C H A P T E R
14
Dietary Quercetin and other Polyphenols:
Attenuation of Obesity
Masuko Kobori
National Food Research Institute, National Agriculture and Food Research Organization, Tsukuba, Ibaraki, Japan
1. INTRODUCTION
Obesity can lead to the development of metabolic
syndrome, increasing the risk of cardiovascular dis-
eases. Vegetables, fruits, and tea are considered to
reduce the risk of cardiovascular disease, and animal
studies suggest that chronic intake of dietary quercetin
attenuates obesity and metabolic syndrome. The atten-
uating effects of polyphenols on obesity are relatively
low; however, habitual intake of polyphenols from die-
tary sources may help to promote health and prevent
or attenuate obesity and metabolic syndrome. This
chapter discusses the physiological functions of quer-
cetin, which is a major component of vegetables and
fruits, and other polyphenols on the attenuation of
obesity and metabolic syndrome.
2. DIETARY PATTERNS RELATED TO
OBESITY AND METABOLIC SYNDROME
Obesity is a well-known high-risk factor for the
development of metabolic syndrome, which is a multi-
plex risk factor associated with hyperglycemia, dyslipi-
demia, and hypertension, and it increases the risk of
developing type 2 diabetes and cardiovascular
disease,1 Obesity (body mass index (BMI) $ 30) and
overweight (BMI $ 25) are major health problems in
high-income countries, and are increasing in low- and
middle-income countries worldwide.2,3 The consump-
tion of a Western-style diet, which is characterized by
a high intake of red meat and processed meat, high-fat
dairy products, and sweet items, can contribute to obe-
sity and metabolic syndrome, which increase the risk
of type 2 diabetes and cardiovascular disease.4
7 The
Polyphenols in Human Health and Disease.
DOI: http://dx.doi.org/10.1016/B978-0-12-398456-2.00014-1
consumption of a diet high in fat and energy is associ-
ated with obesity and the development of metabolic
disorders; however, it is uncertain whether high die-
tary sugar, rather than other carbohydrates, contri-
butes to body weight gain.8
11 Oxidative stress and
inflammation are known to play important roles in the
progression of obesity and metabolic syndrome.12
15
The Mediterranean diet is associated with a low risk
of cardiovascular disease, and it comprises: (1) abun-
dant plant foods such as fruits, vegetables, and whole-
grain cereals, (2) seasonal fresh and locally grown
foods, (3) olive oil as the principal source of dietary
lipids, (4) wine consumed in low to moderate amounts,
generally with meals, (5) fresh fish and seafood, (6)
dairy products, poultry, and eggs consumed in low to
moderate amounts, and (7) red and processed meat
consumed at a low frequency in low amounts.16 The
results of intervention studies suggest that the
Mediterranean diet prevents overweight/obesity and
metabolic syndrome.17,18 Higher consumption of
vegetables and fruits is known to reduce the risk of car-
diovascular diseases and stroke.17,19 Plant polyphenols
or flavonoids, which are abundant in vegetables and
fruits, have been suggested to be the main agents that
reduce the risk of cardiovascular diseases.20
22 Some
cohort and cross-sectional studies have also suggested
that tea, which contains a large amount of polyphenols,
reduces the risk of cardiovascular diseases.23
25
3. TEA
In black and green teas, flavanols, which include
catechin, (2)-epicatechin, (2)-epigallocatechin, (2 ) -epi-
catechin-3-gallate, and (2)-epigallocatechin-3-gallate
163 © 2014 Elsevier Inc. All rights reserved.
164 14. DIETARY QUERCETIN AND OTHER POLYPHENOLS: ATTENUATION OF OBESITY
(EGCG), form the major class of flavonoids. Quercetin,
kaempferol, and several other polyphenols are also
components of tea.23 There have been many intervention
studies on the effect of green tea catechins, which mainly
comprise EGCG, on obesity or body weight
(Figure 14.1).26
30 Phung et al.28 conducted meta-analysis
of 15 randomized control trials (RCTs), which met
specific inclusion criteria, on the effects of green tea cate-
chins on anthropometric variables and showed that
green tea catechins with caffeine decreased BMI, body
weight, and waist circumference compared with caffeine
alone. The analysis revealed that green tea catechins with
caffeine significantly reduced body weight but not BMI
and waist circumference compared with a caffeine-free
control, whereas green tea catechins without caffeine
had no significant effect compared with a caffeine-free
control. Hursel et al.29 performed meta-analysis of 11
studies and concluded that catechins or an EGCG-caf-
feine mixture had a small positive effect on weight loss
and weight maintenance. They also suggested that habit-
ual caffeine intake and ethnicity may influence the effect
of catechins. In the short-term (,1 week), intervention
studies on green tea extracts revealed an increase in
energy expenditure and fat oxidation.26,27,30 They are
considered to be major mechanisms for attenuating the
effects of tea catechins on obesity. Many animal studies
have reported the suppressive effects of green tea cate-
chins on obesity and metabolic syndrome using both
genetic and dietary models of obesity, insulin resistance,
hypertension, and hypercholesterolemia.24,26,27,31
33
Green tea catechins or EGCG decrease body weight,
body fat accumulation, and liver triglyceride, blood glu-
cose, plasma alanine aminotransferase (ALT), and
plasma total cholesterol levels in obesity models, proba-
bly by reducing lipid absorption and increasing energy
expenditure and fat oxidation.27,31
33 Many other
mechanisms have been suggested by in vitro and in vivo
studies.24,27,31
33
OH
HO
O OH
HO
O
HO OH
O
HO
OH
FIGURE 14.1 Structure of (2)-epigallocatechin 3-gallate.
