Accepted Manuscript

Review

Role of quercetin as an alternative for obesity treatment: you are what you eat!

Seyed Fazel Nabavi, Gian Luigi Russo, Maria Daglia, Seyed Mohammad
Nabavi

PII: S0308-8146(15)00171-5
DOI: http://dx.doi.org/10.1016/j.foodchem.2015.02.006
Reference: FOCH 17099

To appear in: Food Chemistry

Received Date: 13 October 2014

Revised Date: 5 January 2015
Accepted Date: 2 February 2015

Please cite this article as: Nabavi, S.F., Russo, G.L., Daglia, M., Nabavi, S.M., Role of quercetin as an alternative
for obesity treatment: you are what you eat!, Food Chemistry (2015), doi: http://dx.doi.org/10.1016/j.foodchem.
2015.02.006

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Role of quercetin as an alternative for obesity treatment: you are what you eat!

Seyed Fazel Nabavi a, Gian Luigi Russo b, Maria Daglia c*1, Seyed Mohammad Nabavi a*1

a
Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran,

Iran
b
Institute of Food Sciences, National Research Council, 83100 Avellino, Italy
c
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section,

University of Pavia, Italy

Corresponding authors:

Maria Daglia, Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical

Technology Section, University of Pavia, Italy, Tel.: +39 0382 987388, fax: + 39 0382422975, e-

mail: maria.daglia@unipv.it

Seyed Mohammad Nabavi, Applied Biotechnology Research Center, Baqiyatallah University of

Medical Sciences, Tehran, Iran, Tel/fax: +98 21 88617712, P.O. Box 19395-5487, e-mail:

Nabavi208@gmail.com
1
These two authors share the senior authorship.

Running title: Quercetin for obesity

Abstract

Obesity is one of the most serious global health problems, which increases the risk of other

different chronic diseases. The crucial role of oxidative stress in the initiation and progression of

obesity leads to the hypothesis that antioxidants can be used as therapeutic agents for obesity

treatment. Among antioxidants, much attention has been paid to polyphenols due to their

negligible adverse effects. Among them, quercetin is one of the most common dietary

antioxidants widely distributed in different plant materials, such as fruits, vegetables and cereals.

Quercetin shows a wide range of biological and health-promoting effects, such as anticancer,

hepatoprotective, antidiabetic, anti-inflammatory and antibacterial activities. Furthermore,

quercetin has anti-obesity activity through mitogen-activated protein kinase and adenine

monophosphate-activated protein kinase signaling pathways. In this study, we reviewed the

available scientific reports concerning the beneficial role of quercetin against obesity with

emphasis on its mechanisms of action.

Keywords: Antioxidants, Obesity, Quercetin, Mitogen-activated protein kinase, Adenine

monophosphate-activated protein kinase

1. Introduction

Obesity is one of the most important leading preventable causes of death throughout the world

(Popkin, 2011), which increases the morbidity rates of a number of metabolic disorders, such as

type 2 diabetes, hypertension, metabolic syndrome and heart diseases, as well as some other

chronic diseases, such as osteoarthritis, cancer, stroke, inflammation and sleep apnea

(Berenbaum, Eymard, & Houard, 2013; Dixon, 2010). According to the epidemiological data, in

2009-2010, more than 35.5% of men and 35.8% of women suffer from obesity in the United

States (Flegal, Carroll, Kit, & Ogden, 2012).

Obesity is defined as a medical condition characterized by the accumulation of abnormal and/or

excessive body fat, which may cause harmful effects on human health (Kopelman, 2000). It is

commonly classified according to the body mass index (BMI) (Kopelman, 2000). The waist–hip

ratio, which evaluates the degree of visceral (major risk factor for metabolic disorders) versus

subcutaneous (benign to metabolic disorders) adiposity, is one of most common and standard

protocols for measuring the health of obese subjects (Chan, Watts, Barrett, & Burke, 2003).

Genetic, social and environmental factors may contribute to the pathogenesis of obesity, such as

polymorphism of some genes, diet, body metabolism, physical activity, intestinal microbiota, as

well as some social status (Karelis, St-Pierre, Conus, Rabasa-Lhoret, & Poehlman, 2004; Zhang,

DiBaise, Zuccolo, Kudrna, Braidotti, Yu, et al., 2009). There are also numerous reports on the

role of oxidative stress in pathophysiology of obesity (Furukawa, Fujita, Shimabukuro, Iwaki,

Yamada, Nakajima, et al., 2004; Keaney, Larson, Vasan, Wilson, Lipinska, Corey, et al., 2003).

