Beneficial Flavonoid in Foods and Anti-Obesity Effect: Food Reviews International

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Beneficial Flavonoid in Foods and Anti-obesity

Effect
Jingwen Liu, Jiaoxian Cao, Yiming Li & Fujiang Guo
To cite this article: Jingwen Liu, Jiaoxian Cao, Yiming Li & Fujiang Guo (2021):
Beneficial Flavonoid in Foods and Anti-obesity Effect, Food Reviews International, DOI:
10.1080/87559129.2021.1923730
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FOOD REVIEWS INTERNATIONAL
https://doi.org/10.1080/87559129.2021.1923730
REVIEW
Beneficial Flavonoid in Foods and Anti-obesity Effect

Jingwen Liu, Jiaoxian Cao, Yiming Li, and Fujiang Guo
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
ABSTRACT KEYWORDS
Obesity is a global health problem. In the past decades, the prevalence rate Flavonoids; obesity; appetite;
of obesity has risen sharply in epidemiology. Obesity has become an increas energy expenditure; gut
ingly severe epidemic burden linked with different kinds of diseases, con microbiota; lipids
metabolism
sisting of cardiovascular disease, diabetes, metabolic associated fatty liver
disease, and even in COVID-19. Beneficial flavonoids in foods, as functional
ingredients, combat obesity and maintain energy balance through multiple
mechanisms. This review provides a brief overview of biological targets,
possible mechanisms and the current therapeutic interventions including
suppressing appetite, increasing energy consumption, regulating gut micro
biota, inhibiting adipogenesis, anti-inflammation. In vitro and in vivo experi
ments as well as available clinical evidence related to the anti-obesity effects
of pure flavonoid and flavonoid-rich extracts are also summarized and
depicted. Furthermore, the metabolism and bioavailability of flavonoids are
also concluded and discussed. Beneficial flavonoids have become promising
candidates for treating and avoiding obesity, but poor bioavailability and
short elimination half-life affects the absorption and efficacy. This paper
reviews the different types of flavonoids and their potential effect of pre
venting obesity, which provide the basis for further research.
Introduction
Obesity has become a growing epidemic burden associated with various noncommunicable diseases,
including cardiovascular disease, diabetes, metabolic associated fatty liver disease, metabolic syn
drome, as well as other comorbid conditions and cancers.[1,12] Obesity results from an imbalance
between energy intake and energy expenditure. Therefore, we can focus on reducing energy intake or
increasing energy expenditure to achieve the goal of losing weight.[3] Diet, physical activity, and
behavioral modifications remain the cornerstones of weight management.[4] Factors that influence and
interact with each other in a complex manner are eating and drinking patterns as well as behaviors.
Recently, scientists and nutritionists have taken obesity, a rarely cured disease, more seriously.
Moreover, they have attempted to identify potential strategies and molecular mechanisms that can
contribute to significant weight loss. These treatment strategies for weight maintenance include reducing
food intake, increasing energy expenditure, regulating gut microbiota, and modulating fat metabolism.[5]
Beneficial functional ingredients from food and nutrition play an increasingly important role in
weight control. Flavonoids, which exist in many dietary foods and nutrition, are increasing in
popularity because of multiple functions in promoting health and preventing disease. In addition to
their antioxidant properties, flavonoids have many biological effects, consisting of anti-inflammatory,
antimicrobial, vasodilatory, as well as insulin sensitivity effects.[6–8]
Flavonoids are secondary metabolites of plants and are commonly found in flowers, fruits, tea,
honey, and wine. Structurally, flavonoids can be chemically abbreviated as C6 (A-ring)-C3 (C-ring)-
C6 (B-ring) flavone skeleton, and has six types of flavonols, flavones, flavanones, isoflavones, flavan-
CONTACT Fujiang Guo gfj@shutcm.edu.cn School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200
Cailun Road, Shanghai 201203, China
© 2021 Taylor & Francis
2 J. LIU ET AL.
3-ols, and anthocyanidins.[9] Various natural flavonoids have been investigated for their ability to
suppress appetite, increase energy expenditure, regulate gut microbiota, and inhibit adipogenesis.
In this paper, the anti-obesity effects of natural flavonoids in functional food are briefly reviewed.
The natural flavonoids and flavonoids extraction with potential anti-obesity effects are summarized
and depicted in Tables 1–2 and Fig. 1, and the related chemical structures are depicted in Fig. 2.
Beneficial flavonoids have become promising candidates for treating and preventing obesity, but poor
bioavailability and short elimination half-life affects the absorption and efficacy. The metabolism and
bioavailability of flavonoids are also discussed and concluded in Fig. 3. The purpose of this review is to
provide the basis for functional flavonoids to treat obesity.
Epidemiology of obesity
According to research data from the World Health Organization in 2016, more than 1.9 billion adults
are overweight. Based on the latest data from CDC, the prevalence of obesity increased from 30.5% to
42.4%, and the prevalence of severe obesity rose from 4.7% to 9.2% from 1999–2000 through
2017–2018 in the United States.[99] 78% of American adults are projected to be overweight or obese
based on recent, nationally-representative data in 2030.[100]
In the past few decades, the prevalence of obesity in China has hardly increased. From 1991 through
2011, the age-adjusted prevalence rate of obesity among Chinese adults increased from 20.5% to
42.3%.[101] According to a series of nationwide surveys conducted by the China Physical Fitness
Surveillance Center, the estimated growth rate of overweight (23.0 ≤ BMI < 27.5 kg/m2) in Chinese
adults increased by 0.27% per year.[102] Obesity has been dramatically rising in children and adoles
cents in the past three decades.[103] A recent study demonstrated that the prevalence rate of bioelec
trical impedance among overfat Chinese adolescents is 36% for girls and 24% for boys.[104] A 20-year-
study in JAMA Network found that the middle-aged (BMI ≥ 23 kg/m2) who gain per 5-kg weight
increase 10% all-cause mortality and more than 20% cardiovascular mortality in China.[105] China
Kadoorie Biobank Collaborative Group recently published an evaluation of the association of BMI
with chronic diseases morbidity and all-cause mortality in Chinese adults. Their paper has concluded
that obesity was a risk factor for primary chronic diseases among Chinese adults.[106]
With the outbreak and spread of the coronavirus disease 2019 (COVID-19), it brings a heavy
economic and social burden to the whole world. According to the report of WHO, there were
4,589,526 confirmed cases of COVID-19, including 310,391 deaths on May 19, 2020.[107] The latest
study has demonstrated that the demand for invasive mechanical ventilation has gradually increased
in obese severity SARS-CoV-2 patients in ICU.[108] The growing evidence has showed that obesity is
likely to become one of the factors with high clinical risk for severe acute respiratory syndrome
coronavirus-2 (SARS-CoV-2).[109–112]
It is widely known that obesity limits movement of the diaphragm and the chest wall, increase airway
closure, and reduce lung volumes.[113,114] In obese individuals, excess fat causes chronic low-grade
inflammation and disrupt the homeostasis of internal environment, which weaken immune response
and delay viral clearance.[115,116] On the other hand, complications associated with obesity, such as
hypertension, diabetes, cardiovascular disease could aggravate the mortality of COVID-19 patients.[117]
Mechanisms of targeting anti-obesity