2. POLYPHENOLS IN THERAPY OF OBESITY AND DIABETES
4. QUERCETIN
4.1 Attenuation of Obesity
The flavonol quercetin is the most common flavonoid
found in vegetables, fruits, and tea (Figure 14.2).34
36
Although it remains a matter of debate, flavonoids,
including quercetin, have been suggested to prevent car-
diovascular disease and other lifestyle-related diseases
by scavenging free radicals, inhibiting lipid peroxida-
tion, and other antioxidative actions.21,37
42 Unlike tea
catechins, there are few human intervention studies on
the effects of quercetin on obesity and overweight.
However, the suppressive effects of quercetin on obesity
and metabolic syndrome are being gradually elucidated
in animal studies. This chapter mainly focuses on the
physiological functions of quercetin, which is a major
component of vegetables and fruits, on the attenuation
of obesity and metabolic syndrome.
Red and yellow onions are particularly rich in quer-
cetin.34,36 Quercetin mostly exists as the glycosides
quercetin 3,40 -O-diglucosides and quercetin 40 -O-gluco-
side in onions.34 The amount of quercetin aglycon in
the diet is much lower than that of quercetin
glycoside; however, the metabolites of quercetin are
similar to those of the glycosides because β-glycosides
are mostly hydrolyzed into aglycones in the
intestine.43
45 Quercetin aglycones are metabolized to
glucuronated, sulfated, and/or methylated quercetin
conjugates.
Recently, we showed that the consumption of a
quercetin-rich diet alleviated obesity and metabolic
syndrome in C57BL/6J mice fed a Western diet, which
was high in fat, cholesterol, and sucrose.46 The
Western diet significantly increases body weight gain,
as well as blood glucose, plasma insulin, total choles-
terol, triglycerides, and non-esterified fatty acid
(NEFA) levels in mice compared with a control
AIN93G diet (Table 14.1). A Western diet containing
0.05% quercetin significantly reduced the body weight
gain and visceral and liver fat accumulation, as well as
improved hyperglycemia, hyperinsulinemia, and dysli-
pidemia in mice after 20 weeks of feeding.
Furthermore, quercetin improved the plasma levels of
OH
OH
HO O
OH
OH O
FIGURE 14.2 Structure of quercetin.
 4. QUERCETIN 165
TABLE 14.1 Effect of Qeurcetin on Obesity in Animal Studies
References Species/ Duration Intervention Outcome
Strain

Kobori Mouse/ 20 weeks 0.05% quercetin 1 high-fat, high-cholesterol, kbody weight, visceral fat
et al.46 C57BL/6J high-sucrose (Western) diet vs. Western diet,
free access
kblood glucose, plasma TG, NEFA, TC, insulin, TNF-α
mplasma adiponectin

kliver fat accumulation, TG, TC, TBARS

mliver total glutathione
khepatic expression of Pparg, Cd36, Srbpf1, Fasn, Ucp2,
Gck
mhepatic expression of Ppara, Gpx1, Cat, Pck1
quercetin improve liver TG, TBARS, total glucathione at 8
weeks
Jung Mouse/ 9 weeks 0.25% quercetin 1 high-fat diet vs. high-fat kbody weight, epididymal adipose tissue weight, lipid
et al.56 C57BL/6J diet, free access droplets size in epididymal fat pads
kserum TG, TC, free cholesterol, total antioxidant status,
TBARS
kliver weight, lipid accumulation, liver TG
khepatic expression of Aldh1b1, Apoa4, Pparg, Abcg5,
Gpam, Cd36, Fasn, Fdft1, CD36, CEBPα, FAS
mhepatic expression of Cyp2c50, Fnta, Pon1, Ppara, Abcg5,
Pon1

Stewart Mouse/ 8 weeks 1.2% quercetin 1 high-fat diet (45 energy%) kplasma insulin
et al.57 C57BL/6J vs. high-fat diet, free access quercetin did not improve insulin resistance

Stewart Mouse/ 8 weeks 0.8% quercetin 1 high-fat diet vs. high-fat kplasma IFN-γ, IL-1α, IL-4
et al.58 C57BL/6J diet, free access quercetin transiently increased energy expenditure at 3
weeks
Rivera Rat/ 10 weeks 10 mg quercetin/kg body weight/day vs. kbody weight
et al.59 Zucker vehicle, oral administration kplasma TG, NEFA, TC, insulin , TNF-α, NOx
obese
mplasma adiponectin

kiNOS in visceral adipose tissue

ksystolic blood pressure
meNOS in aorta and visceral adipose tissue
Panchal Rat/ 8 weeks High-carbohydrate high-fat (H) diet for 8 kfat (total abdominal, retroperitoneal, epididymal,
et al.60 Wister weeks followed by 0.08% quercetin 1 H diet omental)
vs. H diet, free access
kblood glucose
mplasma TG
ksystolic blood pressure
cardiovascular structure and function are improved
kliver weight
kplasma ALT, ALP, LDH, total bilirubin, uric acid

kNrf2, HO-1, NF-κB in liver and heart, caspase-3 in liver

mCPT-1 in liver and heart

(Continued)

2. POLYPHENOLS IN THERAPY OF OBESITY AND DIABETES

166 14. DIETARY QUERCETIN AND OTHER POLYPHENOLS: ATTENUATION OF OBESITY
TABLE 14.1 (Continued)
References Species/ Duration Intervention
Strain
Hoek-van Mouse/ 12 weeks 0.33% quercetin 1 mild-high fat (30% energy
den Hill C57BL/ %) diet vs. mild-high fat diet, free access
et al.61 6JOlaHsd
TG, triglycerides; TC, total cholesterol; PUSA, polyunsaturated fatty acids; ALT, alanin transaminase; ALP, alkaline phosphatase; LDH, lactate dehydrogenase.