Therefore, antioxidants are considered as protective agents to decrease the oxidative-

inflammatory status associated with body weight gain and to be used for the treatment of the

different diseases induced by obesity.

Indeed, therapeutic strategies for obesity are based on the restriction of fatty and sugary food

intake and physical activity increase (Swinburn & Egger, 2002). In recent years, much attention

has been paid to vegetable based foods as novel protective and even therapeutic strategies for

management of several diseases due to their phytochemical constituents (Curti, Capelli, Boschi,

Nabavi, Bongiorno, Habtemariam, et al., 2014; Nabavi, Daglia, Moghaddam, Habtemariam, &

Nabavi, 2014; Nabavi, Nabavi, Habtemariam, Moghaddam, Sureda, Jafari, et al., 2013; Nabavi,

Nabavi, Setzer, Nabavi, Nabavi, & Ebrahimzadeh, 2013). Phytochemicals, such as flavonoids,

have a wide range of beneficial effects with low adverse effects (Nabavi, Habtemariam, Daglia,

Shafighi, Barber, & Nabavi, 2015). Flavonoids may help to prevent and/or reduce oxidative-

inflammatory status associated with obesity through the regulation of different molecular

pathways, such as mitogen-activated protein kinase (MAPK), adenosine monophosphate-

activated protein kinase (AMPK), peroxisome proliferator-activated receptor-α and sterol

regulatory element-binding protein-1c pathways (Ahn, Lee, Kim, Park, & Ha, 2008; Ørgaard &

Jensen, 2008; Yu, Rajapakse, Montani, Yang, & Ming, 2014).

Among flavonoids, quercetin is the most abundant in human dietary sources (Ahn, et al. 2008).

A plethora of evidence reports its promising effect as potent antioxidant and anti-inflammatory

agent against different molecular mechanisms involved in obesity pathogenesis (Ahn, et al. 2008;

Dong, Zhang, Zhang, Bian, Xu, Bao, et al., 2014). The aim of this review is to summarize the

available scientific reports concerning the beneficial role of quercetin against obesity, with

emphasis on its molecular mechanisms of action. Moreover, we provide an overview on

quercetin chemical structure and distribution in the most common plant foods, bioavailability

and safety.
2. Flavonoids

Flavonoids are a group of polyphenolic compounds, which are present in different parts of

plants, such as fruits, leaves, flowers, stem, root and seeds. Flavonoids are characterized by a 15-

carbon flavan structure in their skeleton which contains both aromatic (A and B Rings) and

heterocyclic (C Ring) rings (Fig. 1) (Nabavi, Nabavi, Eslami, & Moghaddam, 2012). The A ring

is generated through the condensation of 3 molecules of malonyl-coenzyme A (malonic acid

derivative, which is produced in the glucose metabolism) (Terao, 2009). C and B rings are

generated through shikimic acid pathway in the metabolism of glucose and produce cinnamic

acid as well as coumaric acid (Korkina, 2007). C-15 chalcone is produced through the

condensation of cinnamic acid and coumaric acid with C-6 product from malonate. As a result

ring closure and thereafter hydration occur to produce 3-hydroxy flavonoids, 3, 4-diol

flavonoids, and other polyphenolic tannins (Van Acker, Hageman, Haenen, van der Vijgh, Bast,

& Menge, 2000). Number and pattern of hydroxyl and methyl groups in the flavonoid skeleton

are one of the most important characteristics of their classification (Choi, et al., 2002). For

example, the presence of a hydroxyl group in position C-3 is the main characteristic of the 3-

hydroxyflavonoids, and also the lack of hydroxyl group is the main characteristic of the 3-

desoxyflavonoids. However, in spite of other flavonoids, in the isoflavonoids structure B ring is

bonded to C-3 of C ring (Reynaud, Guilet, Terreux, Lussignol, & Walchshofer, 2005).

