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In the last few years, several studies have shown a strong association among obesity, altered redox state and inflammation; these studies have also shown that such alterations may be the link between obesity and obesity-related diseases (including Type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease and cancer). Obese subjects usually show high levels of reactive oxygen or nitrogen species, impaired antioxidant defences and increased levels of inflammatory adipokines. Oxidative stress is certainly a result of excessive fat accumulation, but it has also been shown that oxidative stress, per se, leads to weight gain; therefore, it is not easy to establish the correct cause-effect relationship between obesity and oxidative stress. This chapter analyses the main aspects linking oxidative stress to obesity, describing human studies in support of the association between alterations of redox homeostasis and obesity, the molecular mechanisms underlying these modifications and potential non-pharmacological strategies (including weight loss, physical activity, diet, dietary supplementation and microbiota modulation) aimed at reducing oxidative stress in obese individuals.
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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 [
1 ].
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
219 ]. 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 [
2023 ]. 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 [ 2628 ].
Systemic oxidative stress is achieved through
multiple biochemical mechanisms, including
superoxide generation, endoplasmic reticulum
stress, glyceraldehyde autoxidation, enhanced
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 [
31 ].
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 [
3236 ].
Secondly, diet rich in fruits, vegetables, fi sh and
olive oil helps to maintain the right weight and
reduce the risk of metabolic diseases [ 3739 ].
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 [
4044 ]. 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 [
4648 ]. 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.
Free Radical
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
trioxide (N
2 O 3 ) and peroxynitrite (ONOO
Oxidative Damage
Injury caused by RO(N)S to cells and tissues.
Oxidative Stress
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 [
51 ].
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 [
50 ].
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;
NADPH-dependent oxygenase.
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.
Highly oxidizing.
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
Fenton reactions.
Highly toxic.
ROO• ( peroxy radicals )
ROOH ( organic hydroperoxide )
RO• ( alkoxy radicals )
RH + O 2 R• + •OH
R• + O 2 ROO•
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
radical scavenger.
At physiological concentrations, it acts
as intracellular messenger. It conjugates
with GSH
Long half-life.
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
6.2 ).
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) [
57 ].
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
C) [
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 [
59 ].
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 , 6063 ]. 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-
sively depleted.
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
Oxidative damage
to proteins
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.
Oxidative damage
to DNA
8-OHdG Oxidized derivative of deoxyguanosine of nuclear and
mitochondrial DNA.
8-OHG Oxidative derivative of guanosine.
Activation of
anti-oxidant enzymes
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 [
4 ].
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 [
5 ].
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
steatosis) [
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) [
12 ].
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 [
7476 ]. 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
controls [
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 [
84 ].
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 [
88 ].
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 [
90 ].
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
syndrome [
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 [
15 ].
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
Stress-Induced Diseases
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 [
2428 ].
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 [
222 , 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-
duction [
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
ROS overproduction.
Pro-infl ammatory cytokine
increase. Endoplasmic reticulum
Adipose tissue dysfunction Adipose tissue macrophage infi ltration ROS overproduction.
Pro-infl ammatory cytokine
Nrf2 deletion.
Antioxidant enzymes decrease.
Endoplasmic reticulum stress.
Hyperglycemia Increased glycolysis and tricarboxylic acid
ROS overproduction
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.
ROS overproduction.
Pro-infl ammatory cytokine
Hyperleptinemia Increased mitochondrial and peroxisomal
fatty acid oxidation. Monocytes/
macrophages activation
ROS overproduction.
Pro-infl ammatory cytokine
Genetic variants (SNPs) Altered activity of GPx, PON1, catalase,
peroxiredoxins, SOD, NADPH oxidases,
PPARγ, PGC1α, Nrf2
ROS overproduction.
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
nucleotide polymorphisms
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 [
97 ].
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
(PKC) [
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 [
107 ].
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 [
109 ].
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 [
113 ].
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
co-morbidities [
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-
sure [
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 [
117119 ].
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 [
121 ].
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 [ 122124 ]. 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
patients [
125 ].
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 [
128 ].
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 [
130 ].
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-
ponents [
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
stress [
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
women [
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 [
137 ].
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,
bres, fruits and vegetables) deeply contribute to
oxidative stress and metabolic alterations pro-
moting lipotoxicity [
2023 , 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-
ogies [
37 , 139141 ]. 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 [
143 ].
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-
insulinemia [
142 , 144147 ]. 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 [ 150152 ]. 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 [
157159 ].
However, adverse effects have been reported as
well, especially in long-term clinical trials, so that
vitamin E supplementation should be carefully
evaluated [
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
outcomes [
162165 ]. 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-
ity [
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 [
174 ].
Among phytochemicals provided by food of
plant origin, polyphenols constitute the most
abundant and heterogeneous class and indeed,
different categories (phenolic acids, stilbenes,
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
pathologies [
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 [ 177180 ]. 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-
microbiota) [
183 ].
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 [
43 ,
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.