Suppressing appetite
Obesity in individuals has been traditionally considered as a response to excessive food intake;
therefore, appetite control has become a top priority.[118,119] Leptin receptors as well as insulin
receptors are expressed by brain neurons in energy intake.[120,121] Administration of leptin or insulin
directly into the brain reduces food intake, and lack of these two hormones causes obesity.[122,123] The
interaction between leptin with leptin receptor (OB-Rb) in pro-opiomelanocortin (POMC) and
Table 1. Summary of natural flavonoids with potential anti-obesity effects.
Models
Groups Representative components Plant resources (in vivo/in vitro) Outcomes/mechanisms Refs
[10–
Flavones luteolin fruits (kiwi fruit, grapes), food (celery, parsley, peppermint, thyme, and C57BL/6 mice; ↑ lipid/glucose metabolism
13]
oregano, broccoli, spinach, kale, corn), orange juice, honey, tea HepG2 cells (↑ FFA oxidation; ↓ FFA and TG
synthesis);
↑ thermogenesis;
↓ atherogenic lipid profile (↓ HNF4α)
↓ inflammatory marker (EMR1 and
CCL7)
Pathways: AMPK/PGC1α; TLR
[14,15]
tangeretin Citrus fruit rinds, mandarin orange 3T3-L1 cells; ↓ iNOS; ROS
RAW264.7 ↓ inflammatory marker (IL-6, IL-1β,
cells; TNF-α, COX-2);
C2C12 Pathways: AMPK; ERK
myotubes;
HGMCs
[16–
baicalin Scutellaria baicalensis C57BL/6 J; ↓ bodyweight;
18]
C2C12 cells ↓ serum/hepatic lipids;
↓ blood glucose;
Pathways: AKT/AS160/GLUT4;
CaMKKβ/AMPK/ACC
[19–
apigenin tea, wine, juice, shiso, tansy leaf, peppermint, Roman chamomile flowers C57BL/6 J mice; ↑ NAD+ levels; glucose and lipid
22]
ob/ob mice; homeostasis;
HepG2 cells; ↓ food intake; inflammatory
SHSY5Y cells; infiltration; oxidative stress
Pathways: NF-κB/P65/PPAR-γ;
Nrf2/PPAR-γ
[23–
Nobiletin Citrus fruits C57BL/6 J mice; ↓ serum lipids (TG, TC);
26]
LDLR-/- mice; ↑ FFA oxidation (PPAR-α, CPT1α,
HepG2 cells; PGC1α);
3T3-L1 cells; ↓ FFA and TG synthesis (SREBP1c,
HIB1B cells apoB);
(Continued)
3
4
Table 1. (Continued).
Models
[27]
Flavonols 3-methylethergalangin Alpinia officinarum rats ↓ serum lipids (TG, TC)
(Zingiberaceae)
[28–
quercetin fruits (apples, berries, grapes), food (onions, sweet potato, tomatoes, C57BL/6 J mice; ↑ energy expenditures;
J. LIU ET AL.
31]
broccoli, ginkgo biloba, buckwheat), leafy Greens, red wine and tea BALB/c mice; ↑ glucose uptake; ↑ adipocyte
db/db mice; browning
C2C12 cells; ↓ intracellular ROS levels (SOD, GSH
3T3-L1 cells and CAT);
↓ lipogenesis;
↓ inflammatory marker (MCP-1, TNF-α
and IL-6);
Pathways: MAPK/JNK/ERK; AMPK/SIRT1;
TLR-4/NF-κB pathway in intestinal cell
rutin fruits (oranges, grapes, lemons, peaches and berries), buckwheat C57BL/6 J mice; ↑ energy expenditures (↑ BAT activity); [32,33]
STZ-rats; ↑ glucose homeostasis;
db/db mice; Pathways: SIRT1/PGC1α; MAPK/PI3K
C3H10T1/2
cells
[34–
kaempferol tea, vegetables (tomato, broccoli, spinach) and fruits (apples, grapes and C57BL/6 J mice; ↑ FFA oxidation; GLUT4 translocation
36]
berries) INS-1E cells; ↓ caspase 3 in β cells;
HepG2 cells; Pathways: PI3K/PCK; AMPK
[37,38]
tiliroside Potentilla chinesis SD rats; ↑ lipid metabolism; ↑ energy
KK- Ay mice metabolism
↓ body weight; ↓ blood glucose; ↓
serum lipids (TG, TC)
Pathways: AMPK/PPAR-α
[39]
Isoflavonoids daidzein soybeans, tofu and textured vegetable protein SD rats; ↓ blood glucose;
[40–
genistein lupin, fava beans, soybeans, kudzu, ovariectomized ↑ lipid metabolism; ↑ energy
42]
Flemingia macrophylla, Flemingia vestita rats; metabolism;
CD-1 mice ↑ islet β-cell proliferation
↓ food intake; ↓ blood glucose;
Pathways: NF-κB/ERK; JAT/STAT; TGF-β;
calmodulin kinase II and Ca2+ signaling
Flavans-3-ol catechin, green tea, coffee and Ligularia fischeri C57BL/6 J mice; ↑ FFA oxidation; ↑ energy metabolism [43–
46]
epicatechin, HepG2 cells; inhibit pancreatic lipase; insulin
epigallocatechin gallate secretion
↓ inflammatory marker
Pathways: NF-κB
[47]
oolonghomobisflavans A and B, oolong tea pancreatic ↓ pancreatic lipase inhibition
oolongtheanin 3 -O-gallate lipase activity (IC 50: 0.048, 0.108, and 0.068 μM)
(Continued)
Models
[48–
Chalcone licochalcone A Glycyrrhiza uralensis (Leguminosae) C57BL/6 J mice; ↑ induction of adipocyte browning;
50]
3T3-L1 cells ↓lipid accumulation (C/EBPα, SREBP-1,
PPAR-γ, FAS, ACC, SCD1)
[51,52]
phloridzin Bark of apple trees C57BL/6 J mice; ↑ glucose metabolism
STZ-rats ↓ hepatic lipogenesis;
↓ cholesterol synthesis and
esterification;
↓ inflammatory marker;
Inhibit SGLT1/SGLT2
[53,54]
Anthocyanidins cyanidin berries, black bean, purple corn color plants C57BL/6 J mice; ↑ lipid metabolism;
db/db mice; ↓ adipocyte proliferation and
KK-Ay mice adipogenesis;
3T3-L1 cells Pathways: AMPK/LPL
[55–
Flavonolignan silibinin (A and B) Milk thistle C57BL/6 J mice; ↑ glucose homeostasis;
57]
db/db mice; ↓ ROS; lipogenesis;
HepG2 cells; ↓ inflammatory marker (TNF-α);
3T3-L1 cells Pathways: AMPK/SIRT1
HepG2 cells, human liver cancer cell line; 3T3-L1 cells, mouse pre-adipose cells; RAW264.7 cells, mouse macrophage cell lines transformed by Abelson leukemia virus; C3H10T1/2, mouse
mesenchymal stem cell; INS-1 cells, rat insulin secreting β-cells; SY5Y cells, human neuroblastoma; C2C12 cells, mouse myoblast cells; HIB1B cells, mouse brown adipocyte cells; HGMCs, human
glomerular mesangial cells.
5
6
Table 2. Summary of flavonoid extracts with potential anti-obesity effects.