the adipokine adiponectin, which were decreased by
the Western diet, and plasma levels of the pro-inflam-
matory cytokine tumor necrosis factor-α (TNF-α),
which were increased by the Western diet, in mice after
20 weeks. Levels of the oxidative stress markers thio-
barbituric acid-reactive substances (TBARSs) and the
endogenous antioxidant glutathione were increased
and decreased, respectively, and were accompanied by
fat accumulation in the liver of mice fed the Western
diet. Quercetin improved TBARS and glutathione levels
in the liver of mice after 8 weeks of feeding. In the liver,
quercetin also prevented the reduced expression of the
antioxidant enzyme glutathione peroxidase 1 (Gpx1)
and proliferator-activated receptor α (PPARα) (Ppara),
which is involved in the β-oxidation of fatty acids. It
reduced the fat accumulation and improved the expres-
sion of other genes that regulate lipid metabolism, mito-
chondrial transport, and glucose metabolism. Quercetin
suppressed the Western diet-induced expression of the
transcription factor PPARγ (Pparg), which regulates
high-fat diet-induced fat accumulation in the liver, and
the target gene Cd36 after 20 weeks of feeding.47 The
induced expression of the transcription factor sterol
regulatory element binding protein-1c (SREBP-1c)
(Srbpf1), the target fatty acid synthase, and the mito-
chondrial uncoupling protein UCP-2 was significantly
suppressed by quercetin. The expression of phospho-
enolpyruvate carboxykinase (PEPCK) (Pck1), which
regulates gluconeogenesis, and the antioxidant enzyme
catalase was increased by quercetin in the liver of mice
fed the Western diet for 20 weeks. Thus, quercetin
improved oxidative stress and PPARα expression in the
liver and the triglyceride levels in the plasma and then
attenuated hepatic and visceral fat accumulation and
improved other systemic parameters related to meta-
bolic syndrome in mice fed the Western diet. It has
been suggested that oxidative stress induces fat accu-
mulation directly or indirectly via the exacerbation of
insulin resistance.13,48,49 It is likely that quercetin
2. POLYPHENOLS IN THERAPY OF OBESITY AND DIABETES
Outcome
kliver weight
kplasma TG, palmitic acid, oleic acid, linoleic acid
mplasma total PUFA
mhepatic expression of ω-oxidation, Cyp4a10, Cyp4a14,
Cyp4a31, Acot3, cytochrome P450 oxidoreductase (Por),
transcription factor constitutive androstane receptor
(Nr1i3)
gradually reduces fat accumulation by modulating the
expression of genes related to steatosis via the allevia-
tion of oxidative stress in the liver. However, adipose
tissue also plays an important role in metabolic
syndrome.12,50
53 White adipose tissue produces bio-
logically active adipokines, including adiponectin and
the pro-inflammatory cytokine TNF-α. The plasma adi-
ponectin levels have been shown to be reduced in obe-
sity and metabolic syndrome.50 At the same time, the
increased secretion of TNF-α from adipose tissue has
been shown to induce insulin resistance.53
55 We also
found that quercetin decreased oxidative stress in the
visceral adipose tissues of mice fed a Western diet
(unpublished data). The reduction of oxidative stress in
adipose tissue may improve the plasma levels of adipo-
nectin and TNF-α.12 Chronic dietary intake of quercetin
also mediated antioxidative and anti-inflammatory
effects in mice fed a control diet for 20 weeks, i.e., a
reduction of hepatic TBARS generation and plasma
TNF-α levels. In contrast, it did not affect body weight,
fat accumulation, or plasma levels of factors other than
TNF-α in mice fed the control diet. Our results suggest
that quercetin mainly affects the oxidative status and
reduces oxidative stress, which play important roles in
the attenuation of obesity and metabolic syndrome by
dietary quercetin.
Later, Jung et al.56 also showed that 0.025% querce-
tin reduced high-fat diet-induced gains in body
weight, liver weight, and white adipose tissue weight
in C57BL/6J mice after 9 weeks of feeding. They
showed that quercetin altered the expression profiles
of lipid metabolism-related genes, including Fnta,
Pon1, Pparg, Aldh1b1, Apoa4, Abcg5, Gpam, Cd36, Fdft1,
and Fasn in the liver of mice fed a high-fat diet
(Table 14.1). However, Stewart et al.57 showed that 8
weeks of a diet supplemented with 1.2% quercetin did
not improve the insulin resistance induced by a high-
fat diet (45% energy) in C57BL/6J mice (Table 14.1).