6.1 ).
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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I. Savini et al.
... Antioxidants will not be able to completely remove free radicals, resulting in a buildup of reactive oxygen species (ROS) [11][12][13]. Some research [23][24][25] found greater serum MDA levels in breast cancer patients, whereas others found lower levels [22,26]. Our findings backed up the widely held belief that breast cancer is associated with a higher level of MDA than healthy people (data not shown). ...
... Increased generation of oxygen free radicals can induce TAC but not SOD, in concomitant to our findings, Gupta et al., [21] shows decreased SOD activity in breast cancer patients. An increase in SOD activities due to overexpression has been reported [23]. In our study, SOD activities were found significantly lower in positive Her2/ neu expressed patients and not changed in response to other predictive markers, while the activity of TAC is significantly increased with the increase of tumor stage and tumor size. ...
... Our findings could support the potential diagnostic value of MDA and NO in BC. To the best of our knowledge, this is the first study to report the sensitivity and specificity for MDA, NO, SOD and TAC in response to different prognostic factors in BC patients; previous studies focused only on one or few oxidative/antioxidant biomarkers to evaluate oxidative stress status in BC [22,23]. Despite supporting the association of the studied biomarkers with the occurrence and progression of BC, these reports were insufficient to reflect the true status of oxidative stress in those patients or reveal the potential clinical value of the studied biomarkers for the diagnosis or prediction of BC. ...
... Antioxidants will not be able to completely remove free radicals, resulting in a buildup of reactive oxygen species (ROS) [11][12][13]. Some research [23][24][25] found greater serum MDA levels in breast cancer patients, whereas others found lower levels [22,26]. Our findings backed up the widely held belief that breast cancer is associated with a higher level of MDA than healthy people (data not shown). ...
... Increased generation of oxygen free radicals can induce TAC but not SOD, in concomitant to our findings, Gupta et al., [21] shows decreased SOD activity in breast cancer patients. An increase in SOD activities due to overexpression has been reported [23]. In our study, SOD activities were found significantly lower in positive Her2/ neu expressed patients and not changed in response to other predictive markers, while the activity of TAC is significantly increased with the increase of tumor stage and tumor size. ...
... Our findings could support the potential diagnostic value of MDA and NO in BC. To the best of our knowledge, this is the first study to report the sensitivity and specificity for MDA, NO, SOD and TAC in response to different prognostic factors in BC patients; previous studies focused only on one or few oxidative/antioxidant biomarkers to evaluate oxidative stress status in BC [22,23]. Despite supporting the association of the studied biomarkers with the occurrence and progression of BC, these reports were insufficient to reflect the true status of oxidative stress in those patients or reveal the potential clinical value of the studied biomarkers for the diagnosis or prediction of BC. ...
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Background: According to GLOBOCAN estimates, breast cancer was found to be the most often diagnosed cancer in women worldwide, (11.7%) and the fourth leading cause of cancer mortality (6.9%). The present study was aimed to evaluate the involvement of oxidative stress on breast cancer carcinogenesis in Egyptian population. Methods: Lipid peroxidation as evidenced by malondialdehyde (MDA) and nitric oxide (NO) stress as well as the status of the antioxidants superoxide dismutase (SOD) and total antioxidant capacity (TAC) were estimated in serum of 163 breast cancer patients. Correlations between oxidative/ antioxidant profile and different prognostic variables in BC patients were estimated. Results: Lipid peroxidation in BC was enhanced in response to cancer stage and tumor size (p < 0.01). Similarly, NO was increase in response to NPI, Her2/neu and cancer stage (p < 0.02). Inversely in antioxidant, SOD was decrease in response to Her2/neu only (p < 0.002). While, TAC Original Research Article Hegy et al.; AJRB, 10(1): 25-35, 2022; Article no.AJRB.84574 26 was increase in response to cancer stage and tumor size (p < 0.01). We found that oxidative/antioxidant status was dependent on NPI, Her2/neu, cancer stage and tumor size of BC patients. Conclusion: Higher oxidative stress generation and lower SOD activity were found in our study, which supports the oxidative stress concept in breast carcinogenesis.
... In recent years, assessment of MDA of tissues and plasma has been extensively used in numerous cancers including breast cancer. Various studies have examined the possibility of a relationship between lipid peroxidation and breast cancer (Gonenc et al., 2006a;Gönenç et al., 2006b;Hauck and Bernlohr, 2016;Savini et al., 2016;Sreenivasa Rao et al., 2012). Some studies have reported higher serum MDA levels in breast cancer patients (Aldini et al., 2010;Savini et al., 2016) while some have reported lower levels (Abdel-Salam et al., 2011;Gerber et al., 1996;Gonenc et al., 2006;Tas et al., 2005). ...