Models
Plant resources Crude extraction Representative components (in vivo/in vitro) Outcomes/mechanism Refs
J. LIU ET AL.
[58–
Alpinia officinarum 70% ethanol total phenolics: 359.6 ± 6.1 mg of gallic acid equivalents/g Hamsters (2%, 4%, 6%, 8% and ↓ serum lipid (TG, TC);
62]
extraction total flavonoids: 289.9 ± 5.3 mg of rutin equivalents/g 10% w/w, 9 weeks) ↑ liver and the epididymal fat lipid
C57BL/6 J mice (200 mg/kg metabolism
BW, 12 weeks) (↓ C/EBPα, SREBP-1, PPAR-γ, FAS);
3T3-L1 cells ↓ lipid accumulation
[63–
American cranberry water extraction total polyphenols 37.4%, C57BL/6 J mice (200 mg/kg BW, ↑ lipid catabolism; insulin sensitivity
66]
(Vaccinium flavonols 9.4%, 8 weeks; 0.8% w/w, ↓ hepatic steatosis (↓ 29% in lipid
macrocarpon total proanthocyanidins 10.0% 10 weeks) droplet size)
Aiton) ↓ inflammatory marker (COX2, TNFα,
NF-κβ/IKβ, TLR4/NF-κB)
Regulate gut microbiota
(↑ Akkermansia muciniphila)
[67]
Ashitaba lyophilized xanthoangelol Tsumura Suzuki obese diabetic ↓ plasma PAI-1;
(Angelica keiskei exudation 4-hydroxyderricin (TSOD) mice (0.75% w/w, ↓ serum insulin and glucose
koidzumi) one week) ↓ inflammatory marker (TNF-α)
[68]
90% ethanol total chalcones 97% (xanthoangelol 7.3 g/kg, 4-hydroxyderricin Wistar rats (3% w/w, 11 weeks) ↓ serum lipid (TG, TC, FFA),
extraction 3.45 g/kg) ↑serum HDL (↑APOA1, ABCA1)
↓ serum insulin and glucose
↑ hepatic fatty acid β-oxidation
(ACOX, CPT1)
Artichoke leaf water extraction 80% luteolin in the extract (w/w) C57BL/6 N mice ↓ inflammatory marker (↓ IL-6, IL-1β); [69]
(Cynara scolymus ↓ gastric inhibitory polypeptide
L.) ↓ hepatic glucogenic enzymes
[70]
freeze-dried caffeic acid derivatives 8.89% ICR mice ↓ SOD, GSH
powder chlorogenic acid 0.98% (Acute alcohol-induced liver ↓ degeneration inflammatory
cynarin 0.56% injury model, 12 mL/kg BW infiltration and necrosis of
alcohol/day) hepatocytes
Pathways: TLR4/NF-κB
[71]
Black chokeberry methanol cyanidin-3-xyloside, cyanidin-3-glucoside chlorogenic acid, C57BL/6 J mice (100 and ↑ insulin sensitivity; ↓ bodyweight;
(Aronia extraction amygdalin, prunasin 200 mg/kg BW) serum lipid
melanocarpa) 3T3-L1 cells (10 μM) ↓ adipocyte differentiation (↓ CEBP,
FAS)
60% ethanol Anthocyanins Wistar rats ↑ serum adiponectin, ↓serum TNF-α, [72]
extraction (fructose-rich diet + 100 and IL-6
200 mg/kg BW, 6 weeks) ↓ blood glucose (↑ Pi3k, Glut1 and
Glut4, ↓Gsk3β)
↑ PPAR-γ, ↓ LPL, FAS, Fabp4
(Continued)
Models
[73,74]
Black soybeans ethanol extraction delphinidin-3-glucoside 25.2% 3T3-L1 cells (50 μg/mL) ↓ cell lipid accumulation (PPAR-γ)
petunidin-3-glucoside 6.5% adipose-derived stem cells
cyanidine-3-glucoside 68.3% (100 and 200 μg/mL)
[75]
acidic water and cyanidine-3-glucoside 9.0% KK-Ay mice (22 g/kg BW ↓ blood glucose; ↑ insulin sensitivity
ethanol total procyanidins 35.5% diet,6 weeks) ↓ gluconeogenesis in the liver
extraction total polyphenols 68.7% L6 cells (10 μM) (G6pase, PEPCK)
total isoflavones 0.5% Pathways: AMPK/GLUT4
[76]
Bamboo leaf methanol orientin, isoorientin, vitexin, and luteolin 3T3-L1 cells (100 μg/mL) ↓adipocyte differentiation (SREBP-1 c,
(Phyllostachys extraction C/EBPα, PPAR-γ);
bambusoides) water ↓ inflammatory marker
extraction Pathway: AMPK
[77]
Bamboo leaf water extraction total flavonoids SD rats (3% and 5% w/w, ↓ accumulation of lipid droplets
(Sasa 11 weeks) (adipose: ↓C/EBPβ; liver: ↓ SREBP-1,
quelpaertensis) FAS)
↓ inflammatory cell infiltrations
[78–
Corn silk ethanol extraction total phenolics: 34.6 ± 0.2 milligram of gallic acid equivalents/g 3T3-L1 cells (800 μg/mL) ↓ bodyweight, ↓organs weight (the
80]
(Zea mays L.) total flavonoids: 16.8 ± 0.4 milligram of rutin equivalents/g Alloxan-induced mice (1, 2 liver, white adipose tissue)
and 4 g/kg BW, 20 days) ↓ lipid droplets
STZ-mice (300 and 500 mg/ (↓ C/EBPβ, C/EBPα, PPAR-γ, Ap2)
kg BW, 6 days) ↑ insulin sensitivity and recover the
injured β-cells
Pathways: AKT, ERK1/2
[81]
(purple) corn silk ethanol extraction quercetin, anthocyanins, derivatives of phenolic acids 3T3-L1 cells (250–1000 μg/mL) ↓ lipid accumulation
(Zea mays L.) (quercetin, cyanidin, pelargonidin, delphinidin, petunidin, (↓ lipid droplets, ↓ glycerol released
peonidin, malvidin, cyanidin glucoside, cyanidin contents);
malonylglucoside, pelargonidin glucoside, peonidin glucoside)
Citrus reticulata water extraction synephrine 16.0 ± 1.08 mg/g, narirutin 4.52 ± 0.31 mg/g, hesperidin C57BL/6 J mice (1% w/w, ↑ browning of inguinal WAT (↑ UCP1, [82,83]
(Citrus reticulata 9.14 ± 0.32 mg/g, nobiletin 2.54 ± 0.07 mg/g, tangeretin 8 weeks) PRDM16, Cidea);
L.) 1.67 ± 0.05 mg/g ↓ hepatic steatosis; serum lipid
hydroxylated polymethoxyflavones Inhibit porcine pancreatic lipase
Pathway: AMPK; PPAR-γ, LXR
[84]
supercritical fluid Polymethoxyflavones and hydroxyl Polymethoxyflavones C57BL/6 J mice (0.5% w/w, ↓ SREBP-1 and perilipin 1
extraction 16 weeks) Change gut microbiota
3T3-L1 cells (200 μg/mL) (↑ percentage of Prevotella and
Lactobacillus,
↓ percentage of rc4-4, Ruminococcus
and Akkermansia)
7
(Continued)
8
Models
[85,86]
J. LIU ET AL.
Hawthorn 70% ethanol flavonoids 3.6% Hamsters (250 mg/kg BW, ↓ food intake; serum lipid
(Crataegus extraction 7 days) ↑PPAR-α (epididymal adipose tissue)
pinnatifida Bge.) SD rats (5% and 10% w/w, ↓ 3T3-L1 differentiation
4 weeks) Liver: ↑ PPAR-α (↑ ACOX-1, ACADM,
3T3-L1 cells (25 and 50 μg/ CPT-1)
mL)
C57BL/6 J mice (250 mg/kg
BW, 7 days)
[87]
Licorice root crude powder isoliquiritigenin ovariectomized C57BL/6 mice ↑ liver/fat lipid metabolism;
(Glycyrrhiza extracts (50 mg/kg BW, 5 weeks) ↓ bodyweight, serum lipid
[88]
glabra L.) ethanol/medium- glabridin 12.0% KK-Ay mice ↑ femoral muscle mass (↓ MuRF1,
chain (1 or 1.5 g/kg BW, 4 weeks) atrogin-1)
triglycerides Pathway: mTOR/P70 S6K, p38/FoxO3a
extraction and Akt/FoxO3a
[89]
ethanol extraction flavonoids 16.7 g/100 g extract KK-Ay mice ↓ plasma glucose, blood pressure
(glycycoumarin, glycyrin, dehydroglyasperin C and (0.1, 0.2 or 0.3 g/100 g diet/ ↑ PPAR-γ ligand-binding activity
dehydroglyasperin D, liquiritin) day, 4 weeks)
[90]
supercritical CO2 glycyrrhizic acid 16.3 ± 0.65 mg/g extract 3T3-L1 cells (25 and 50 μg/mL) 25 μg/mL extract partially inhibited
extraction glabridin 45.12 ± 0.14 mg/g extract C57BL/6 J mice (0.1% and differentiation, 50 μg/mL extract
isoliquiritigenin 2.62 ± 0.11 mg/g extract 0.25% w/w, 8 weeks) completely blocked differentiation
↑ oxygen consumption rate
Adipose: ↓ PPAR-γ, FAS, Ap2; Liver:
↓ PEPCK, G6Pase
[91]
Noni leaf methanol rutin, kaempherol, quercetin, myricetin, fisetin, hesperitin, SD rats (150 and 300 mg/kg ↓ pancreatic and lipoprotein activity;
(Morinda citrifolia extraction quercitrin, naringin, and genistein BW, 12 weeks) serum lipid
[92]
L.) / scopoletin, epicatechin Bal/c mice (200 and 400 mg/kg ↑ weight-loaded swimming time
BW, 6 weeks) skeletal muscle/liver: lipid catabolism
(↑ ACADM); anti-oxidant
(↑ SOD2); glucose metabolism (↑
PDK4, GLUT4)
[93–
Red onion 60% ethanol quercetin C57BL/6 J mice (0.5% w/w, ↓ bodyweight; adipocyte size and
95]
extract 8 weeks) number; adipose tissue inflammation
3T3-L1 cells (50, 100 and (↓ IL-6)
150 μg/ml)
(Continued)
Models
[96]
Salacia reticulata aqueous epigallocatechin, epigallocatechin gallate, C57BL/6 J (0.1% w/w, 9 weeks) ↑ energy metabolism (oxygen
extraction catechin, mangiferin consumption)
↑ glucose/lipid metabolism
[97]
mangiferin 0.24%, Tsumura Suzuki obesity ↓ lipogenesis (PPAR-γ, Fabp4, CD36,
(−)-epicatechin 0.076%, (+)-catechin 0.04% diabetes (TSOD) mice (0.25% LPL) ↑ lipolysis (ATGL, HSL)
(−)-epigallocatechin 0.11%, and 0.5% w/w, 12 weeks); pathway: AMPK
and (−)-epigallocatechin gallate 0.03% 3T3-L1 cells (25, 50 and
100 μg/ml)
[98]
total polyphenols 6.8%, Wistar fatty (fa/fa) rats (0.2% w/ ↑ cecum mass
mangiferin 0.65% w, 6 weeks) ↑ total amount of short-chain fatty
acids
9
10 J. LIU ET AL.
Figure 1. Antiobesity mechanisms of flavonoids.
Figure 2. Chemical structures of flavonoids with antiobesity activity.

Figure 3. Metabolism pathway of dietary flavonoids in vivo.
11
12 J. LIU ET AL.
agouti-related protein (AgRP) promoted signal transducer and activated phosphorylated transcription
3 (STAT3), which dimerizes and transports from the cytoplasm into the nucleus, where it binds to the
POMC and AgRP promoters.
The working mechanism is to stimulate the expression of POMC and inhibit the expression of
AgRP, thus reducing food intake and increasing energy consumption.[124] Hypothalamic arcuate
nucleus (ARC) is a key to the regulation of food consumption. It involves two main types of neurons
that control feeding.[125] Neurons produce neuropeptide Y (NPY) and AgRP to increase appetite,
while neurons co-express POMC and cocaine and amphetamine-regulated transcript (CART) to
inhibit appetite.[126,127] AgRP neurons express peripheral hormonal signal receptors, including insu
lin, leptin, and ghrelin, [128] indicating that antagonism of melanocortin receptors in the central
nervous system (CNS) is essential in weight regulation.[129]
Flavonoids have been postulated as possible modulators of food intake, though activating anorexi
genic signals (POMC/CART), suppressing orexigenic signals (NPY/AgRP) and increasing the expres
sion of leptin in the hypothalamus.
Regulating gut microbiota

Dysbiosis in the intestinal microbiota has been associated with obesity.[130–132] Intestinal microbiota
increases the capacity to harvest energy from the diet and modulates lipopolysaccharides levels to
activate inflammation and the onset of obesity.[133]
Flavonoids are usually consumed together with aglycones as glycosides and released in the small
intestine epithelium or lumen. Unlike dietary nutrients and micronutrients, large amounts of ingested
flavonoids are not absorbed in the proximal intestine and reach the colon, where they exposed to
microbiome-mediated hydrolysis and fermentation.[134,135] Research on ingestion has suggested that
such flavonoid catabolites are easily absorbed in the colon and reach substantially higher systemic
concentrations than parent compounds possessing longer half-lives.[136]
The intestinal microbiota has a significant effect on the transformation of flavonoids compounds,
thus affecting the health-promoting of human being, which involves three major catabolic pathways of
flavonoids in the transformation process, including hydrolysis (O-deglycosylations and ester hydro
lysis), cleavage (C-ring cleavage; delactonization, demethylation), and reduction (hydrogenation of
double bonds and dihydroxylation).[137] The prebiotic effects of flavonoid glycosides observed in
specific bacterial populations of the human gut microbes may also be explained by using additional
glycosylates, including flavonoid hesperidin, rhamnosides, rutin, luteolin, eriocitrin.[138–142] Various
bacterial species or strains catalyze reactions through various metabolic pathways and produce
different flavonoid metabolites .[143–145] Human intestinal bacterium Slackia transformed soybean
isoflavones daidzein and genistein into equol and 5-hydroxy-equol, respectively.[146] However,
Escherichia coli HGH21 and the gram-positive strain HGH6 convert daidzin and genistin into their
respective aglycones daidzein and genistein.[147] Flavonoids can to change intestinal microecology and
may produce positive health benefits to the intestinal tract by affecting the adhesion of bacteria to
intestinal cells. However, the compounds, strains, and differentiated degrees of intestinal cells affected
by bacterial adhesion.[148,149]
The classical “prebiotic-like” effect of polyphenols (e.g., grapeseed, wine, cocoa, green tea, pome
granate, and blueberry) has been explained by the fact that polyphenols, such as quercetin, naringenin,
[150,151]
regulate the gut microbiota to enhance the growth of lactobacillus and bifidobacteria and
inhibit the growth of many pathogens in experiments in vitro and in vivo.[152–158]
Increasing energy expenditure