The difference in the heterocyclic ring is responsible for the classification of these compounds

into some subclasses, such as flavones, flavonols, flavanols and flavanones (Nabavi, Nabavi,

Mirzaei, & Moghaddam, 2012). It is well known that the substitution pattern of the A and B

rings is responsible for the radical-scavenging and antioxidant activities of flavonoids (Nabavi, et

al. 2012a). The antioxidant activity of flavonoids depends on the presence and number of the
free hydroxyl groups in their skeleton. For example, in the flavonols chemical class, number and

pattern of hydroxyl groups in the B ring are responsible for their free radical scavenging

potential (Nabavi, et al. 2012a).

3. Quercetin chemistry

Quercetin (Fig. 2) is known as potent natural antioxidant and scavenger of reactive oxygen and

nitrogen species (ROS and RNS) under in vitro and in vivo conditions (Nabavi, et al. 2012a). It

shows potent scavenger activity against superoxide and hydroxyl radicals, nitric oxide and also

peroxynitrite (Choi, Chung, Kang, Jung, Kim, No, et al., 2002; López-López, Moreno,

Cogolludo, Galisteo, Ibarra, Duarte, et al., 2004; Wilms, Kleinjans, Moonen, & Briedé, 2008).

The presence of the catechol moiety in B ring and free hydroxyl groups in the quercetin structure

is responsible for its antioxidant and free radical scavenger potential (Nabavi, et al. 2012a).

Quercetin directly quenches free radicals and lipid peroxides and indirectly enhances the

generation of non-enzymatic antioxidants (such as reduced glutathione) and increases the

activities of antioxidant enzymes under in vivo conditions (Nabavi, et al., 2012a).

Quercetin is an important aglycone flavonoid which is characterised by the presence of a phenyl

benzo(c)pyrone-derived structure (Nabavi, et al. 2012a). Commonly, flavonoids are present in

nature as glycosides (Rice-Evans, 2001). In vegetable foods, quercetin is commonly found in the

glycoside form, esterified with rhamnose and rutinose, which influence its bioavailability

(Manach, Scalbert, Morand, Rémésy, & Jiménez, 2004). For example, quercetrin and rutin,

which are the glycosides obtained from the aglycone quercetin, are bound to rhamnose and

rutinose (Formica & Regelson, 1995).

Although 24% of aglycone forms of quercetin is absorbed through gastrointestinal tract and

quercetin glycosides are absorbed only in the small intestine, 52% of quercetin glycosides was

absorbed due to their hydrophilic character. (Erlund, Kosonen, Alfthan, Mäenpää, Perttunen,

Kenraali, et al., 2000; P. Hollman, De Vries, van Leeuwen, Mengelers, & Katan, 1995). It has

also been reported that conjugation of quercetin with a glycoside moieties significantly increases

its absorption (Manach, Morand, Demigné, Texier, Régérat, & Rémésy, 1997). It can be

suggested that the increase in the absorption of quercetin glycosides is through the

deglycosylation and/or carrier-mediated transport (Lesser, Cermak, & Wolffram, 2004). During

deglycosylation, quercetin glycosides change to the aglycone form through the activity of β-

glucosidases and thereafter the aglycone form is absorbed through the gastrointestinal tract

(Cermak, Landgraf, & Wolffram, 2003). Intestinal lactase phlorizin hydrolase plays an important

role towards quercetin glycosides in the perfused small intestine of experimental animals (Day,

Gee, DuPont, Johnson, & Williamson, 2003). In the carrier-mediated transport, quercetin

glycosides are hydrolysed by β-glucosidases and this process is facilitated via sodium-dependent

glucose transporter-1 as well as multi-drug resistance protein 2 (Chen, Zhou, & Ji, 2010).

Thereafter, quercetin is metabolized into the sulphated, glucuronidated and methylated forms in

different organs, such as liver, kidney, colon and small intestine (Crespy, Morand, Manach,

Besson, Demigne, & Remesy, 1999). It has also been reported that in the colon and small

intestine, the aglycone form of quercetin has been broken and produce small phenolics (Hollman,

De Vries, van Leeuwen, Mengelers, & Katan, 1995). In addition, half-live values, reported for

quercetin and its metabolites, are between 11-28 h (Nieman, Henson, Gross, Jenkins, Davis,

Murphy, et al., 2007).