They also showed that 0.8% quercetin increased the
 4. QUERCETIN
energy expenditure in C57BL/6J mice fed a high-fat
diet after 3 weeks, although the effect diminished after
8 weeks (Table 14.1).58 In the experiment, quercetin
reduced the concentrations of the inflammatory mar-
kers interferon-γ (IFN-γ), interleukin-1α (IL-1α), and
IL-4 in mice fed a high-fat diet during the night phase
after 8 weeks of feeding.
Orally administered quercetin significantly reduced
body weight gain in obese and lean Zucker rats at a
dose of 10 mg/kg of body weight after 10 weeks of
daily treatment (Table 14.1).59 Obese Zucker rats have
many of the characteristics of human metabolic syn-
drome, such as insulin resistance, dyslipidemia, hyper-
insulinemia, and hypertension. Quercetin reduced the
increased systolic blood pressure and high plasma con-
centrations of triglycerides, total cholesterol, NEFA,
and insulin in obese Zucker rats at doses of 2 and
10 mg/kg body weight/day. Higher doses of quercetin
increased the plasma adiponectin concentration,
reduced the plasma nitrate and nitrite (NOx) levels,
lowered the visceral adipose tissue (VAT) TNF-α pro-
duction, and enhanced VAT endothelial nitric oxide
synthase (eNOS) expression in obese Zucker rats.
Therefore, its anti-inflammatory effects on adipose tis-
sue were considered to be connected with the reduc-
tion of body weight gain and the improvement of
metabolic syndrome.
Panchal et al.60 fed Wistar rats with a high-
carbohydrate and high-fat diet for 8 weeks followed
by dietary supplementation with 0.8 g/kg quercetin
for 8 weeks, and observed that quercetin reduced
abdominal fat and systolic blood pressure levels as
well as attenuated cardiovascular remodeling and
non-alcoholic fatty liver disease (Table 14.1). Quercetin
supplementation attenuated the changes in the expres-
sion of makers of oxidative stress and inflammation in
the liver and heart such as nuclear factor-related fac-
tor-2 (Nrf2), heme oxygenase-1 (HO-1), and nuclear
factor kappa B (NF-κB) along with higher fatty acid
oxidation; therefore, it was suggested that decreases in
oxidative stress and inflammation were the mechan-
isms by which quercetin attenuates metabolic syn-
drome, cardiovascular remodeling, and non-alcoholic
fatty liver disease.60 Hoek-van den Hil et al.61 showed
that 0.33% (w/w) quercetin increased the expression
of genes related to ω-oxidation, such as cytochrome
P450 (Cyp)4a10, Cyp4a14, Cyp4a31, and Acyl-CoA
thioesterase 3 (Acot3), and decreased serum palmitic
acid and oleic acid levels in the liver of mice fed a
medium- to high-fat diet (30% energy in the form of
fat) for 12 weeks (Table 14.1). In the experiment, quer-
cetin did not affect the body weight, energy intake, or
hepatic lipid accumulation in mice fed the medium- to
high-fat diet.
2. POLYPHENOLS IN THERAPY OF OBESITY AND DIABETES
167
Green tea extract has been shown to increase energy
expenditure and fat oxidation, whereas quercetin did
not affect the resting energy expenditure in healthy
humans. Egret et al.62 reported that supplementation of
50, 100, or 150 mg/day quercetin for 2 weeks did not
affect body energy consumption and resting energy
expenditure as well as plasma antioxidative capacity
or concentrations of serum uric acid, plasma α- and
γ-tocopherols, oxidized low-density lipoprotein (LDL),
and TNF-α as assessed by the ferric-reducing antioxi-
dant potential and oxygen radical absorbance capacity
assays in 35 healthy volunteers. Quercetin aglycone
(150 mg) supplementation did not affect the fasting
resting energy expenditure significantly in healthy,
normal-weight women after 24 hours.63
Obesity is a complex multifactorial chronic disease
caused by interactions among numerous factors. The
habitual intake of quercetin probably attenuates or pre-
vents obesity, mainly via the suppression of increased
oxidative stress and related inflammation. Further epi-
demiological studies are required to elucidate the role
of dietary quercetin in the attenuation of obesity.
4.2 Antioxidative and Anti-Inflammatory
Actions
Antioxidative activity is a major candidate mecha-
nism by which quercetin attenuates obesity. Indeed,
quercetin is a well-known antioxidant both in vitro and
in vivo.64
70 Quercetin has singlet oxygen quenching
and free radical scavenging capacities.64,68 It is known
to suppress lipid peroxidation and hydrogen peroxide
production by the mitochondria and improve the
redox status of tissues and plasma.66,67,69,70 Reactive
oxygen species (ROS) are known to induce inflamma-
tory responses by the activation of mitogen-activated
protein kinase (MAPK) and NF-κB pathways as well
as the subsequent induction of the expression of
inflammatory cytokines such as TNF-α, IL-1β, and IL-
6.71,72 Quercetin is thought to suppress inflammation,
mainly by decreasing oxidative stress. Boesch-
Saadatmandi et al.73 showed that a high-fat diet con-
taining 0.2% quercetin reduced the expression of redox
factor-1 (Ref-1), which is upregulated by oxidative
stress and regulates NF-κB signaling, and induced the
expression of the micro RNAs miR-125b and miR-122
in the liver of C57BL/6J mice fed a high-fat diet for 6
weeks. miR-125b and miR-122 are known to be related
to inflammation and lipid metabolism, respectively. It
was suggested that quercetin reduced the expression
of the inflammation genes C-reactive protein (CRP),
IL-6, and monocyte chemoattractant protein 1 (MCP-1)
at least partly by decreasing Ref-1 and increasing miR-
125b and miR-122.