Recently, researchers suggested activating browning of white adipose tissue (WAT) and beige adipo
cytes tissue (BAT) as therapeutic targets to inhibit obesity. It is worth noting that the actual amount of
BAT found in adults is typically quite low.[159] Excessive WAT accumulation has harmful
FOOD REVIEWS INTERNATIONAL 13
consequences on metabolic health.[160,161] Compared to WAT, which primarily stored in the form of
triacylglycerols, BAT can dissipate energy in the form of heat to maintain thermal homeostasis.[162]
Therefore, activation of browning leads to increased energy expenditure and reduced adiposity, thus
contributing to improved energy homeostasis.
Several researches provide some evidence that several flavonoid constituents from food are involved
in activating the browning of WAT, including green tea extract, [163] raspberry, [164] grape seed
proanthocyanidin extract[165] and broccoli sprout extract, [166] could improve obesity by promoting
thermogenic process. The mechanism of flavonoids regulating browning may be related to varieties of
transcription factors and coactivators through activating 5ʹ-AMPactivated protein kinase (AMPK) to
regulate the differentiation and thermogenesis of brown and beige fat, including uncoupling protein 1
(UCP1), CCAAT/enhancer-binding protein α (C/EBPα), peroxisome proliferator-activated receptor γ
(PPAR-γ), PPAR-γ coactivator 1a (PGC1a) and PR domain zinc finger protein 16 (PRDM16).
As a unique marker in brown and beige fat, UCP1 maintains temperature and induce
thermogenesis.[167] C/EBPα and PPAR-γ are crucial transcription factors in the process of adipocyte
differentiation.[168] C/EBPα also participates with insulin-induced glucose uptake in mature
adipocytes.[168] PGC1a could combine with PPAR-γ and retinoid X receptor (RXR), forming PGC1a-
PPAR-γ complex, which induces UCP1 expression.[169] PRDM16, as a coactivator, could combine
with the promoter region of UCP1,[170] which is stabilized by PPAR-γ agonists promote the conver
sion of WAT to BAT fat .[171] As energy sensors, AMPK and sirtuin-1 (SIRT1) also activate PGC1a in
muscle and hepatocytes, which may alter the browning process .[159,172] Fibroblast growth factor 21
(FGF21) is mediated by binding with ATF2 enable to 3ʹ-5ʹ-Cyclic adenosine monophosphate (cAMP)
pathway to increase UCP1 in a cold environment.[173]
Regulating lipid metabolism

In obese individuals, WAT expansion is a significant component of the metabolic syndrome, which
leads to increased plasma free fatty acids (FFAs) levels and excess fat accumulation.[174,175] Excessive
FFAs flow into the liver, which causes liver steatosis. To increase fatty acid catabolism is another
possible target for weight loss, and it is mainly achieved by stimulating hormone-sensitive lipase,
activating fatty acid β-oxidation, and inhibiting fatty acid synthase activity and adipocyte differentia
tion. Citrus flavonoids and green tea epigallocatechin gallate possess the ability to increase lipolysis
and induce fatty acid β-oxidation through modulation of peroxisomal acyl-coenzyme A oxidase 1
(ACOX1), PGC1α, carnitine acyl transferase 1 (CPT1), hormone sensitive lipase (HSL) and acetyl-
CoA carboxylase (ACC).[176,177]
Inhibition of pancreatic lipase and reduction of lipid absorption is an attractive method to identify
potent agents. Reports have indicated that several flavonoids demonstrate the potential for the inhibition
of pancreatic lipase, including luteolin, naringenin, neohersperidin, nobiletin, tangeretin, rutin, isogink
getin, bilobetin, ginkgetin, and sciadopitysin.[178–183] The total extracts from different foods and nutrition
have also been reported to possess the potential for inhibiting pancreatic lipase, including Xanthoceras
sorbifolium Bunge (Sapindaceae), [184] Capparis sicula Duhamel (Capparaceae), [185] tea leaves of
Camellia sinensis (L.) Kuntze, [186] Kiwis (Actinidia chinensis), [187] and Moricandia arvensis (L.) DC.[188]
Anti-inflammation
Obesity is related with inflammation statues, which involves various organs, such as liver, pancreas,
adipose tissue, skeletal muscle tissue, intestinal, and heart. Inflammation is not only the result of
obesity, but also the cause of inducing insulin resistance, disrupting energy balance, and metabolic
homeostasis .[189] In the COVID-19 pandemic, cytokine storm causes systemic inflammatory response
syndrome (SIRS), which releasing plenty of proinflammatory cytokines and chemokines by immune
response cells.
14 J. LIU ET AL.
A high-fat-diet could change intestinal flora and intestinal permeability, leading to an increase of
lipopolysaccharide (LPS), which releases proinflammatory cytokines and induce insulin resistance by
Toll-like receptor (TLR4).[190,191] In adipose tissue M1 macrophages could be recruited and generate
proinflammatory cytokines, leading to an imbalance of M1/M2 macrophages.[192] Inflammatory
infiltration caused by hepatic macrophages also releases proinflammatory cytokines, which result in
insulin resistance in the liver.[189] Flavonoids mainly by suppressing proinflammatory cytokines,
including tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), inter
feron-γ (IFN-γ), interleukin-6 (IL-6), interleukin-1β (IL-1β) and nitric oxide (NO) and activating
anti-inflammatory cytokines (adiponectin). The anti-inflammation mechanism of flavonoids could
inhibit the inflammatory cascade of mitogen-activated protein kinases (MAPK), nuclear factor kappa
light chain enhancer of activated B cells (NF-κB) pathway.
Types of flavonoids with potential anti-obesity effects

Natural flavonoids have been extensively researched in the treatment of obesity as well as metabolic
disorders as they can regulate rates of hydrate digestion and insulin or glucose uptake of various
cellular signaling pathways that affect lipids and carbohydrates, which in turn increase antioxidant
defense and reduce inflammation.
Flavones
Luteolin is in many fruits, vegetables, and herbs. Luteolin and quercetin activate AMPK/PGC1α
signaling in differentiated primary brown and subcutaneous adipocytes.[193] Western diet supplemen
ted with 100 mg/kg luteolin ameliorates atherosclerotic plaque development in low-density lipopro
tein receptor knockout (LDLR−/-) mice by decreasing human myeloid leukemia mononuclear cells
(THP-1)-derived macrophages via AMPK/Sirt1.[194] Dietary supplements with 0.01% luteolin (w/w)
significantly improve insulin resistance by promoting AMPKα1 signaling in adipose tissue macro
phages in high-fat-diet (HFD) mice.[10] HFD+0.005% Luteolin (w/w) suppresses hepatic lipogenesis
and lipid absorption to improve hepatic steatosis and increases PPAR-γ in adipose tissue. It relieves
diet-induced obesity and its comorbidity by regulating the interplay between the liver and adipose
tissue.[11] In human hepatoma HepG2 cells and human intestinal Caco2 cells, Luteolin could decrease
hepatocyte nuclear factor 4α (HNF4α) and apolipoprotein B (apo B).[12] Luteolin also improves
chronic low-grade inflammation by decrease human epidermal growth factor-like module containing
mucin-like hormone receptor 1 (EMR1) and C-C motif chemokine ligand 7 (CCL7), which modulate
the TLR signaling pathway in adipose tissue.[13]
Tangeretin (5, 6, 7, 8, 4ʹ-pentamethoxyflavone), mainly extracted from citrus plants, also prevents
diseases associated with obesity. Tangeretin decreases inflammatory marker (IL-6, IL-1β, TNF-α,
cyclooxygenase-2, COX-2) and increases glucose uptake in coculture of 3T3-L1 adipocytes and
RAW 264.7 cells.[14] Tangeretin could improve glucose tolerance via AMPK pathway in obese
mice.[15] In human glomerular mesangial cells, tangeretin (2.5, 5, and 10 μM) inhibits high glucose-
induced cell proliferation, oxidative stress, and extracellular matrix expression. It indicates that it may
be a potential agent in the treatment of diabetic nephropathy.[16]
Baicalin is a flavone glycoside, that is found in the roots of Scutellaria baicalensis and Scutellaria
lateriflora. It also has been used as a kind of natural supplement. Baicalin (100, 200, and 400 mg/kg/d)
dose-dependently inhibits the hepatic Ca2+/CaM-dependent protein kinase β (CaMKKβ)/AMPK/
ACC pathway to reduce the degree of hepatic steatosis.[16] Dai et al. carried out quantitative chemo
proteomic profiling and identified carnitine palmitoyl transferase 1α (CPT1α), the controlling enzyme
for fatty acid oxidation, as the critical target of baicalin. Baicalin has unique anti-steatosis activity and
directly activates hepatic CPT1α.[17] Baicalin treatment (50 mg/kg/day, i.p., for 21 days) reduces body
weight and food intake. Also, it relieves insulin resistance through the protein kinase B (Akt)/glucose
transporter type 4 (GLUT4) and P38 mitogen-activated protein kinase (MAPK)/PGC1α/GLUT4