... Various studies have examined the possibility of a relationship between lipid peroxidation and breast cancer (Gonenc et al., 2006a;Gönenç et al., 2006b;Hauck and Bernlohr, 2016;Savini et al., 2016;Sreenivasa Rao et al., 2012). Some studies have reported higher serum MDA levels in breast cancer patients (Aldini et al., 2010;Savini et al., 2016) while some have reported lower levels (Abdel-Salam et al., 2011;Gerber et al., 1996;Gonenc et al., 2006;Tas et al., 2005). Our findings supported the common observation that breast malignancies are related to an increased level of MDA. ...
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Abstract BACKGROUND: Breast cancer is caused by breast tissue malignant cells and it has become one of the main medical concerns with a socio-economic significance especially for women. Among the multiple factors involved in the initiation, progression, and invasion of breast cancer, oxidative stress plays an important role. Antioxidant status, lipid peroxidation, and oxidative stress in newly diagnosed breast cancer patients were determined to find a defined pattern of oxidative stress in these patients. METHODS: The malondialdehyde (MDA) levels (as an indicator of lipid peroxidation), glutathione peroxidase (GPX), and superoxide dismutase (SOD) activities of newly diagnosed breast cancer patients (n=38) and controls (n=38) were assessed using blood samples. RESULTS: MDA level and SOD activity were significantly higher in the breast cancer patients compared to the healthy subjects group (p<0.05). Compared to the healthy group, GPX activity decreased significantly in patients group (p<0.05). CONCLUSIONS: High lipid peroxidation is an important risk factor for breast cancer and the increased levels of superoxide anion in breast cancer cells may be a reason for the induction of SOD activity. Nevertheless, oxidative stress is an important factor in development and progression of breast cancer. Further studies on it can lead to a more helpful approach to management of breast cancer. KEYWORDS: Breast cancer; lipid peroxidation; oxidative stress; superoxide dismutase; glutathione peroxidase
... Multiple intertwined genetic, psychosocial, and neuro-immuno-endocrine factors have been proposed to contribute to the association of obesity and SUD, including the gut-brain axis, inflammation and oxidative stress [40][41][42][43][44]. In particular, much evidence shows that overweight and obesity are associated with alterations in oxidative stress and mitochondrial functions in peripheral organs and in the brain [45][46][47][48]. In parallel, drugs of abuse have been shown to increase oxidative stress occurring in dopaminergic neurotransmission [49][50][51][52][53]. ...
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Affective and substance-use disorders are associated with overweight and obesity-related complications, which are often due to the overconsumption of palatable food. Both high-fat diets (HFDs) and psychostimulant drugs modulate the neuro-circuitry regulating emotional processing and metabolic functions. However, it is not known how they interact at the behavioural level, and whether they lead to overlapping changes in neurobiological endpoints. In this literature review, we describe the impact of HFDs on emotionality, cognition, and reward-related behaviour in rodents. We also outline the effects of HFD on brain metabolism and plasticity involving mitochondria. Moreover, the possible overlap of the neurobiological mechanisms produced by HFDs and psychostimulants is discussed. Our in-depth analysis of published results revealed that HFDs have a clear impact on behaviour and underlying brain processes, which are largely dependent on the developmental period. However, apart from the studies investigating maternal exposure to HFDs, most of the published results involve only male rodents. Future research should also examine the biological impact of HFDs in female rodenrts. Further knowledge about the molecular mechanisms linking stress and obesity is a crucial requirement of translational research and using rodent models can significantly advance the important search for risk-related biomarkers and the development of clinical intervention strategies.
... Where noticed an increase in the levels of (GPT, GOT) that the increase in enzyme activity it can lead to abnormal structural and functional changes that the occur of hepatic cells, and these changes may increase the necrosis of hepatocytes (Necrosis). Thus, the enzymes are released into the bloodstream [16] . The results of the albumin concentration showed a significant decrease, and the result was (3.004±0.456) ...
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Atherosclerosis is a syndrome that affects arterial blood vessels. Arteriosclerosis thickens the walls of blood vessels as a result of accumulation of macrophages and white blood cells, and fat accumulation is more pronounced over time. Blood pressure, smoking, obesity, lifestyle, sugar and age are risk factors. Atherosclerosis. The symptoms and signs of atherosclerosis differ depending on the arteries affected by atherosclerosis. This study was conducted in the Pharma lab in the city of Fallujah and samples were collected from the Fallujah General Hospital. 50 samples were collected, 30 of which were patients with atherosclerosis and the remaining 20 samples were for healthy people. The samples included both males and females between the ages of 30 to 78 years. A questionnaire was used to collect some information from patients and corrections that included (gender, age, blood pressure, smoking, Weight and blood sugar) and some tests were performed (Cholesterol , TG, HDL, LDL, VLDL, GOT, GPT, ALP, Albumin). The results showed a significant increase in concentrations of Chol, TG, LDL, VLDL, GOT, GPT, ALP) in patients with atherosclerosis and a significant decrease in concentrations of both HDL and ALB in patients with atherosclerosis at the probability level (P ≤ 0.05). The results also showed that males are more susceptible to arteriosclerosis than Females, and also showed that the greater the age, the greater the risk factors for atherosclerosis. The more risk factors for atherosclerosis increase with increasing body mass. As for smoking, the results indicated that it has an effect on atherosclerosis, as people who smoke have increased risk factors for atherosclerosis, and disease risk factors increase with increased blood pressure and sugar.