4. Quercetin as a food supplement

Quercetin is the main flavonol in human nutrition (Hollman, De Vries, van Leeuwen, Mengelers,

& Katan, 1995). It is widely distributed in different types of fruits and vegetables (Alinezhad,

Azimi, Zare, Ebrahimzadeh, Eslami, Nabavi, et al., 2013). Onions, apples and wine are

considered highly rich sources of quercetin. It has also been reported that quercetin is found in

different plant species, such as tea, lovage, pepper, coriander, fennel, radish, dill and berries

(Aras, Khokhar, Qureshi, Silva, Sobczak-Kupiec, Pineda, et al., 2014). As already mentioned, in

plants quercetin is commonly found as glycoside forms (Rice-Evans, 2001). Among them, rutin

is the most common and important glycoside form of quercetin which is widely found in

different plant species (Manach, Morand, Demigné, Texier, Régérat, & Rémésy, 1997). Other

glycoside forms of quercetin commonly found in the human diet, are 3-rutinoside (occurring in

black tea), 4'-O-glucoside (onions), quercetin galactosides (apples) and quercetin arabinosides

(berries) (Hollman, van Trijp, Buysman, Mengelers, de Vries, & Katan, 1997).

Despite the wide range of pharmacological activities of quercetin, there are some limitations for

clinical trials on quercetin. The median lethal dose for oral administration of quercetin is 160

mg/kg in mice (Ossola, Kääriäinen, & Männistö, 2009). However, long-term quercetin

consumption has no significant side effects on haematological and urinary factors (Dunnick &

Halley, 1992). In addition, quercetin is reported to be a safe compound and there is no scientific

report on its carcinogenicity as well as genotoxicity after oral administration of quercetin even at

high doses (up to 2000 mg/kg) (Harwood, Danielewska-Nikiel, Borzelleca, Flamm, Williams, &

Lines, 2007). Despite these considerations, quercetin has synergistic effects with methylmercury

for its neurotoxicity (Martins, Braga, da Silva, Dalmarco, de Bem, dos Santos, et al., 2009). It

has also been reported that in spite of the anti-inflammatory effect of quercetin, it resulted in also
showing pro-inflammatory effects under in vivo conditions (Nicolau, Dovichi, & Cuttle, 2003).

People with pancreatitis and asthma are the most vulnerable subjects to the pro-inflammatory

activities of quercetin due to the effects of quercetin plasma extravasation induced by substance

P and bradykinin in the trachea and pancreas, through inhibition of the neutral endopeptidase

(Nicolau, Dovichi, & Cuttle, 2003).

5. Quercetin and obesity

In recent years, circumstantial evidence suggests that quercetin and other polyphenols are able to

ameliorate obesity through different molecular pathways (Figure 3). One of the first observations

in this direction was published in 2005 and referred to the glucose transporter, GLUT4, which

mediates insulin stimulated glucose uptake in adipocytes and muscles and whose up-regulation is

associated with obesity. In rat adipocytes, quercetin, myricetin and catechin-gallate were able to

inhibit the uptake of methylglucose over the concentration range of 10–100 µM, with quercetin

possessing the lower Ki value (16 µM) (Strobel, Allard, Perez-Acle, Calderon, Aldunate, &

Leighton, 2005). By means of computer simulation, the same authors suggested that these

flavonoids might directly bind the glucose transporter GLUT4 (Strobel, Allard, Perez-Acle,

Calderon, Aldunate, & Leighton, 2005). More recently, several good reviews have been

published on the role of dietary phytochemicals, including quercetin, in obesity (Kobori, 2014;

Siriwardhana, Kalupahana, Cekanova, LeMieux, Greer, & Moustaid-Moussa, 2013). However, it

is necessary to make a clear distinction between the anti-obesity effects of quercetin when it is

administered as pure aglycone, from its putative functions and when it is present in polyphenolic

extracts, as reported in many works cited in the above mentioned reviews. For example,

lingonberries were shown to prevent obesity in C57BL/6J mice due to the presence of quercetin
glycosides (Heyman, Axling, Blanco, Sterner, Holm, & Berger, 2014); similarly, the positive

effects of bioactive compounds from Sambucus nigra L. flowers in ameliorating glucose and

lipid metabolism was associated to the presence of quercetin and its derivatives (quercetin-3-O-

rutinoside, quercetin-3-O-glucoside, quercetin-3-O-5″-acetylglycoside) (Bhattacharya,

Christensen, Olsen, Christensen, Grevsen, Faergeman, et al., 2013). The interpretation of these

studies is complicated by the possibility that the positive outcomes are the result of the

synergistic interaction between the different bioactive employed compounds (Rayalam, Della-

Fera, & Baile, 2008). Another example is represented by resveratrol in combination with

genistein and quercetin, which synergistically decreased adipogenesis in murine and human

adipocytes (Rayalam, Della-Fera, & Baile, 2011a). However, focusing on the “direct” effects of

quercetin administration may help to better hypothesize its potential mechanism of action.