pathways in diet-induced obese mice.[18]
Apigenin inhibits POMC and CART in N29-2 neuronal cells and human SHSY5Y neuroblastoma
cells.[19] Apigenin binds and activates PPAR-γ as a regulator by inhibiting translocation of the p65/
PPAR-γ complex into nuclei, and significantly reduces the infiltration of inflammatory in the liver and
adipose tissues in HFD and ob/ob mice.[20] Apigenin (30 mg/kg) has been found to regulate PPAR-γ
target genes depending on the activation of nuclear factor erythroid-2-related factor 2 (Nrf2) to
improving obesity-induced MAFLD.[21] As CD38 inhibitor, apigenin suppresses acetylation of p53
and RelA-p65 through increasing nicotinamide adenine dinucleotide (NAD+) levels, which will
enhance glucose and lipid homeostasis.[22]
Nobiletin in citrus fruits is related to enhancing stress in adipocytes by inducing 3T3-L1 white
adipocytes browning and activating HIB1B brown adipocyte cells.[23] Nobiletin could ameliorate
hepatic steatosis by increasing FFA oxidation (peroxisome proliferator-activated receptor α, PPAR-
α, CPT1α, and PGC1α) and decrease hepatic TG synthesis in vivo and in vitro .[25,26]
Flavonols
3-Methylethergalangin from the rhizome of Alpinia officinarum, as an inhibitor of pancreatic lipase,
significantly reduces the serum triacylglycerol (TG) level in mice with corn oil feeding-induced
triglyceridemia and serum TG and cholesterol (TC) levels in mice with Triton WR-1339-induced
hyperlipidemia.[27]
Quercetin, exists in plants and diets, such as red wine, onions, green tea, apples, berries, ginkgo
biloba. It demonstrates anti-adipogenesis activity by activating the AMPK signal pathway in 3T3-L1
preadipocytes.[28] Quercetin possesses anti-inflammatory properties, which suppresses the increase in
the number of macrophages, reduction in the ratio of CD4(+) to CD8(+) T cells in epididymal adipose
tissue through MAPK/c-Jun N-terminal kinase (JNK)/extracellular signal-regulated kinases (ERK)
pathway, [29] and adipose tissue macrophage infiltration and inflammation through AMPKα1/SIRT1
pathway.[30] Quercetin protects against oxidative stress in alloxan-induced hyperglycemia mice by
improving glutathione (GSH) superoxide dismutase (SOD), catalase (CAT) and glutathione-
S-transferase (GST) levels.[31]
Rutin, a flavonoid compound found in common rue, buckwheat, capers, and other plants, and
sometimes taken as a dietary supplement, reduces adiposity, increases energy expenditure, as well as
improves glucose homeostasis in both db/db mice and diet-induced obesity. Rutin has been reported
to directly bind to SIRT1, leading to hypoacetylation of PGC1a, which eventually activates the number
of mitochondria and UCP1 activity in BAT.[22] Besides, rutin (500 μM) increases glucose uptake in rat
soleus muscle through the phosphoinositide 3-kinases (PI3K) and MAPK pathways.[23]
Kaempferol exits in various plants and foods derived from plant, has protective effects on cultured
clonal beta-cells and human pancreatic islets, which inhibit cellular apoptosis exposed to chronic high
glucose via B-cell lymphoma-2 (Bcl-2)/AKT/caspase-3 pathway[34] or cyclic adenosine monopho
sphate (cAMP)/protein kinase A (PKA)/cAMP-responsive element-binding protein (CREB)
pathway[35] or phosphoinositide 3-kinase (PI3K)/protein kinase C (PKC) pathway[36] in beta-cells
and human islets cells, thus providing evidence that kaempferol might be an anti-diabetic compound.
Tiliroside has been found in several dietary plants, such as rose, strawberries, and raspberries. The
administration of tiliroside (10 mg/kg, two weeks) significantly inhibit body weight gain in normal
mice.[37] In obese-diabetic KK-Ay mice, tiliroside (100 mg/kg, 21 days) enhanced fatty acid oxidation
through enhanced adiponectin signaling associated with the activation of both AMPK and PPAR-α.[38]
Trans-tiliroside from Potentilla chinesis was found to exert antihyperglycemic, antihyperlipidemic, and
antioxidant effects in mice with alloxan-induced diabetes (0.4, 0.8, and 1.6 mg/kg/day, respectively;
15 days) and streptozotocin-induced diabetes (1.2 and 0.3 mg/kg/day, respectively; 10 weeks).[195]
16 J. LIU ET AL.
Isoflavonoids
Postmenopausal women usually develop obesity and insulin resistance because of decreased serum
estrogen levels. Several studies in vivo and in vitro have demonstrated that estrogen downregulates
hypothalamic NPY, increases anorectic corticotrophin-releasing hormone, subsequently reducing
food intake.[196,197] Daidzein, the soybean isoflavone, has been known as analogous to 17β-estradiol,
which is the ligand for estrogen receptor (ER) and which results in the induction of estrogen-activated
factors.[198] Fujitani et al. have elucidated the relationship between the dynamics of appetite-mediated
neuropeptides and the anorectic effect of daidzein in female rats, implying that daidzein induces
anorexia by suppressing the expression of NPY and increasing the expression of corticotrophin-
releasing hormone in the hypothalamus.[199] Isoflavones (genistin, genistein, daidzin, and daidzein)
decreases food intake by reducing ghrelin and NPY levels in ovariectomized rats.[39] Genistein and
daidzein, estrogen-like compounds chiefly in legumes and especially soybeans, potentially exert
antioxidative effects on insulin resistance and inhibit ERK/Janus kinase (JAK)/signal transducer and
activator of transcription (STAT) pathways in rat insulinoma cells and isolated rat islets.[39–41]
Furthermore, genistein augments leucine/glutamine-stimulated insulin secretion in Ca2+/calmodulin
kinase II (CaMK II) overexpressing INS-1 rat insulinoma cells.[42]
Medicarpin, a derivative of isoflavonoids, has been screened as a molecule inducer that is responsible for
developing brown and beige adipocyte characteristics in C3H10T1/2 mesenchymal stem cells by activating
of the AMPK pathway, which promotes the formation of multilocular lipid droplets and expression of
mitochondrial biogenesis-related genes, such as PPAR-γ, PRDM16, UCP1, and PGC1α.[200]
Flavan-3-ol
Flavan-3-ols are derivatives of flavans, including catechin, epicatechin gallate, epigallocatechin, epi
gallocatechin gallate, proanthocyanidins, theaflavins, and thearubigins.[201] The four major catechins
in green tea contain 59.0% epigallocatechin gallate, 19% (–)-epigallocatechin, 13.6% (–)-epicatechin
-3-gallate, and 6.4% (–)-epicatechin.[43] Tea catechins have been demonstrated to affect fat oxidation
partly, inhibit pancreatic and gastric lipases, and influence the metabolic capacity of gut microbiota.
Therefore, they have potential effects on weight loss and weight maintenance by promoting energy
expenditure.[44–47] (-)-Epicatechin and its derivatives promote mitochondrial biogenesis, such as
peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC1α), mitochondrial transcrip
tion factor A (TFAM), and UCP1 and upregulate the expression of brown adipose tissue-specific
proteins in vitro and in vivo.[202–204] The effect of green tea (-)-epigallocatechin gallate (EGCG) and
green tea polyphenols is not dependent on an intact leptin receptor, as indicated by the response of
leptin-receptor-defective Zucker rats with obesity to EGCG.[205] EGCG alters the diurnally oscillating
expression pattern of vital appetite-regulating genes, including AgRP, POMC, and CART, and
essential circadian genes clock circadian regulator (Clock) and aryl hydrocarbon receptor nuclear
translocator-like 1 (Bmal1) in the hypothalamus of mice with diet-induced obesity, indicating its
central effect on feeding regulation.[206]
Chalcone
Licochalcone A from Glycyrrhiza uralensis effectively recovers metabolic homeostasis and ameliorates
obesity by significantly suppressing the differentiation of 3T3-L1 preadipocytes and inducing the
brown fat.[48,49] In Glycyrrhiza glabra roots, isoliquiritigenin and licuroside, as members of the class of
chalcones, exhibit intense pancreatic lipase-inhibitory activity, with IC50 values of 7.3 ± 0.7 μM and
14.9 ± 0.8 μM. Besides, a molecular docking study on isoliquiritigenin verified that it bound with the
critical amino acid residues of the pancreatic lipase active site.[50]
Phlorizin has been regarded as a useful molecule in the managing of postprandial hyperglycemia in
diabetes and related disorders. Supplementation of phlorizin in the diet at a dose of 0.02% can prevent
HFD-induced collagen accumulation in the liver and WAT and suppress plasma proinflammatory
adipokines levels (TNF-α, MCP-1, IFN-γ, and IL-6).[51] As a competitive inhibition of (sodium-
dependent glucose transporters) SGLT1/SGLT2, oral administration of phlorizin (5, 10, 20, and
40 mg/kg) significantly reduces blood glucose levels and improves dyslipidemia in mice with strepto
zotocin (STZ)-induced diabetes.[52] Xanthohumol, a prenylated flavonoid from hops, increases energy
expenditure and can reduce the generation of reactive oxygen species through mitochondrial uncou
pling and stress response induction.[207]
Anthocyanidins
Numerous anthocyanidins have attracted attention because of their wide distribution in fruits and
vegetables.[208] Grape seed proanthocyanidins (GSPE), as food intake limiting agents, has been
reported to inhibit food intake through CART in acute treatment of 1 g GSPE/kg BW.[209] Recently,
proanthocyanidins from grape seeds have been found to potentiate hypothalamic leptin/STAT3,
which leads to signaling that improves the central and peripheral leptin resistance associated with diet-
induced obesity.[210] In db/db mice, cyanidin-3-glucoside limits weight gain, maintain glucose home
ostasis and induces brown-like adipocytes (beige) formation in subcutaneous white adipose tissue
(sWAT).[53] In KK-Ay mice, an AIN-93 G diet with cyanidin-3-O-β-glucoside (1 mg/kg) regulated TG
metabolism through the AMPK-lipoprotein lipase (LPL) signaling pathway.[54]
Flavonolignan
As a flavonolignan in milk thistle seed, silibinin has been wildly concerned due to treatment in liver
disorders, hypoglycemic and hypolipidemic effects.[55] It has been reported that silibinin might
influence the NAD+/Sirt1/AMPK axis to prevent hepatic steatosis.[56] In STZ-induced rats, silibinin
could prevent the development of obliterated retinal capillaries through decreasing leukostasis and
retinal intercellular cell adhesion molecule-1 (ICAM-1) level, which provides the possibility of treating
diabetic retinopathy.[57]
Flavonoid extracts with potential anti-obesity effects