168 14. DIETARY QUERCETIN AND OTHER POLYPHENOLS: ATTENUATION OF OBESITY
In plasma, quercetin mostly exists as glucuronated,
sulfated, and/or methylated quercetin conjugates.
These conjugates are known to retain their antioxidant
properties.74,75 However, RCT showed that quercetin
supplementation for over 12 weeks at doses of 500 mg
or 1000 mg/day with 125 mg or 250 mg vitamin
C/day, respectively, did not affect the antioxidant
status in human plasma.76 Thus, quercetin supplemen-
tation may not affect the antioxidant status under
healthy, normal conditions. Egert et al.77 reported that
supplementation of quercetin at a dose of 150 mg/day
for 6 weeks reduced the oxidized LDL concentration in
overweight subjects, although Edwards et al.78 showed
that supplementation with 730 mg quercetin for 28
days did not affect the oxidative stress indices in
hypertensive subjects.
Smokers have a high and sustained free radical
load, which confers a relatively high risk of cardiovas-
cular disease. Lee et al.79 reported that consumption of
a quercetin-rich supplement derived from onion peel
extract, which contained 100 mg of quercetin, for 10
weeks reduced the serum concentrations of total cho-
lesterol, LDL cholesterol, and glucose as well as the
systolic and diastolic blood pressure in healthy male
smokers.
4.3 Alleviation of Diabetes
The antioxidant action of quercetin is likely to alle-
viate some lifestyle-related diseases. To elucidate the
molecular mechanism by which quercetin alleviates
diabetes, we performed comprehensive gene expres-
sion analysis of the liver of streptozotocin (STZ)-
induced diabetic mice, which were fed a diet contain-
ing quercetin.80 We found that quercetin improved
liver injury and other diabetic symptoms, mainly via
the reduction of oxidative stress in the liver and pan-
creas. We provided a diet that contained 0, 0.1, or 0.5%
quercetin to STZ-induced diabetic mice for 2 weeks.
Diets containing 0.1 or 0.5% quercetin reduced the
STZ-induced increase in blood glucose levels. The diet
containing 0.5% quercetin improved plasma insulin
levels, which were reduced by STZ, after 2 weeks of
feeding. The liver is the major organ that is adversely
affected by diabetes. The diets that contained 0.1 or
0.5% quercetin reduced the liver injury level in STZ-
induced diabetic mice according to terminal deoxynu-
cleotidyl transferase mediated dUTP nick end labeling
(TUNEL) staining, which identified nuclear DNA frag-
mentation in damaged cells. Thus, quercetin alleviated
the overall diabetic symptoms induced by STZ in
mice. Quercetin is metabolized in the intestine or the
liver, and it gradually accumulates in other organs;81
therefore, we examined the effect of quercetin on
2. POLYPHENOLS IN THERAPY OF OBESITY AND DIABETES
hepatic gene expression in the liver of STZ-induced
diabetic mice using a DNA microarray. Cluster analy-
sis of significantly up- or downregulated hepatic gene
expression with STZ showed that the 0.5% quercetin
diet suppressed the STZ-induced alteration of gene
expression. STZ induced the expression of genes
related to the immune response, stress, cell cycle, and
cell death, whereas it suppressed the expression of
genes related to protein metabolism and biosynthesis.
However, gene set enrichment analysis (GSEA), an
analytical method used to identify changes in the
expression of functional gene groups, of the microar-
ray data revealed that only the gene set containing cell
cycle regulators such as the cyclin-dependent kinase
inhibitor p21(WAF1/Cip1) (Cdkn1a) was significantly
downregulated by quercetin. Thus, quercetin
improved the deleterious effects on hepatic gene
expression that were induced by STZ, and its greatest
effect was on the expression of the gene set associated
with the cell cycle. STZ induces pancreatic β-cell death
and causes type 1 diabetes mellitus. STZ-induced oxi-
dative stress is also the main pathway for the develop-
ment and exacerbation of induced diabetes. Cdkn1a,
which regulates cell division by arresting the cell cycle
at the G1 and S phases, is known to regulate hepatic
cell growth and is induced by oxidative stress.82
84
Quercetin decreased the level of the oxidative stress
marker TBARS in the liver of STZ-induced diabetic
mice. Therefore, quercetin probably alleviates liver
injury in STZ-induced diabetic mice by recovering the
progression of cell proliferation as a consequence of
suppressing the Cdkn1a expression induced by STZ
and by the increased oxidative stress during diabetes.
Similarly, quercetin also reduced the levels of TBARS
and Cdkn1a expression in the pancreas. Presumably,
quercetin increases pancreatic insulin production by
promoting cell proliferation via the suppression of
Cdkn1a expression induced by STZ. Our results indi-
cate that quercetin attenuates diet-induced obesity and
STZ-induced diabetic symptoms, mainly by reducing
oxidative stress in tissues.