The suppressive effects of quercetin against obesity have been widely studied in animal models

and cell lines, but we must emphasize that there is a limited number of interventional studies on

human subjects. In his recent review, Kobori reported a list of studies on the effect of quercetin

on obesity in mouse and rat model systems (Masuko Kobori, 2014). Briefly, in C57BL/6J mice,

studies from different research groups demonstrated that a high-fat diet containing quercetin

(0.05-0.25%) decreased body weight, liver fat accumulation, blood glucose, plasma and liver

triacylglycerol, improved TBARS and glutathione levels in the liver. These events correlated

with the suppressed expression of important genes including PPARγ, a transcription factor which

regulates high-fat diet-induced fat accumulation in the liver (Jung, Cho, Ahn, Jeon, & Ha, 2013).

These results were confirmed in an animal model of obesity where, in Zucher obese rats,

quercetin increased the plasma adiponectin concentration, reduced plasma nitrate and nitrite

levels, and enhanced visceral adipose tissue endothelial nitric oxide synthase expression (Rivera,
Moron, Sanchez, Zarzuelo, & Galisteo, 2008). In Wistar rats, quercetin ameliorated the

expression of markers of oxidative stress and inflammation, such as nuclear factor-related factor-

2 (Nrf2), heme oxygenase-1 (HO-1), and nuclear factor kappa B (NF-κB), suggesting that

quercetin anti-inflammatory effects on adipose tissue can be associated with the reduction of

body weight (Panchal, Poudyal, & Brown, 2012). In contrast, in a more recent investigation, rats,

which were fed a high-fat and high-sucrose diet and supplemented with 30 mg/kg body

weight/day of quercetin, did not show any significant reduction in body weight or adipose tissue

sizes and no changes were observed in the activity of lipogenic enzymes, lipoprotein lipase and

muscle triacylglycerol content. However, quercetin significantly reduced basal glucose and

insulin, suggesting a more effective role as an anti-diabetic than as an anti-obesity factor (Arias,

Macarulla, Aguirre, Martinez-Castano, & Portillo, 2014). A relatively recent field of interest

regards the role of quercetin in the offspring of rat obese dams. A recent work demonstrated that

obese dams, which were administered 50-200 mg/kg body weight of quercetin intragastrically

during gestation and lactation, generated a F1 with reduced birth weight and postnatal body

weight gain improving glucose metabolism and insulin sensitivity and alleviating endoplasmic

reticulum stress and related inflammation (Wu, Zhao, Xu, Lyv, Feng, Fang, et al., 2014). Similar

observations were reported in C57BL/6 mice, where the offspring of dams fed high saturated fat

diet showed hyperglycemia, insulin resistance, obesity and hypertension throughout postnatal

life. These effects were alleviated when pregnant dams were supplemented with quercetin during

pregnancy (Liang, Oest, & Prater, 2009).

The use of cellular models is of great help in understanding how quercetin interferes with lipid

metabolism to prevent obesity, at molecular level. In many cases, the protective effects of this

compound have been linked to its anti-inflammatory and/or antioxidant properties. In HUVEC
cells, the negative effect of leptin addition on the expression of short chain leptin receptor

isoform (Ob-Ra), ERK1/2 phosphorylation and NF-κ B activation was reduced by the addition of

125 µM quercetin, suggesting that the suppression of inflammation by quercetin may be of

clinical relevance in the prevention of the diseases induced by leptin-resistant in obesity (Indra,

Karyono, Ratnawati, & Malik, 2013). A similar anti-inflammatory effect of quercetin has been

shown in macrophages, which infiltrate white adipose tissue, contributing to the chronic

inflammation observed in obese subjects. In this model system, quercetin lowered the basal

expression of inflammatory genes, such as those coding for TNF-α, IL-6, IL-8, IL-1β, interferon-

γ inducible protein-10, and cyclooxygenase-2, a marker of prostaglandin production (Overman,

Chuang, & McIntosh, 2011). In primary human adipocytes, the anti-inflammatory effect of

quercetin is even broader. This compound attenuates the following TNF-α-mediated events: 1)

phosphorylation of extracellular signal-related kinase and c-Jun-NH₂ terminal kinase, 2) NF-κB

transcriptional activity, 3) expression of PPARγ, 4) serine phosphorylation of insulin receptor

substrate-1 and protein tyrosine phosphatase-1B gene expression (Chuang, Martinez, Xie,

Kennedy, Bumrungpert, Overman, et al., 2010).