Some natural flavonoids-riching foods or extracts have also been proved to be directly related to
obesity in various in vivo and in vitro models.
Alpinia officinarum (A. officinarum) Hance belongs to the ginger family (Zingiberaceae). Its
rhizomes, much like ginger, are extensively used in Asian cuisine and have been traditionally used
for many decades in Asia and Africa to treat several ailments, inflammation, pain, stomachache, and
the common cold.[211] In addition to its medicinal applications, A. officinarum is also consumed as
a decoction, infusion, or juice.[212] So far, several flavonoids, including apigenin, galangin, galangin-
3-methylether, kaempferide, and pinocembrine, have been identified and isolated from the
rhizome.[213] Recent studies have suggested that it can inhibit lipid accumulation during differentia
tion of 3T3-L1 and suppress adipogenic and lipogenic genes, such as C/EBPα, fatty acid synthase
(FAS), sterol regulatory element-binding protein-1 (SREBP-1), and PPAR-γ in HFD mice.[58,59] In
HFD hamsters, its extracts have demonstrated antihyperlipidemic activity through the total alleviation
of enlarged organs (liver, kidney, and spleen) and reductions in serum TC and TG levels.[60] Several
in vivo other studies have reported that its extracts exerted potential anti-obesogenic activity by
targeting fatty acid oxidation and metabolism. Ethanolic extract of ginger shows higher DPPH and
ABTS+ scavenging activities in vivo and decreases SREBP-1 and FAS to relieve liver lipid synthesis and
lipolysis in HFD mice.[61] Ginger phytochemicals have been found that it mainly participates in fatty
acid β-oxidation (PPAR-α) according to biomarker network analysis.[62]
American cranberry (Vaccinium macrocarpon Aiton) is gaining recognition because of its antiox
idant activity.[214] Polyphenol-rich American cranberry extract (200 mg/kg) prevents diet-induced
18 J. LIU ET AL.
obesity in high-fat and high-sucrose-fed mice, associated with improvements in gut-liver homeostasis
and glucose tolerance and the normalization of insulin sensitivity.[63,64] Polyphenol-rich American
cranberry extract could increase Akkermansia muciniphila in the gut, which could reverse hepatic
steatosis (decreasing hepatic TC and TG)[63] and improve insulin resistance .[64] Furthermore, poly
phenol-rich American cranberry extract has demonstrated impressive efficacy in reducing COX2 and
TNF-α in the liver, an effect that appears to connect with the mitigation of TLR4/NF-κB
signaling.[65,66]
Ashitaba (Angelica keiskei koidzumi), whose fresh leaves and dried powder are used as food in
Japan, contains an abundance of chalcones and flavanones. In the past few decades, ashitaba extracts
and their isolated constituents have been proven to possess anti-diabetic and anti-obesity
properties.[215,216] As a popular dietary supplement, A. keiskei koidzumi (ashitaba) extract has been
found to reduce plasma plasminogen activator inhibitor-1 (PAI-1) levels and improve food absorption
efficiency to alleviate the risk of thrombotic diseases and metabolic states in Tsumura Suzuki obese-
diabetic mice.[67] Furthermore, A. keiskei extract, constituting 3% of a diet fed to fructose-drinking
rats, enhanced the expression of fatty acid β-oxidation and high-density lipoprotein (HDL) produc
tion in the liver, suggesting antihypertriglyceridemic effect.[68]
Artichoke (Cynara scolymus L.), a herbaceous plant belonging to the Asteraceae family, contains
various phenolic compounds, including chlorogenic acid, cynarin, luteolin, and cymaroside.[217]
Numerous studies have indicated that artichoke, employed either as a health food or herbal supple
ment, can offer additional support for the treatment of dyslipidemia.[69,218–220] In a lipid profile study,
artichoke extracts have been found to decrease serum TC, TG, and LDL levels .[220] Long-term
supplementation with 0.005% (w/w) luteolin-rich artichoke leaf extract could inhibit adiposity pro
duction, promote biliary sterol excretion, and suppress lipogenesis.[70] Therefore, these studies
suggested using artichoke for effective weight control and lipid regulation.
Black chokeberry (Aronia melanocarpa (Michx.) Elliot) is of great interest to scientists because it has
one of the highest antioxidant levels.[221] Black chokeberry has a high content of total polyphenol
ranging from 690 to 2560 mg gallic acid, equivalent to fresh weight of 100 g.[222,223] Black chokeberry
is traditionally used to treat colds, hypertension, and atherosclerosis[224,225] and is mainly used as
a nutritional supplement and for making juices, jams, wine, and food colorants.[226,227]
A. melanocarpa extract-treated (100 or 200 mg/kg) HFD mice exhibited significant decreases in body
weight, and serum TG level and improved insulin sensitivity in a dose-dependent manner, [71] demon
strating that the extract was potentially beneficial for obesity suppression. In fructose-rich diets induced
diabetes rats, black chokeberry extract has reduced the risk of insulin resistance through upregulation of
insulin receptor substrate1 (Irs1), PI3k, and GLUT4 expression.[72]
Black soybean (Glycine max L. Merr) is regarded as the best antioxidant compared with other
soybeans because of its seed coat.[228] In the black soybean seed coat, the average content of anthocyanins
ranges from 0.87 mg/g to 23.52 mg/g, of which cyanidine-3-glucoside is the main anthocyanin.[229] In
3T3-L1 cells and subcutaneous adipose-derived stem cells, the anthocyanins in black soybean have been
proved to reduce adipose tissue mass, resulting in fewer mature adipocytes and the inhibition of
adipocyte differentiation.[73,74] 12.5 and 50 μg/mL of black soybean anthocyanins (cyanidine-
3-O-glucoside, delphinidin-3-O-glucoside and petunidin-3-O-glucoside) inhibited cell proliferation
and expression of PPAR-γ in 3T3-L1 cells.[73] 100 and 200 μg/mL of black soybean ethanol extract
did not increase lipid accumulation in Oil red O staining of subcutaneous adipose-derived stem cells.[74]
Moreover, another study investigated the effect of black soybeans extracts (22.0 g/kg) in KK-Ay mice. It
revealed that it could enhance hyperglycemia and insulin sensitivity by activating the AMPK pathway.[75]
Anthocyanins from black soybean could reduce body weight and food intake through its modulatory
effect on NPY and γ-aminobutyric acid B1 receptor (GABAB1R) in the hypothalamus.[230] Feeding
a high soy isoflavone diet (26.41% soy that contained 1500 μg/g genistein and 800 μg/g daidzein) to
ovariectomized female rats could reduce feed intake and weight gain.[231]
The bamboo leaf has been consumed as a treatment for hypertension, arteriosclerosis, and
cardiovascular disease for more than 1000 years.[232] Ethyl acetate (EtOAc) extract of bamboo leaf
has been demonstrated to inhibit JNK and p38 in macrophages.[233] Recently, several studies have
proposed that bamboo leaf extracts can serve as a potential treatment for modulating lipid metabolism
and anti-inflammation. Bamboo leaf extract inhibits adipogenesis, such as SREBP-1 c, C/EBPα, PPAR-
γ in 3T3-L1 adipocytes and bamboo leaf extract has demonstrated greater efficacy than ethanol-based
bamboo leaf extract.[76] Supplementation of HFD with bamboo leaf extract (3% and 5%, w/w), serum
lipid values TC, TG, and LDL-c have significantly decreased. Bamboo leaf extract could reduce
SREBP-1 and FAS to improve liver lipid accumulation.
Corn silk (Zea mays L.), a traditional Chinese herbal medicine, has been widely used to treat edema,
gout, and nephritis.[79] Numerous studies have demonstrated the anti-diabetic and hypolipidemic
properties of corn silk, indicating that it could treat or prevent metabolic syndrome.[78] The study
suggested that ethanolic purple corn silk extract, which is composed of anthocyanins, quercetin,
derivatives of phenolic acids (cyanidin, pelargonidin, delphinidin, petunidin, peonidin, malvidin,
cyanidin glucoside, cyanidin malonylglucoside, pelargonidin glucoside, peonidin glucoside, and
quercetin), inhibits adipocyte proliferation and adipogenesis through decreasing C/EBPβ, C/EBPα,
PPAR-γ, and Ap2.[81] Besides, Hsu et al. suggested that corn silk extract might reduce adipogenesis
through the inhibition of the galectin-12 expression pathway.[79] In mice with STZ-induced diabetes,
crude flavonoids extracted from corn silk decreased serum lipid values (TC and TG), bodyweight, and
especially blood glucose level.[80]
Citrus fruits contain various health-promoting ingredients, especially flavonoids.[234] Immature
Citrus extract has been reported to markedly attenuate lipid accumulation in the liver and WAT,
increase thermogenesis, and induce the browning process.[176] It has been reported that HFD with 1%
w/w citrus extract could inhibit PPAR-γ and liver X receptor (LXR) signaling in the liver to combat
obesity.[82,83] Poly methoxy flavones and hydroxyl poly methoxy flavones from citrus has been shown
to change intestinal flora by increasing Prevotella and decreasing rc4-4 bacteria.[84] Numerous studies
have shown that mature orange (Citrus aurantium L.) potentially increases energy expenditure and
lipolysis and inhibits pancreatic lipase, and thus promoting weight loss.[235,236]
Hawthorn (Crataegus pinnatifida Bge.), called ShanZha in China, has been used to treat hyperten
sion, atherosclerosis, and myocardial dysfunction under the British Herbal Pharmacopoeia.[237] The
Chinese Drug and Food Administration approved the use of hawthorn fruit for the treatment of
hyperlipidemia. It has been used to make traditional candy haw rolls, fruit juices, jams, jellies, and
wines. Flavonoids and its derivatives are the most abundant chemical components of
C. pinnatifida.[238] Hyperin is probably the main constituent of C. pinnatifida with antihyperlipidemic
effects.[239] Kuo et al. have demonstrated the positive impact of ShanZha extract on obesity or
dyslipidemia induced by a high-fat diet in hamsters, characterized by the activation of PPAR-α,
which was reversed by combined treatment with the PPAR-α antagonist MK886.[85] Oral administra
tion of ShanZha extract (250 mg/kg for seven days) can effectively improve hyperlipidemia in HFD
mice by increasing PPAR-α expression in the liver.[86]
Licorice, the root of Glycyrrhiza glabra L., has been widely used as a natural sweetener and herbal
medicine for several decades. Licorice flavonoid oil and licorice root extract have been reported to
possess the ability to control blood glucose levels and improve multiple metabolic parameters in
diabetic KK-Ay mice and under conditions of low estrogen and in a high-fat diet model.[87–90] In
menopause model of ovariectomized mice, dietary licorice root reduced body weight gain and liver
steatosis.[87] Licorice ethanolic extract (100 to 300 mg/kg BW, four weeks) could prevent abdominal
obesity and hypertension in HFD-induced mice.[89] Oral administration of licorice flavonoid oil (1 and
1.5 g/kg BW, four weeks) could improve muscle mass via the mammalian target of rapamycin
(mTOR)/p70 S6K and Akt/Forkhead box O3 (FoxO3a) signaling in diabetic KK-Ay mice.[88]
Glabridin-rich supercritical fluid extract of licorice decreased phosphoenolpyruvate carboxykinase
(PCK1) and glucose 6-phosphatase (G6Pase) to alleviate hepatic gluconeogenesis.[90]
Noni (Morinda critrifolia L.) is a folk medicinal plant with large amounts of flavonoids and is
beneficial in the treatment of obesity and obesity-related metabolic dysfunction.[92,240,241] As
a “starvation fruit”, Noni is a staple food in the Pacific islands. M. citrifolia leaf extract achieves the
20 J. LIU ET AL.
highest percentage of LPL inhibition, at 66.0 ± 2.1%, of all fruit extracts.[242] In vivo, supplementation
of 150 and 300 mg/kg M. citrifolia leaf extract significantly controlled bodyweight and increased fecal
fat excretion, demonstrating promise as a natural anti-obesity agent.[91]
Onion peels contain higher levels of quercetin derivatives, a flavonoid subgroup known as flavo
nols, than do onion bulbs.[93] Onion peel extract has demonstrated the ability to reduce mesenteric fat,
[94]
inhibit lipogenesis and adipogenesis, increase fatty acid oxidation, [95] and promote adipocyte
browning.[243]
Salacia reticulata is widely distributed in Sri Lanka and southern India and has been extensively
used in Ayurvedic medicine for the treatment of diabetes.[244] S. reticulata is also consumed as a food
supplement that prevents obesity and diabetes in Japan because it suppresses postprandial
hyperglycemia.[97] It has recently been reported to effectively suppress postprandial hyperglycemia
and exhibit anti-obesity and hepatoprotective effects.[98] Its extract, used in the prevention of obesity,
controls adipocyte differentiation into mature adipocytes .[245] It also enhances the expression of
lipogenesis genes and suppresses that of lipolysis genes through activation of AMPKα in
adipocytes.[96]
Clinical trials
Natural products (food components and medicinal plant-derived substances) are generally considered
to possess less toxicity and induce fewer side effects than synthetic drugs and have become promising
candidates for treating and preventing obesity. Although a growing body of research on flavonoids as
interventions in animal models supports their anti-obesity effects, clinical evidence remains insuffi
cient by now (Table 3).
Citrus-derived flavonoids
Sinetrol-XPur, designed by Fytexia, is a citrus extract standardized to polyphenols from the family of
flavanones. A study has enrolled 47 adults with overweight who took a citrus polyphenolic extract-
Sinetrol-XPur (900 mg/day) for 12 weeks, and the results have revealed that waist and hip circumfer
ence and abdominal fat dramatically decreased.[246] In another randomized, double-blind, crossover
trial, Cases et al. have demonstrated that Sinetrol-XPur treatment with the same dosage provided
evident preservation of skeletal muscle mass during weight loss.[273]
Moro orange (Citrus sinensis L. Osbeck) is a cultivar of red-orange, particularly rich in active
compounds, such as anthocyanins, hydroxycinnamic acids, flavone glycosides, and ascorbic acid.[274]
A clinical study has revealed the effects of Moro orange on weight loss management.[247]
Daily grapefruit consumption (one half of a fresh grapefruit with each meal) has been reported to
exert significant reductions in weight loss and waist circumference.[248,249] Moreover, a 6-month
clinical trial has suggested that bergamot (Citrus bergamia) juice supplementation had beneficial
effects on plasma lipid levels in subjects with moderate hypercholesterolemia.[275]
Kerimi et al. compared the acute effect of pomegranate juice and a polyphenol-rich extract on
postprandial blood glucose concentration. The results showed that pomegranate juice was more
effective than pomegranate extracts to reduce postprandial blood glucose. In contrast, microbial
metabolites of pomegranate polyphenols had the potential to further regulate sugar metabolism
much later in the postprandial period.[251]
The limited number of clinical trials using interventions with citrus fruits remains a source of
concern. Although a few clinical studies have reported that citrus-derived flavonoids cause no
significant changes in body weight, they possess potential anti-inflammation and antioxidant abilities
as well as potential to improve glucose and lipid metabolism levels.
Table 3. Natural ingredients with anti-obesity effects in clinical trials.
Intervention Constituents Study type Participants Content/day Outcome Refs
[246]
Citrus polyphenolic extract with polyphenols (catechin) 12-week, overweight adults 900 mg ↑ SOD, GSH;
red orange, grapefruit, sweet flavanones (naringin) randomized, (n = 47) ↓ waist-to-hip
orange and guarana Sinetrol- double-blind, ratio;
XPur (polyphenolic citrus dry placebo- ↓ C-reactive
extract) controlled trial protein, fibrinogen
[247]
Moro orange juice anthocyanins, flavone 12-week, overweight adults 299 and 745 mg ↓ BMI, waist
(Citrus sinensis (L.) Osbeck) glycosides, randomized, (n = 30) circumference,
hydroxycinnamic acids and double-blind, leptin, SOD,
ascorbic acid placebo- systolic and
(hesperidin, narirutin, controlled trial diastolic blood
didymin) pressures
[248]
Fresh grapefruit flavone glycosides 6-week, randomized, overweight adults one half of a fresh grapefruit/each meal ↓ body weight
double-blind, (n = 85) (average weight
placebo- loss of
controlled trial −0.61 ± 2.23 kg)
[249]
Grapefruit and grapefruit juice 12-week, overweight adults 127 g grapefruit juiceor one half of a fresh ↓ energy intakes
randomized, (n = 85) grapefruit/each meal 20–29%
double-blind, ↓ weight loss
placebo- 7.1%
controlled trial ↓ waist
circumferences
4.5 cm
↑ HDL-C
Bergamot juice (Citrus bergamia) 150 mg of flavonoids 6-month, moderate Bergavit ↓ TC, TG, LDL-C, ↑ [250]
(neoeriocitrin 16%, randomized, hyperlipidemic 500 mg and 1000 mg HDL-C
neohesperidin 47%, and double-blind, adults (n = 80)
naringin 37%) placebo- (plasma LDL-C
controlled trial concentrations
between 160
and 190 mg/dl)
[251]
Pomegranate juice and punicalin, punicalagin, ellagic 3-week, randomized, healthy adults 200 ml and 400 mg ↓ blood glucose
pomegranate extract acid hexose, ellagic acid, crossover, (n = 16)
malic acid, citric acid, placebo-
fructose controlled studies
(Continued)
21
22
[252]
Freeze dried strawberry powder anthocyanins 6-week, randomized, type 2 diabetes 50 g ↓ C-reactive protein,
J. LIU ET AL.
double-blind, (n = 23) (500 g fresh strawberries) MDA, HbA1c