The dihydrochalcone phloridzin is a flavonoid that
is typically found in apples and processed apple
foods.85
88 To compare the effect of quercetin with
that of other flavonoids, we fed a diet containing
phloridzin to STZ-induced diabetic mice for 2 weeks89
Phloridzin possesses antioxidant properties;85,87 how-
ever, unlike quercetin, 0.5% phloridzin did not sup-
press STZ-induced lipid peroxidation in the liver,
which indicates that the antioxidant ability of dietary
quercetin is more pronounced than that of dietary
phloridzin in STZ-induced diabetic mice. Moreover,
the 0.5% phloridzin diet failed to improve hypoinsuli-
nemia and had no effect on the altered hepatic gene
expression in STZ-induced diabetic mice. These results
 4. QUERCETIN
also suggest that quercetin alleviates STZ-induced dia-
betic symptoms by suppressing oxidative stress in tis-
sues. Reportedly, ingested phloridzin is mainly
hydrolyzed in the small intestine, although 0.5% phlor-
idzin has been suggested to reduce the blood glucose
levels in STZ-induced diabetic mice by inhibiting the
sodium/glucose cotransporter gene SGLT1 expression
in the small intestine.90
92
Interperitoneally injected or orally administered
quercetin has been shown to reduce oxidative stress
and protect against pancreatic β-cell damage, kidney
injury, osteopenia, and testicular damage in STZ-
induced diabetic rodents.70,93
99 Oral administration of
quercetin for 45 days decreased blood glucose, plasma
TBARS, and hydrogen peroxide levels but increased
superoxide dismutase and catalase activity in the ery-
throcytes of STZ-induced diabetic rats.70 Coskun
et al.93 showed that interperitoneally injected quercetin
reduced the elevation of pancreatic tissue malondialde-
hyde (MDA), which is a marker of lipid peroxidation;
increased the activities of the antioxidant enzymes glu-
tathione peroxidase, superoxide dismutase (SOD), and
catalase in pancreas; and protected against islet cell
degeneration in STZ-treated rats after three days. Dias
et al.94 showed that interperitoneally injected quercetin
suppressed the elevation of TBARS, hydrogen
peroxide-initiated chemiluminescence, SOD, and cata-
lase activity in the liver of STZ-induced diabetic rats
after 8 weeks. Oral administration of quercetin
improved renal dysfunction and the levels of MDA,
glutathione, SOD, and catalase in the kidneys of STZ-
induced diabetic rats.95 Quercetin was shown to
protect against the progression of nephropathy in STZ-
induced diabetic rats.96 Recently, Wang et al.97
reported that quercetin regulated renal urate transport-
related proteins to reduce hyperuricemia and lipid
metabolism-related genes to alleviate kidney lipid
accumulation as well as suppressed renal NLRP3
inflammasome activation in STZ-treated rats.
4.4 Alleviation of Hypertension
RCTs have shown that quercetin supplementation
reduces the systolic and/or diastolic blood pres-
sure.98,99 Edwards et al.78 showed that supplementa-
tion with 730 mg quercetin/day for 28 days reduced
systolic and diastolic blood pressure in stage 1 hyper-
tensive patients but did not affect the oxidant stress
indices measured in the plasma and urea. Egert
et al.100 showed that supplementation with 150 mg
quercetin for 6 weeks reduced systolic blood pressure
and plasma oxidized LDL levels in overweight or
obese subjects. Apolipoprotein (apo)E, which is an
important modulator of many stages of lipoprotein
2. POLYPHENOLS IN THERAPY OF OBESITY AND DIABETES
169
metabolism, is a polymorphic protein with three com-
mon isoforms in humans: apoE2, apoE3, and apoE4.
ApoE3 is the wild-type and most common isoform,
whereas the apoE4 genotype is associated with a sig-
nificantly higher risk of cardiovascular disease. Egert
et al.77 re-analyzed the data according to the apoE phe-
notypes and showed that quercetin supplementation
reduced systolic blood pressure in the apoE3 group
(overweight-obese carriers of the apo ε3/ε3 genotype)
as well as decreased plasma oxidized LDL and plasma
TNF-α levels in the apoE3 and apoE4 groups.
Reducing oxidative stress is thought to be the major
mechanism that mediates the hypotensive effects of
quercetin; however, some animal and human studies
have shown that quercetin reduces blood pressure
without suppressing oxidative stress.101 Thus, querce-
tin may reduce blood pressure by decreasing oxidative
stress and by other mechanisms.101
Menendez et al.102 proposed that glucuronidated
quercetin derivatives, which are metabolites of orally
ingested quercetin, act as carries of quercetin and
deliver the free aglycone in situ via deconjugation.
They showed that the major metabolite quercetin 3-O-
glucuronide was deconjugated in the vascular bed
where it had an inhibitory effect on vascular contrac-
tion.102 The authors also reported that, in addition to
orally administered quercetin, intravenous injection of
the metabolites quercetin 3-O-glucuronide and iso-
rhamnetin 3-O-glucuronide reduced the mean blood
pressure in spontaneously hypertensive rats (SHR),
while the hypotensive effects were abolished by a spe-
cific inhibitor of β-glucuronidase.103 They suggested
that quercetin is deconjugated and inhibits the
α-adrenergic-induced hypercontractile response in
resistance arteries. Thus, the release of quercetin from
its glucuronidated metabolites was suggested to be
responsible for its vasorelaxant and hypotensive
effects.
