-Lipoic acid (LA) in human ther-
apeutics was found to bring strength in several
human supplementation studies. LA increases the
Nrf2-mediated anti-oxidant responses and pre-
vents obesity-induced oxidative stress and lipo-
apoptosis in rat liver [
170 ]. Administration of LA
to patients with Type 2 diabetes decreases plasma
oxidative products and improves insulin sensitiv-
171 ]. Oral LA supplementation promotes
body weight loss in healthy overweight/obese
subjects [ 172 , 173 ]. The mechanisms accounting
for these positive effects not only mainly rely on
modulation of redox homeostasis, but also on
increased insulin sensitivity, mitochondrial bio-
genesis and promotion of browning process in
white adipose tissue [
Among phytochemicals provided by food of
plant origin, polyphenols constitute the most
abundant and heterogeneous class and indeed,
different categories (phenolic acids, stilbenes,
ﬂ avonoids, chalcones, lignans and curcuminoids)
can be identiﬁ ed on the basis of their structures.
Depending on chemical structure, bioavailability
and metabolism, each phytochemical exerts dis-
tinct physiological effects through multiple
(sometimes overlapping) mechanisms. Referring
to a more comprehensive review about the best
characterized biological properties of each bioac-
tive compound [
7 ], here we only emphasize that
polyphenols may modulate inﬂ ammation and
redox state, as well as adipocyte differentiation
and lipid metabolism [
175 ]. In this way they
exert protective effects on oxidatively triggered
41 , 176 ]. Short-term clinical trials
have indeed pointed out a positive role of speciﬁ c
compounds on obesity, glucose tolerance and
cardiovascular risk factors [ 177 – 180 ]. A particu-
lar class deserves to be mentioned is isoﬂ avones
(genistein, daidzein and glycitein), because they
are analogues of estrogens, therefore, their ability
to exert anti-adipogenic and anti-lipogenic effects
mainly rely on binding to estrogen receptors, thus
modulating the expression of genes involved in
adipose development, insulin sensitivity and
fatty acid metabolism rather than only on antioxi-
dant activity [
181 , 182 ]. However, it should be
6 Oxidative Stress and Obesity
recalled that many of the positive effects ascribed
to polyphenols have been demonstrated by in
vitro studies and in vivo biological relevance has
not been established yet, especially considering
the low bioavailability and rapid body metabo-
lism of these bioactive phytochemicals.
Another interesting ﬁ nding is that the interac-
tion of polyphenol-gut microbiota represents an
additional modulator of oxidative stress- mediated
pathologies. Indeed, studies have shown that
microbiota modulates the activity of different
polyphenols (thus explaining the inter-individual
variability observed in polyphenol supplementa-
tion studies), and, meanwhile, polyphenols
change intestinal redox state (thus modulating
quantitative and qualitative features of gut-
Microbial activities and gut ‘dysbiosis’ are
involved in controlling the body weight and
insulin- resistance [
184 , 185 ]. On the other hand,
probiotics (healthy micro-organisms, including
Biﬁ dobacteria and Lactobacilli ) and prebiotics
(non-viable food components, such as inulin-
type fructans, able to modulate microbiota com-
position) may confer health beneﬁ ts for obese
individuals, lowering oxidative unbalance [
185 ]. Indeed, daily consumption of probiotics
has been shown to improve antioxidant parame-
ters (TAC, enzymatic activities of SOD and GPx)
and to decrease oxidative markers (MDA, oxLDL
and 8-isoprostanes), both in healthy subjects and
type 2 diabetic patients [ 186 , 187 ].
Numerous investigations indicate that obesity
is strictly linked to changes in redox state.
Abnormal production of ROS and nitrogen
species, due to unhealthy lifestyle (chronic
hyper-nutrition, low quality diet and sedentary
life), affects white adipose tissue, endothe-
lium and muscle biology, thus leading to
obesity-associated pathologies (including
NAFLD, diabetes, hypertension, cardiovascu-
lar diseases and cancer) (Fig.
Governmental and non-governmental orga-
nizations are developing new strategies for
prevention and control of obesity, especially
concerning lifestyle intervention, in order to
limit morbidity and mortality rates, as well as
health care costs. Approaches aimed at modu-
lating redox homeostasis are emerging as
novel tools for preventing or slowing down
progression of obesity- associated pathologies.
Studies on humans claim that the ﬁ rst goal to
be achieved should be to reduce oxidative
stress by combination of weight loss, physical
activity and high quality diet. Obese individu-
als might also beneﬁ t from regular consump-
tion of foods with high antioxidant natural
compounds rather than from supplementation
with antioxidant compounds. This is because
of paucity of data (often controversial and not
conclusive) concerning clinical trials with
speciﬁ c nutrients. More promising appears to
be a diet rich in polyphenols, widely distrib-
uted in fruits, vegetables and some plant-
derived beverages (such as coffee and tea),
which are effective in counteracting weight
gain and oxidative stress. Moreover, their bio-
logical activity may be enhanced by modulat-
ing composition of gut microbiota that
represents a novel way of dealing with redox
unbalance in overweight or obese individuals.
In conclusion, the winning strategy for lower-
ing risk factors of obesity- associated compli-
cations remains weight loss through physical
activity and diet rich in fruits, vegetables and
spices (containing antioxidant vitamins and
phytochemicals), ﬁ sh (containing ω-3 poly-
unsaturated fatty acids) and low-fat, fermented
dairy products (especially those containing
I. Savini et al.
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