placebo-
controlled trial
[253]
12-week, hyperlipidemic 10 g ↓ postprandial
randomized, adults (400 mg polyphenols) lipemia
single-blind, (n = 24)
crossover,
placebo-
controlled trial
[254]
8-week, randomized, overweight adults 50 g ↓ LDL-C, small LDL
double-blind, with metabolic (2006 mg polyphenols) particles, serum
placebo- syndrome (n = malondialdehyde,
controlled trial 27) and adhesion
molecules
[255]
Wild blueberry anthocyanin 6-week, randomized, healthy men 25 g ↑ Bifidobacteri,
(Vaccinium angustifolium) juice double-blind, (n = 20) Lactobacillus
placebo- acidophilus
controlled trial
[256]
Freeze dried blueberry powder 8-week, randomized, overweight adults 50 g ↓ blood pressure
(Vaccinium angustifolium) double-blind, with metabolic (1624 mg polyphenols) ↓ MDA
(Vaccinium corymbosum) placebo- syndrome (n =
controlled trial 48)
[257]
6-week, randomized, overweight adults 45 g ↑ insulin sensitivity
double-blind, with insulin (1624 mg polyphenols)
placebo- resistant (n =
[250]
8-week, randomized, postmenopausal 22 g ↓ systolic blood
double-blind, women with pressure and
placebo- pre- and stage diastolic blood
controlled trial 1-hypertension pressure
(n = 48) ↓ brachial-ankle
pulse wave
velocity
[258]
6-week, randomized, adults with 45 g ↓ ROS, TNF-α, IL-6,
double-blind, metabolic TLR4, GMCSF
placebo- syndrome (n = ↑ myeloid DC
(Continued)
[259]
Cranberry polyphenol 12-week, type 2 diabetes 1500 mg ↓ TC, LDL-C
randomized, (n = 30)
double-blind,
placebo-
controlled trial
[260]
4-week, randomized, type 2 diabetes 55 g ↓ postprandial
double-blind, (n = 13) (140 mg flavonols) insulin and
placebo- glucose
controlled trial
[261]
Cranberry juice 8-week, randomized, overweight adults 480 mL ↓ ox-LDL, MDA
double-blind, with metabolic (458 mg polyphenols)
placebo- syndrome (n =
[262]
Oolong tea and green tea extract catechins, epicatechin (EC), 12-week, healthy men 1 bottle ↓ BMI, waist
epigallocatechin (EGC), randomized, (n = 20) (690 mg catechins) circumference,
epicatechin gallate (ECG), double-blind, LDL-C
and epigallocatechin placebo-
gallate (EGCG) controlled trial
[262]
Green tea extract 3-month, overweight adults 379 mg ↓ TC, TG, LDL-C,
randomized, with ↑HDL-C
double-blind, hypertensive ↓ systolic blood
placebo- (n = 56) pressure and
controlled clinical diastolic blood
trial pressure
↓ TNFα and CRP
[263]
12-week, overweight adults 583 mg catechins ↓ bodyweight, BMI,
randomized (n = 240) body fat ratio,
double-blinded waist
controlled parallel circumference
multicenter trial ↓ LDL-C
↓ systolic blood
pressure
[264]
8-week, randomized, overweight men 800 mg EGCG ↓ body fat ratio,
double-blind, (n = 88) diastolic blood
placebo- pressure
controlled trial
[265]
6-week, randomized, overweight 3 capsules ↑ leptin;
double-blind, women (n = (856.8 mg EGCG ↓ LDL-C
crossover and 73) 236.1 mg ECG