Kawai et al.104 reported that quercetin 3-O-glucuro-
nide was specifically accumulated in atherosclerotic
lesions in the human aorta, particularly in
macrophage-derived foam cells. They also suggested
that injured/inflamed arteries containing activated
macrophages with a higher β-glucuronidase activity
were potential targets of quercetin metabolites.
4.5 Conclusion
A number of studies have reported that quercetin
can directly affect a range of physiologically active
molecules. For example, quercetin inhibits the activi-
ties of proteins such as P-glycoprotein, protein kinase
C, and topoisomerase II by binding to ATP-binding
sites.105 Quercetin inhibits the expression of heat shock
170 14. DIETARY QUERCETIN AND OTHER POLYPHENOLS: ATTENUATION OF OBESITY
proteins and acts as a phytoestrogen and an activator
of SIRT1.106
108 However, most of these effects have
only been demonstrated in vitro at relatively high con-
centrations of quercetin.
Janssen et al.109 fed healthy volunteers 200 g onions/
day, which provided 114 mg quercetin/day, or 5 g
fried parsley/day, which provided 84 mg apigenin/
day, for 2 weeks and found no significant effect of
onion or parsley on platelet aggregation, which is
inhibited by quercetin or apigenin in vitro. They con-
cluded that the in vitro anti-aggregatory effects of fla-
vonoids are caused by concentrations that cannot be
attained in vivo by dietary consumption; therefore, the
effects of dietary flavonols and flavones on cardiovas-
cular risk may not be mediated by platelet aggregation
or cyclooxygenase activities.
In summary, quercetin has little effect on healthy,
normal people; however, it probably attenuates obesity
and metabolic syndrome by reducing excessive oxida-
tive stress and inflammation during disease progres-
sion. This is likely to be an additional pathway for
alleviating hypertension using quercetin.
5. RESVERATROL
Resveratrol (3,5,40 -trihydroxy-trans-stilbene) is a stil-
bene found in grapes, wine, peanuts, and soy
(Figure 14.3).110 Red wine, which contains cis- and
trans-resveratrol and the 3-O-β-glucosides cis- and
trans-piceids, is the most abundant dietary source of
resveratrols; however, their contents are lower than
those of many other polyphenols.110,111 Zamora-Ros
et al.112 estimated the dietary intake of resveratrol and
piceid in the adult Spanish population using a vali-
dated diet history method and reported that resvera-
trol and piceid were mainly obtained from wine and
the estimated medians and means for resveratrol and
piceid were 100 and 933 μg/day, respectively. They
showed that approximately 32% of the population did
not consume resveratrol and piceid. Thus, the dietary
intake of resveratrol is limited, although the beneficial
OH
H
H resveratrol for 30 days and found that resveratrol did
HO OH
FIGURE 14.3 Structure of resveratrol.
2. POLYPHENOLS IN THERAPY OF OBESITY AND DIABETES
effects of resveratrol on health have received wide-
spread attention because it has been reported to be the
most potent activator of the protein deacetylase SIRT1
and it enhances the physiology of middle-aged mice
on a high-calorie diet and increases their sur-
vival.108,113,114 SIRT1 was shown to regulate the pro-
cesses related to the effects of calorie restriction, such
as glucose and insulin production, fat metabolism, and
cell survival. Baur et al.114 fed 1-year-old mice with a
high-calorie diet containing 0.04% resveratrol and
found that resveratrol induced changes associated
with a longer lifespan, including increased insulin sen-
sitivity, increased AMP-activated protein kinase
(AMPK) and proliferator-activated receptor-γ coactiva-
tor 1α (PGC-1α) activity, increased mitochondrial
number and improved motor function, and increased
survival. Barger et al.115 reported that a low dose of
resveratrol (0.005% in the diet) mimicked the effects of
calorie restriction on the gene expression profiles asso-
ciated with insulin-mediated glucose uptake in muscle,
cardiac and skeletal muscle aging, and prevention of
age-related cardiac dysfunction. Lagouge et al.116 fed
8-week-old mice with a high-fat diet containing 0.4%
resveratrol and found that resveratrol increased energy
expenditure and aerobic capacity by increasing SIRT1-
mediated PGC-1α activity and mitochondrial function
in muscle and brown adipose tissue. Under these con-
ditions, resveratrol reduced the body weight gain and
improved insulin sensitivity. Using AMPK (α1 and
α2)-deficient mice, Um et al.117 showed that resveratrol
(0.4% in a high-fat diet) improved the metabolic rate,
insulin sensitivity, and body weight gain via AMPK,
which also regulates insulin sensitivity and mitochon-
drial biogenesis. Resveratrol was suggested to increase
mitochondrial function via an SIRT1-dependent or
-independent pathway.117,118 Choi et al.119 reported
that a lower dose of resveratrol (0.005% of diets) sup-
pressed body weight gains and improved high-fat
diet-induced obesity in C57BL/6J mice.
Many of these supplements are commercially avail-
able; however, only a few results of intervention trials
with resveratrol have been reported. Brasnyo et al.120
showed that supplementation with 2 3 5 mg resvera-
trol/day for 4 weeks significantly decreased the insu-
lin resistance and urinary hydroxyl radial marker
ortho-tyrosine excretion in type2 diabetic patients.