... Superoxide radicals generated due to oxidative stress are taken up by SOD and converted to hydrogen peroxide and water. The former is in turn taken up by CAT or GPx and converted to oxygen and water (CAT) or the respective alcohol and water (GPx) depending on which enzyme catalyzed the reaction, though, GPx is more suited to hydroperoxides [11,61]. Our data showed that SOD increased copiously in the arsenic exposed group when compared with the Normal control (Fig. 6). ...
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Arsenicosis remains a global health concern due to devastating health effects. Clerodendrum volubile and vernonia amygdalina have tremendous bioactivities against oxidative stress-related diseases. The study, therefore, appraised the effects of flavonoids fractions from C. volubile and V. amygdalina (FCV and FVA respectively) against arsenic-induced oxidative stress in rats. Thirty male Wistar rats (120 ± 10 g) were divided into six groups of five each; Control (distilled water), arsenic alone (40 ppm sodium arsenite), arsenic + FCV (100 mg/kg), arsenic + FVA (100 mg/kg), arsenic + FCV and FVA (50 mg/kg each), and arsenic + vitamin C (100 mg/kg). The treatment commenced after four-week long arsenic exposure and lasted another four weeks. Blood, liver and kidneys of the rats were collected after sacrifice following an overnight fast. Arsenic caused significant (p<0.05) reductions in the total thiols levels in the plasma, liver, and kidneys, as well as the lowering of catalase and glutathione peroxidase activities. Contrariwise, malondialdehyde and nitric oxide levels, as well as superoxide dismutase activities increased in the non-treated arsenic exposed group. FCV and FVA, both singly or in combination, abrogated the oxidative stress indices and enhanced the antioxidant species in the treated groups. Groups treated with vitamin C also showed improved antioxidant status with concomitant reductions in oxidative stress markers. This study concludes that flavonoids fractions from C. volubile and V. amygdalina could be a viable weapon against arsenic-induced hepato-renal oxidative stress in rats.
... , and oxidative stress (Savini, Gasperi, & Catani, 2016) are all possible mechanisms by which obesity occurs and develops. Many studies have shown that obesity can cause lipid and glucose metabolism disorders, thus inducing metabolic diseases such as diabetes, hypertension, atherosclerosis, and non-alcoholic fatty liver (Boulange, Neves, Chilloux, Nicholson, & Dumas, 2016;Despres & Lemieux, 2006;Haslam & James, 2005;Mozaffarian, 2016). ...
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Small‐leaved Kuding tea (SLKDT; Ligustrum robustum ) is a traditional Chinese tea. We systematically investigated the effect of SLKDT extract on obesity. SLKDT‐controlled weight gain in mice fed a high‐fat diet. Tissue specimen results showed that the SLKDT extract alleviated liver damage and fat accumulation. Meanwhile, SLKDT extract improved dyslipidemia by decreasing total cholesterol, triglycerides, and low‐density lipoprotein cholesterol levels and increasing high‐density lipoprotein cholesterol levels. Furthermore, SLKDT extract reduced alanine aminotransferase, alkaline phosphatase, and aspartate transaminase levels in the serum and liver tissues; decreased inflammatory cytokines, including interleukin (IL)‐1β, tumor necrosis factor‐α, interferon‐γ, and IL‐6; and increased the anti‐inflammatory cytokines, IL‐4 and IL‐10. The quantitative PCR results showed that SLKDT extract upregulated the mRNA expressions of peroxisome proliferator‐activated receptor (PPAR)‐α, lipoprotein lipase, carnitine palmitoyltransferase 1, and cholesterol 7 alpha hydroxylase and downregulated PPAR‐γ and CCAAT/enhancer‐binding protein‐alpha mRNA expressions in the obese mouse livers to reduce adipocyte differentiation and fat accumulation, promote fat oxidation, and improve dyslipidemia, thereby inhibiting the immune response and alleviating liver injury. SLKDT shows a potential for preventing obesity and regulating obesity‐related syndrome, so it is possible to be further developed as a novel treatment for fighting obesity.