Quercetin being a pleiotropic and multi-functional flavonoid (Russo, Russo, & Spagnuolo, 2014;

Russo, Russo, Spagnuolo, Tedesco, Bilotto, Iannitti, et al., 2014; M. Russo, Spagnuolo, Tedesco,

Bilotto, & Russo, 2012), it is not surprising that its mechanisms of action may differ depending

on cellular models. Circumstantial evidence associates the anti-obesity capacity of quercetin to

its ability to interact with AMPK (adenosine monophosphate-activated protein kinase). This

kinase is considered a key checkpoint to ensure energy balance both in cells and organisms by

“sensing” the intracellular AMP/ATP ratio (it is activated when AMP is high and drops down

sharply with high ATP). Quercetin, together with other natural occurring compounds (e.g.,
resveratrol, EGCG, berberine), is considered an “indirect” activator of AMPK probably

inhibiting mitochondrial function, which would increase the cellular AMP/ATP ratio (Russo,

Russo, & Ungaro, 2013). Recently, it has been proposed that quercetin can alleviate adipose

tissue macrophage infiltration and inflammation in mice supplemented with high-fat diet. This

mechanism involves enhanced phosphorylation of AMPK catalytic subunit and expression of its

positive regulator SIRT1 (Dong, et al., 2014). This observation goes in the same direction of an

early work where firstly quercetin was reported to attenuate adipogenesis and decrease

expression of adipogenesis-related factors in 3T3-L1 preadipocytes by the up-regulation of the

levels of phosphorylated AMPK (Ahn, Lee, Kim, Park, & Ha, 2008). A more simplistic

interpretation of the beneficial role of quercetin in obesity resides in its antioxidant properties.

This may explain why not only quercetin but also epicatechin and at least other 14 polyphenols

exert an anti-inflammatory effect on 3T3-L1 preadipocytes exposed to H₂O₂ by reducing IL-6

secretion. Importantly, such antioxidant and anti-inflammatory effects were observed in co-

exposition (polyphenol and prooxidant during) or pretreatment (polyphenol, then prooxidant)

conditions (Hatia, Septembre-Malaterre, Le Sage, Badiou-Beneteau, Baret, Payet, et al., 2014).

In addition, the common antioxidant capacity of polyphenols is in agreement with the synergistic

effect of resveratrol when associated with genistein and quercetin in decreasing adipogenesis in

murine and human adipocytes (Rayalam, Della-Fera, & Baile, 2011b). Therefore, it is necessary

to evoke this or others “indirect” mechanisms in the absence of the identification of the “direct”

and specific targets of quercetin able to explain its capacity to attenuate obesity. Good candidates

appear to be the sugar transporters, such as GLUT4 cited above (Strobel, Allard, Perez-Acle,

Calderon, Aldunate, & Leighton, 2005), and GLUT2. In the latter case, the uptake of glucose and

fructose is inhibited by quercetin in non-competitive manner on the apical side of Caco-2E cells,
indicating that binding sites on GLUT2 for sugar and quercetin are different and suggesting that

the intraluminal concentration of quercetin or its glucosides can be physiologically relevant to

inhibit glucose in vivo transport in apical enterocytes (Kwon, Eck, Chen, Corpe, Lee, Kruhlak, et

al., 2007). Interesting hypotheses of potential quercetin substrates come from bioinformatics

studies. Through this approach, quercetin resulted in binding to adipose tissue cannabinoid-1

receptors (CB1R) with a binding energy comparable to the well known drug, rimonabant. CB1R

inverse agonists reduce body weight, but displayed neuropsychiatric side effects; therefore, there

is interest to develop new compounds which block peripheral CB1Rs maintaining weight loss

(Shrinivasan, Skariyachan, Aparna, & Kolte, 2012).

As already mentioned, a limited number of human studies have been performed to evaluate the

effect of quercetin on weight loss and weight maintenance, which were recently reviewed by

Hurt and Wilson (Hurt & Wilson, 2012). In one study, quercetin was combined with vitamin C

and niacin and was administered to a heterogeneous group of adults, not all overweight or obese.