Resveratrol improved the insulin resistance and oxida-
tive stress in diabetic patients. Timmer et al.121 treated
11 healthy, obese, middle-aged men with 150 mg/day
not reduce the body weight but reduced the intrahepa-
tic lipid content; systolic blood pressure; the homeosta-
sis model assessment (HOMA) index (an indicator of
improved insulin sensitivity); the plasma glucose, tri-
glyceride, and ALT levels; and levels of the
 6. OTHER POLYPHENOLS
inflammatory markers TNF-α and IL-6. Resveratrol
supplementation reduced the sleeping and resting
metabolic rate. It also increased the AMPK activity and
SIRT1 and PGC-1α protein levels and improved mito-
chondrial function in muscle. It was concluded that
resveratrol supplementation had beneficial effects on
the metabolic profiles of healthy, obese men, which
appeared to reflect the effects observed during calorie
restriction and in animal models, without affecting the
safety parameters. In contrast, Poulsen et al.122 treated
healthy, obese men (mean age, approximately 35
years) with 1500 mg/day resveratrol for 4 weeks and
found that resveratrol supplementation did not affect
the glucose turnover, insulin sensitivity, body compo-
sition, blood pressure, resting energy expenditure,
lipid oxidation rates, or inflammatory and metabolic
biomarkers. In non-obese, postmenopausal women
with normal glucose tolerance, supplementation with
75 mg/day resveratrol for 12 weeks did not affect the
body composition, insulin sensitivity, resting metabolic
rate, plasma lipid, inflammatory markers, or the puta-
tive molecular targets AMPK and SIRT1.123
Thus, resveratrol may improve insulin resistance
and obesity by increasing mitochondrial function
through the activation of AMPK, SIRT1, or PGC-1α in
type2 diabetic patients or obese people, although the
beneficial effects have not been completely demon-
strated. In particular, we should pay attention to the
safety of excessive resveratrol supplementation
because the normal dietary intake of resveratrol is
much lower than that of other common polyphenols
such as catechins and quercetin.
6. OTHER POLYPHENOLS
Curcumin, which is typically found in the spice
turmeric, has been shown to possess physiological
functions such as antioxidant, anti-inflammatory, and
anti-angiogenesis properties (Figure 14.4). However,
the attenuation action and mechanism of its effects on
obesity and metabolic syndrome have not been
completely demonstrated. Ejaz et al.124 showed that
0.05% curcumin supplementation reduced body
weight and fat gain, angiogenesis in adipose tissue,
and serum cholesterol levels in mice fed a high-fat diet
for 12 weeks. Curcumin increased the AMPK activity,
which is a regulator of energy metabolism, and the
expression of carnitine palmitoryltransferase-1 (κ-1),
which induces fatty acid metabolism. Curcumin
reduced the expression of the adipogenesis- and lipo-
genesis-regulated transcriptional factors PPARγ and
CCAAT/enhancer binding protein α (CEBPα) and the
angiogenesis-related vascular endothelial growth fac-
tor (VEGF) and its receptor.
2. POLYPHENOLS IN THERAPY OF OBESITY AND DIABETES
171
OH
H
OH
O
H
O
H
H
HO
HO
FIGURE 14.4 Structure of curcumin.
Weisberg et al.125 found that 3% curcumin diets
reduced body weight and ameliorated diabetes in high
fat-induced obese and reptin-deficient ob/ob C57BL/6J
mice. Curcumin reduced macrophage infiltration and
adiponectin production in adipose tissue, and inflam-
matory gene expression and the transcriptional factor
NF-κB activity in the livers. Similarly, Shao et al.126
showed that a high-fat diet containing 0.4% curcumin
attenuated body weight and fat gain, and the insulin
resistance induced by a high-fat diet in C57BL/6J
mice. They suggested that curcumin attenuated insulin
resistance and obesity by attenuating the expression of
the lipogenic genes carbohydrate responsive element-
binding protein (ChREBP) and SREBP1-c in the liver
and the inflammatory NF-κB and c-Jun N-terminal
kinase (JNK) pathways in adipocytes but not by stimu-
lating Wnt signaling. There is a report on human inter-
vention trials to test the effects of curcumin on obesity
and metabolic syndrome.127 A recent RCT reported by
Mohammadi et al.128 showed that curcuminoid supple-
mentation (1 g/day for 30 days) reduced the serum tri-
glyceride concentrations but did not affect other lipid
parameters, body mass index, or body fat in obese
patients.
The anthocyanin cyanidine 3-glucoside has been
reported to attenuate obesity or obesity associated
with insulin resistance in vivo.129,130
7. CONCLUSION
The attenuating effects of polyphenols on obesity
are relatively low and have not been completely dem-
onstrated in most cases; however, the results of RCTs
suggest that tea catechins attenuate obesity, mainly by
increasing energy expenditure and fat oxidation.
Quercetin possibly improves obesity and metabolic
syndrome, mainly by reducing excessive oxidative
172 14. DIETARY QUERCETIN AND OTHER POLYPHENOLS: ATTENUATION OF OBESITY
stress. Resveratrol may improve insulin resistance and
obesity by increasing mitochondrial function via the
activation of AMPK, SIRT1, or PGC-1α, although the
dietary intake of resveratrol is limited. The habitual
intake of these polyphenols from dietary sources prob-
ably contributes to better health, and they may prevent
or alleviate obesity and metabolic syndrome.
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