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During pregnancy, appropriate nutritional support is necessary for the development of the foetus. Maternal nutrition might protect the foetus from toxic agents such as free radicals due to its antioxidant content. In this study, 90 mothers and their children were recruited. DNA damage mediated by oxidative stress (OS) was determined by the levels of 8-hidroxy-2′-deoxyguanosine (8-OHdG) in the plasma of women and umbilical cord blood. The mothers and newborns were categorised into tertiles according to their 8-OHdG levels for further comparison. No relevant clinical differences were observed in each group. A strong correlation was observed in the mother–newborn binomial for 8-OHdG levels (Rho = 0.694, p < 0.001). In the binomial, a lower level of 8-OHdG was associated with higher consumption of calories, carbohydrates, lipids, and vitamin A (p < 0.05). In addition, the levels of 8-OHdG were only significantly lower in newborns from mothers with a higher consumption of vitamin A and E (p < 0.01). These findings were confirmed by a significant negative correlation between the 8-OHdG levels of newborns and the maternal consumption of vitamins A and E, but not C (Rho = −0.445 (p < 0.001), −0.281 (p = 0.007), and −0.120 (p = 0.257), respectively). Multiple regression analysis showed that the 8-OHdG levels in mothers and newborns inversely correlated with vitamin A (β = −1.26 (p = 0.016) and −2.17 (p < 0.001), respectively) and pregestational body mass index (β = −1.04 (p = 0.007) and −0.977 (p = 0.008), respectively). In conclusion, maternal consumption of vitamins A and E, but not C, might protect newborns from DNA damage mediated by OS.
Introduction: The Coronavirus Disease-2019 (COVID-19) pandemic has spread rapidly, infecting more than 194 million and killing more than 4 million people worldwide. Algeria has not escaped this scourge; according to World Health Organisation (WHO), 162,155 confirmed cases and 4,063 deaths have been recorded from 3rd January 2020 to 26th July 2021. Recent studies have indicated the critical role of an altered immune system, and oxidative stress in the pathological process contributing to several complications during COVID-19 disease. Aim: To determine blood markers, oxidant/antioxidant status and biochemical parameters in patients recovered from COVID-19 and compare with those who have never contracted COVID-19; considered as controls. Materials and Methods: The present case-control study was conducted in Tiaret, Algeria, between May 2021 and June 2021. Thirty healthy volunteers who had never contracted COVID-19 and 16 volunteers who recovered from COVID-19 in the last six months were included in the study. Blood samples were taken after 8 to 12 hours of fasting, the blood markers and biochemical parameters were evaluated. The participant with chronic diseases (diabetes, hypertension, cardiovascular diseases, kidney disease) was excluded. Student’s t-test was performed for statistical comparison between the two groups. Statistical analysis was performed using Excel Microsoft 2010 software. Results: The control group consisted of 46.7% males (n=14) and 53.3% females (n=16). While, the case group consisted of 62.5% males (n=10) and 37.5% females (n=6). The plasma levels of Low Density Lipoprotein-Cholesterol (LDL-C), p-value=0.004** and creatinine increased significantly in the cases compared to the controls. While, total cholesterol, p-value=0.04* and Glutamate Pyruvate Transaminase (GPT), p-value=0.03* increased significantly in the case group on comparision to the control group. On the other hand, erythrocyte Malondialdehyde (MDA) levels, p-value=0.009** increased very significantly in the case group compared to controls. The erythrocyte activity catalase decreased significantly in the case group compared to the controls. But erythrocyte Reduced glutathione (GSH) decreased very significantly in group cases compared to controls. Conclusion: The findings in the present study confirmed the persistence of metabolic alterations and oxidative stress in COVID-19 patients after recovery. Antioxidant supplementation is recommended to improve redox status and reduce oxidative stress after recovery
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BACKGROUND: Our previous systematic review has demonstrated that antioxidant supplements may increase mortality. We have now updated this review. OBJECTIVES: To assess the beneficial and harmful effects of antioxidant supplements for prevention of mortality in adults. METHODS: Search methods: We searched The Cochrane Library, Medline, Embase, Lilacs, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science to February 2011. We scanned bibliographies of relevant publications and asked pharmaceutical companies for additional trials. Selection criteria: We included all primary and secondary prevention randomized clinical trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention. Data collection and analysis: Three authors extracted data. Random-effects and fixed-effect model meta-analyses were conducted. Risk of bias was considered in order to minimize the risk of systematic errors. Trial sequential analyses were conducted to minimize the risk of random errors. Random effects model meta-regression analyses were performed to assess sources of intertrial heterogeneity. MAIN RESULTS: Seventy-eight randomized trials with 296,707 participants were included. Fifty-six trials including 244,056 participants had low risk of bias. Twenty-six trials included 215,900 healthy participants. Fifty-two trials included 80,807 participants with various diseases in a stable phase. The mean age was 63 years (range 18 to 103 years). The mean proportion of women was 46%. Of the 78 trials, 46 used the parallel-group design, 30 the factorial design, and 2 the cross-over design. All antioxidants were administered orally, either alone or in combination with vitamins, minerals, or other interventions. The duration of supplementation varied from 28 days to 12 years (mean duration 3 years; median duration 2 years). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects model meta-analysis (21,484 dead/183,749 (11.7%) versus 11,479 dead/112,958 (10.2%); 78 trials, relative risk (RR) 1.02, 95% confidence interval (CI) 0.98 to 1.05) but significantly increased mortality in a fixed-effect model (RR 1.03, 95% CI 1.01 to 1.05). Heterogeneity was low with an I2- of 12%. In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertribal heterogeneity. Meta-regression analysis did not find a significant difference in the estimated intervention effect in the primary prevention and the secondary prevention trials. In the 56 trials with a low risk of bias, the antioxidant supplements significantly increased mortality (18,833 dead/146,320 (12.9%) versus 10,320 dead/97,736 (10.6%); RR 1.04, 95% CI 1.01 to 1.07). This effect was confirmed by trial sequential analysis. Excluding factorial trials with potential confounding showed that 38 trials with low risk of bias demonstrated a significant increase in mortality (2822 dead/26,903 (10.5%) versus 2473 dead/26,052 (9.5%); RR 1.10, 95% CI 1.05 to 1.15). In trials with low risk of bias, beta-carotene (13,202 dead/96,003 (13.8%) versus 8556 dead/ 77,003 (11.1%); 26 trials, RR 1.05, 95% CI 1.01 to 1.09) and vitamin E (11,689 dead/97,523 (12.0%) versus 7561 dead/73,721 (10.3%); 46 trials, RR 1.03, 95% CI 1.00 to 1.05) significantly increased mortality, whereas vitamin A (3444 dead/24,596 (14.0%) versus 2249 dead/16,548 (13.6%); 12 trials, RR 1.07, 95% CI 0.97 to 1.18), vitamin C (3637 dead/36,659 (9.9%) versus 2717 dead/ 29,283 (9.3%); 29 trials, RR 1.02, 95% CI 0.98 to 1.07), and selenium (2670 dead/39,779 (6.7%) versus 1468 dead/22,961 (6.4%); 17 trials, RR 0.97, 95% CI 0.91 to 1.03) did not significantly affect mortality. In univariate meta-regression analysis, the dose of vitamin A was significantly associated with increased mortality (RR 1.0006, 95% CI 1.0002 to 1.001, P = 0.002). AUTHORS' CONCLUSIONS: We found no evidence to support antioxidant supplements for primary or secondary prevention. Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing.
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Excess of saturated free fatty acids, such as palmitic acid (PA), in hepatocytes has been implicated in non-alcoholic fatty liver disease. α-lipoic acid (LA) is an antioxidant that protects against oxidative stress conditions. We have investigated the effect of LA in the early activation of oxidative and endoplasmic reticulum stress, lipid accumulation and Nrf2-mediated antioxidant defenses in hepatocytes treated with PA or in rats fed with high fat diet. In primary human hepatocytes, a lipotoxic concentration of PA triggered endoplasmic reticulum stress, induced the apoptotic transcription factor CHOP and increased the percentage of apoptotic cells. Co-treatment with LA prevented these effects. Similar results were found in mouse hepatocytes where LA attenuated PA-mediated activation of caspase 3, reduced lipid accumulation by decreasing PA uptake and increasing fatty acid oxidation and lipophagy, thereby, preventing lipoapoptosis. Moreover, LA augmented the proliferation capacity of hepatocytes after PA challenge. Antioxidant effects of LA ameliorated reactive oxygen species production, endoplasmic reticulum stress and protected against mitochondrial apoptosis in hepatocytes treated with PA. Co-treatment with PA and LA induced an early nuclear translocation of Nrf2 and activated antioxidant enzymes, whereas reduction of Nrf2 by siRNA abolished the benefit of LA on PA-induced lipoapoptosis. Importantly, post-treatment with LA reversed the established damage induced by PA in hepatocytes, as well as prevented obesity-induced oxidative stress and lipoapoptosis in rat liver. In conclusion, our work has revealed that in hepatocytes, Nrf2 is an essential early player in the rescue of oxidative stress by LA leading to protection against PA-mediated lipoapoptosis. Copyright © 2015. Published by Elsevier Inc.
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The prevalence of the metabolic syndrome, a cluster of cardiovascular risk factors associated with obesity and insulin resistance, is dramatically increasing in Western and developing countries. This disorder consists of a cluster of metabolic conditions, such as hypertriglyceridemia, hyper-low-density lipoproteins, hypo-high-density lipoproteins, insulin resistance, abnormal glucose tolerance and hypertension, that-in combination with genetic susceptibility and abdominal obesity-are risk factors for type 2 diabetes, vascular inflammation, atherosclerosis, and renal, liver and heart diseases. One of the defects in metabolic syndrome and its associated diseases is excess of reactive oxygen species. Reactive oxygen species generated by mitochondria, or from other sites within or outside the cell, cause damage to mitochondrial components and initiate degradative processes. Such toxic reactions contribute significantly to the aging process. In this article we review current understandings of oxidative stress in metabolic syndrome related disease and its possible contribution to accelerated senescence.