The differences in BMI or body composition were observed only in the subgroup of overweight

and obese subjects (Knab, Shanely, Henson, Jin, Heinz, Austin, et al., 2011). Two other studies

evaluated the effects of quercetin on obesity and metabolic syndrome in overweight-obese

subjects with various apolipoprotein E (APOE) genotypes (Egert, Boesch-Saadatmandi,

Wolffram, Rimbach, & Muller, 2010; Pfeuffer, Auinger, Bley, Kraus-Stojanowic, Laue,

Winkler, et al., 2013). In one case, all subjects consuming 150 mg/day of quercetin experienced a

decrease in waist circumference, triacylglycerol concentration and increase of HDL

concentrations (Pfeuffer, et al., 2013). On the contrary, in a different study, carried out on 93

overweight-obese subjects with metabolic syndrome, serum C-reactive protein, body weight,

waist circumference, fat mass, and fat-free mass were not significantly different, compared with
placebo. In addition, quercetin decreased serum HDL cholesterol increasing the LDL/HDL

cholesterol ratio, suggesting a negative effect of this compound since it worsened the LDL/HDL

ratio without improving anthropomorphic measures (Egert, Boesch-Saadatmandi, Wolffram,

Rimbach, & Muller, 2010). Currently, to our knowledge, only one clinical trial is ongoing

(ClinicalTrials.gov). The purpose of this study is to investigate whether quercetin affects the way

by which glucose is absorbed by the body in obese subjects or diabetic obese (with type 2

diabetes) subjects.

The current knowledge on the protective effects of quercetin against obesity seems to correlate

with its capacity to suppress increased oxidative and related inflammation stress in adipocytes.

However, a lot of work is still necessary before asserting that habitual intake of quercetin can

attenuate or prevent obesity. More epidemiological studies on overweight subjects are required

and, from a nutritional and molecular point of view, it must be determined the role of quercetin

metabolites, since, as a consequence of the low bioavailability of the molecule, these compounds

are the only ones present at detectable concentrations in the bloodstream and tissues after oral

administration of quercetin (Russo, Russo, & Spagnuolo, 2014).

6. Conclusion and recommendations

We concluded that the beneficial role of quercetin on obesity is connected to its antioxidant

actions and regulation of mitogen-activated protein kinase and adenine monophosphate-activated

protein kinase signaling pathways and other signaling pathways. Indeed, quercetin restricts

obesity via reducing of obesity mediated oxidative stress and activated the mitogen-activated

protein kinase and adenine monophosphate-activated protein kinase signaling pathways as well

as other signaling pathways. However, there is a lack of clinical trials on the anti-obesity effect
of quercetin and therefore, to make a decision and conclusion on the beneficial role of quercetin

on obesity, as well as obesity related diseases, is not feasible. Despite this, it can be suggested

that quercetin can be used as an alternative for available therapeutic strategies of obesity.

Finally, we recommend that future works should be performed to find the most effective doses

for anti-obesity effect of quercetin and potential molecular mechanism underlying this effect, as

well as its direct role on lipid profiling and obesity related diseases.

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Figures caption.

Fig. 1. Basic molecular structure of flavonoids.

Fig. 2. Chemical structure of quercetin.

Fig. 3. Proposed anti-obesity mechanisms of quercetin. AMPK: AMP-activated protein kinase;

GLUTS: Glucose transporters; VAT iNOS: visceral adipose tissue inducible nitric oxide

synthase; NF-kB: nuclear factor kappa B; Nrf2: Nuclear factor erythroid-derived 2-like 2; ROS:

reactive oxygen species; ERK: extracellular signal-related kinase; JNK: c-Jun-NH₂ terminal

kinase; PPAR γ: Peroxisome proliferator-activated receptor gamma; CPT: carnitine

palmitoyltransferase 1; HO-1: heme oxygenase-1; PTP1B: protein tyrosine phosphatase-1B;

serine phosphorylation of IRS-1: serine phosphorylation of insulin receptor substrate-1.

Figure 1.
Figure 2.
Highlights

1) In human nutrition, quercetin represents the main flavonol.

2) Quercetin is able to ameliorate obesity.

3) Quercetin restricts obesity via reduction of obesity-mediated oxidative stress.