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Hypothalamus is a key area involved in the control of metabolism and food intake via the integrations of numerous signals (hormones, neurotransmitters, metabolites) from various origins. These factors modify hypothalamic neurons activity and generate adequate molecular and behavioral responses to control energy balance. In this complex integrative system, a new concept has been developed in recent years, that includes reactive oxygen species (ROS) as a critical player in energy balance. ROS are known to act in many signaling pathways in different peripheral organs, but also in hypothalamus where they regulate food intake and metabolism by acting on different types of neurons, including proopiomelanocortin (POMC) and agouti-related protein (AgRP)/neuropeptide Y (NPY) neurons. Hypothalamic ROS release is under the influence of different factors such as pancreatic and gut hormones, adipokines (leptin, apelin,…), neurotransmitters and nutrients (glucose, lipids,…). The sources of ROS production are multiple including NADPH oxidase, but also the mitochondria which is considered as the main ROS producer in the brain. ROS are considered as signaling molecules, but conversely impairment of this neuronal signaling ROS pathway contributes to alterations of autonomic nervous system and neuroendocrine function, leading to metabolic diseases such as obesity and type 2 diabetes. In this review we focus our attention on factors that are able to modulate hypothalamic ROS release in order to control food intake and energy metabolism, and whose deregulations could participate to the development of pathological conditions. This novel insight reveals an original mechanism in the hypothalamus that controls energy balance and identify hypothalamic ROS signaling as a potential therapeutic strategy to treat metabolic disorders.
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Aims: Obesity is characterized by a low-grade systemic inflammatory state and adipose tissue (AT) dysfunction, which predispose individuals to the development of insulin resistance (IR) and metabolic disease. However, a subset of obese individuals, referred to as metabolically healthy obese (MHO) individuals, are protected from obesity-associated metabolic abnormalities. Here, we aim at identifying molecular factors and pathways in adipocytes that are responsible for the progression from the insulin-sensitive to the insulin-resistant, metabolically unhealthy obese (MUHO) phenotype. Results: Proteomic analysis of paired samples of adipocytes from subcutaneous (SC) and omental (OM) human AT revealed that both types of cells are altered in the MUHO state. Specifically, the glutathione redox cycle and other antioxidant defense systems as well as the protein-folding machinery were dysregulated and endoplasmic reticulum stress was increased in adipocytes from IR subjects. Moreover, proteasome activity was also compromised in adipocytes of MUHO individuals, which was associated with enhanced accumulation of oxidized and ubiquitinated proteins in these cells. Proteasome activity was also impaired in adipocytes of diet-induced obese mice and in 3T3-L1 adipocytes exposed to palmitate. In line with these data, proteasome inhibition significantly impaired insulin signaling in 3T3-L1 adipocytes. Innovation: This study provides the first evidence of the occurrence of protein homeostasis deregulation in adipocytes in human obesity, which, together with oxidative damage, interferes with insulin signaling in these cells. Conclusion: Our results suggest that proteasomal dysfunction and impaired proteostasis in adipocytes, resulting from protein oxidation and/or misfolding, constitute major pathogenic mechanisms in the development of IR in obesity. Antioxid. Redox Signal. 23, 597-612.
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Oxidative stress (OS) is important in the pathogenesis of atherosclerosis. Paraoxonase-1 (PON1) is an enzyme found in the circulation associated with high-density lipoprotein (HDL). HDL-associated enzyme PON1 has an important role in the attenuation of atherogenic low-density lipoprotein (LDL) oxidation. The aim of this study was to determine PON1 and arylesterase (AREST) enzyme levels in relation to insulin resistance (IR) or obesity among children and adolescents. The study included healthy school children and adolescents. Blood was drawn for the determination of blood glucose, lipid, PON1 and AREST enzyme levels. Overall, we observed a positive correlation between PON1 enzyme activity and high-density lipoprotein cholesterol (HDL-C) levels (r = 0.189, P = 0.014). The correlation appeared to be more significant in boys (r = 0.271, P = 0.009). For subjects with IR and obesity, PON1 enzyme activity did not correlate with HDL-C levels (r = 0.038, P = 0.790), instead PON1 levels correlated negatively with BMI (r = -0.309 and P = 0.026). Multiple linear regression analysis was performed to find the predictors of log PON1 activity. HDL-C level was the strongest predictor of PON1 activity in the lean control group, while BMI appeared to be the strongest predictor in the subjects with obesity or IR. In conclusion, determinants of PON1 enzyme activity are variable in children and adolescents based on IR and obesity. Future studies will shed light on the underlying mechanisms and biomarkers of OS in children and may reveal possible targets for therapeutic intervention.
Oxidative stress and low-grade systemic inflammation may contribute to the pathogenesis of obesity-induced comorbidities, including nonalcoholic fatty liver disease. Increasing intake of dietary antioxidants might be beneficial, but there are few data in obese children. To examine the effect of antioxidant supplementation on biomarkers of oxidative stress, inflammation, and liver function, we randomly assigned overweight or obese children and adolescents (n = 44; mean ± SD age: 12.7 ± 1.5 y) participating in a lifestyle modification program to a 4-mo intervention with daily antioxidants (vitamin E, 400 IU; vitamin C, 500 mg; selenium, 50 μg) or placebo. We measured anthropometrics, antioxidant status, oxidative stress (F2-isoprostanes, F2-isoprostane metabolites), inflammation, liver enzymes, fasting insulin and glucose, and lipid profile at baseline and endpoint. There was a significant treatment effect of antioxidant supplementation on antioxidant status [α-tocopherol, β = 23.2 (95% CI: 18.0, 28.4); ascorbic acid, β = 70.6 (95% CI: 51.7, 89.4); selenium, β = 0.07 (95% CI: 0.01, 0.12)] and oxidative stress [8-iso-prostaglandin F2α, β = -0.11 (95% CI: -0.19, -0.02)] but not on any of the inflammatory markers measured. There was a significant treatment effect on alanine aminotransferase [β = -0.13 (95% CI: -0.23, -0.03)], a trend toward a significant effect on aspartate aminotransferase [β = -0.04 (95% CI: -0.09, 0.01)], and no significant effect on γ-glutamyltransferase [β = -0.03 (95% CI: -0.11, 0.06)]. In summary, antioxidant supplementation for 4 mo improved antioxidant-oxidant balance and modestly improved liver function tests; however, it did not reduce markers of systemic inflammation despite significant baseline correlations between oxidative stress and inflammation. The study was registered at as NCT01316081.
Cancers have been the leading cause of death worldwide and the prevalence of obesity is also increasing in these few decades. Interestingly, there is a direct association between cancer and obesity. Each year, more than 90000 cancer deaths are caused by obesity or overweight. The dietary pattern in Crete, referred as the traditional Mediterranean diet, is believed to confer Crete people the low mortality rates from cancers. Nevertheless, the anti-obesity effect of the Mediterranean diet is less studied. Given the causal relationship between obesity and cancer, the anti-obesity effect of traditional Mediterranean diet might contribute to its anti-cancer effects. In this regard, we will critically review the anti-cancer and anti-obesity effects of this diet and its dietary factors. The possible mechanisms underlying these effects will also be discussed.
Adipose tissue is a complex organ with endocrine, metabolic and immune regulatory roles. Adipose depots have been characterized to release several adipocytokines that work locally in an autocrine and paracrine fashion or peripherally in an endocrine fashion. Adipocyte hypertrophy and excessive adipose tissue accumulation, as occurs during obesity, dysregulates the microenvironment within adipose depots and systemically alters peripheral tissue metabolism. The term "adiposopathy" is used to describe this promotion of pathogenic adipocytes and associated adipose - elated disorders. Numerous epidemiological studies confirm an association between obesity and various cancer forms. Proposed mechanisms that link obesity/adiposity to high cancer risk and mortality include, but are not limited to, obesity-related insulin resistance, hyperinsulinemia, sustained hyperglycemia, glucose intolerance, oxidative stress, inflammation and/or adipocktokine production. Several epidemiological studies have demonstrated a relationship between specific circulating adipocytokines and cancer risk. The aim of this review is to define the function, in normal weight and obesity states, of well-characterized and novel adipokines including leptin, adiponectin, apelin, visfatin, resistin, chemerin, omentin, nesfatin and vaspin and summarize the data that relates their dysfunction, whether associated or direct effects, to specific cancer outcomes. Overall research suggests most adipokines promote cancer cell progression via enhancement of cell proliferation and migration, inflammation and anti-apoptosis pathways, which subsequently can prompt cancer metastasis. Further research and longitudinal studies are needed to define the specific independent and additive roles of adipokines in cancer progression and reoccurrence.
Abstract : Oxidative stress (OS) is important in the pathogenesis of atherosclerosis. Paraoxonase-1 (PON1) is an enzyme found in the circulation associated with high-density lipoprotein (HDL). HDL-associated enzyme PON1 has an important role in the attenuation of atherogenic low-density lipoprotein (LDL) oxidation. The aim of this study was to determine PON1 and arylesterase (AREST) enzyme levels in relation to insulin resistance (IR) or obesity among children and adolescents. The study included healthy school children and adolescents. Blood was drawn for the determination of blood glucose, lipid, PON1 and AREST enzyme levels. Overall, we observed a positive correlation between PON1 enzyme activity and high-density lipoprotein cholesterol (HDL-C) levels (r = 0.189, P = 0.014). The correlation appeared to be more significant in boys (r = 0.271, P = 0.009). For subjects with IR and obesity, PON1 enzyme activity did not correlate with HDL-C levels (r = 0.038, P = 0.790), instead PON1 levels correlated negatively with BMI (r = − 0.309 and P = 0.026). Multiple linear regression analysis was performed to find the predictors of log PON1 activity. HDL-C level was the strongest predictor of PON1 activity in the lean control group, while BMI appeared to be the strongest predictor in the subjects with obesity or IR. In conclusion, determinants of PON1 enzyme activity are variable in children and adolescents based on IR and obesity. Future studies will shed light on the underlying mechanisms and biomarkers of OS in children and may reveal possible targets for therapeutic intervention.