placebo- 115.5 mg EGC
controlled clinical 71.9 mg EC
trial 63.7 mg GCG)
[266]
23
7-day, double-blind, healthy men (n = 1 g ↓ postprandial

randomized, 30) hyperglycemia
controlled,
crossover study
(Continued)
24
J. LIU ET AL.
[267]
Nutrition supplement vitamin C, α-tocopherol, green 8-week, randomized, obese n-3 PUFA ↓ HOMA-IR
tea extract, and lycopene double-blind, adolescents, (1000 mg eicosapentaenoic acid [EPA] and ↑ Adipor1 and
placebo- aged 1000 mg docosahexaenoic acid [DHA]), 567 mg Adipor 2 mRNA
controlled trial 13–18 years vitamin C, 390 mg α-tocopherol, 416 mg green (modulation of the
(n = 70) tea extract (45% epigallocatechin-3-gallate), and CpG methylation
16.5 mg lycopene status)
[268]
Yerba mate and green tea epicatechin and phenolic 8-week, randomized, overweight adults 1 L ↑ leptin and PON-1
acids double-blind, with
placebo- hypertensive
controlled trial (n = 142)
[269]
Bauhinia forficata Link tea flavonoids 3-month, quasi- type 2 diabetes 4.30 mg trigonelline and 1.02 mg rutin ↓ TC, TG
experimental (n = 13)
study
[270]
Epicatechin and the nonalkalized epicatechin and procyanidins 3-month, 4-way healthy men (n = 1.6 mg epicatechin/kg BW ↓ food intake
cocoa mixture randomized, 14)
crossover,
placebo-
controlled trial
[271]
Licorice flavonoid oil glabridin 8-week, randomized, overweight adults 300, 600, 900 mg ↓ visceral fat area,
double-blind, (n = 84) body weight, BMI
placebo- and LDL-C
controlled trial
[272]
Concord grape juice anthocyanins procyanidins 12-week, overweight adults 480 mL ↓ serum glucose
catechin, quercetin and randomized, (n = 76) and insulin
myricetin double-blind,
placebo-
controlled trial
Berry-derived flavonoids
Strawberries constitute a rich source of ellagitannins and anthocyanins and more than 40 phenolic
compounds have been isolated and identified.[94] In a randomized, double-blind controlled trial,
individuals with type 2 diabetes have been treated with freeze-dried strawberry supplementation
(50 g/day) for six weeks. There was a significant decreasing trend in hemoglobin A1c (HbA1C),
C-reactive protein (CRP), and malondialdehyde (MDA) levels.[95] In a postprandial study on hyperli
pidemia adults, freeze-dried strawberry intervention (10 g/day) showed significant attenuation of
postprandial lipemia and lipid oxidation.[243] Basu et al. have proved that freeze-dried strawberry
supplementation (50 g/day) resulted in a significant decrease in the number of small low-density
lipoprotein (LDL) particles, serum malondialdehyde level, and the number of adhesion molecules.[244]
These clinical trials indicated that strawberry improved glycemic control and antioxidant status and
reduced lipid peroxidation and inflammatory.
Chromatographic profiling has shown that in highbush (Vaccinium corymbosum) and lowbush
(Vaccinium angustifolium Aiton.) blueberries, anthocyanins account for approximately 35% to 74% of
total phenolic compounds, followed by hydroxycinnamic acid derivatives, flavonols, and flavan-
3-ols.[276] In a randomized, double-blind repeated-measure crossover study, Vendrame et al. have
revealed that blueberry treatment (25 g/day) significantly increased Bifidobacterium spp compared
with total eubacteria, [255] suggesting that blueberries could positively modulate the composition of
intestinal microbiota. It has been reported that blueberries could improve hypertension and insulin
resistance in adults with obesity and metabolic syndrome and adults with obesity and insulin
resistance, respectively.[256,257] Also, a study on phase 1-hypertension in postmenopausal women
employing an 8-week blueberry diet showed that blueberries improved blood pressure and arterial
stiffness.[250] Moreover, the blueberries treatment also significantly increased myeloid DC and reduced
the gene expression of TNFα, IL-6, TLR4, and serum granulocyte-macrophage colony-stimulating
factor (GMCSF) in patients in a randomized, double-blind, placebo-controlled trial.[258]
Several clinical studies have revealed that cranberries juice and raw cranberries extract, which are
rich in anthocyanins, flavan-3-ols, and flavonols, have anti-oxidant ability and the ability to reduce
postprandial insulin and glucose levels.[259–261]
Tea-derived flavonoids and polyphenols

Tea, a popular global beverage, has been suggested to have the potential to prevent and manage several
diseases associated with obesity. Reports have indicated that green tea contributes to weight loss,
[262,277]
reduced postprandial hyperglycemia, glucose homeostasis, [266] improved serum lipid profiles,
[278]
and reduced blood pressure.[264] In a 6-week randomized, double-blind, crossover, and placebo-
controlled clinical trial, green tea extract demonstrated a 25.7% increase in leptin and a 4.8% decrease
in LDL-C levels in overweight and obese women.[265] Although positive results have been reported
concerning obesity-related diseases in human clinical trials, many have reported nonsignificant
findings on bodyweight control.[279–281]
Apart from traditional tea beverages, infused herbal beverages, and nutrition supplements have
attracted the attention of an increasing number of scientists. McMorrow et al. evaluated an anti-
inflammatory nutrition supplement (consisting of long-chain n-3 polyunsaturated fatty acid, vitamin
C, α-tocopherol, green tea extract, and lycopene). They have reported a 40% reduction in the
homeostatic model assessment of insulin resistance (HOMA-IR) values in obese adolescents.[267]
Balsan et al. compared and evaluated the effect of yerba mate and green tea on leptin and paraox
onase-1 serum levels in adults with overweight; the results revealed that yerba mate surpassed green
tea in terms of antioxidant capacity by increasing serum levels of paraoxonase-1 and HDL-C.[268]
Nagao et al. evaluated the efficacy of oolong and green tea extracts (690 mg catechins/day) in reducing
body fat mass and subcutaneous fat area over 12 weeks.[263] In a 3-month quasi-experimental pilot
study, consuming 0.4% Bauhinia forficata Link tea twice a day caused significant reductions in TC and
26 J. LIU ET AL.
TG levels (by 48 and 17 mg/dL, respectively).[269] Greenberg et al. have investigated the relationship
between appetite and the epicatechin and procyanidins present in dark chocolate. And the results
indicated that epicatechin at a dose of >1.6 mg/kg body weight might useful for controlling human
food intake.[270]
However, little attention has been paid to the safety of tea-derived flavonoids and herbal beverages
and the influence of potential factors such as tea-drinking habits and intake amount. Hence, well-
controlled and long-term human studies are warranted.
Metabolism and bioavailability of flavonoids

Dietary flavonoids undergo phase I and II metabolism in the intestine and liver by microbiota and
enzymes before systemic circulation for bioactivity. Flavonoids are mainly absorbed in intestine,
which are converted to free aglycones and conjugated to O-glucuronides, sulfate, and O-methyl
forms by UDP-glucuronosyltransferases, sulfotransferases, and O-methyl transferase
enzymes.[282,283] These metabolites (glucuronate, sulfate and methyl groups) via bile excretion entry
into the enterohepatic circulation, while another part of metabolites pumps into systemic circulation
by intestinal efflux transporters (ABC transporters).[284] Flavonoids are degraded into phenolic acids
by the microflora in the colon. Metabolism pathway of dietary flavonoids is shown in Fig. 3.
Flavonoids mainly exist as flavonoids glycosides in plants, which have higher relative molecular
weight and polarity, and therefore it is hard to penetrate the intestinal wall. It is well known that the
poor bioavailability of flavonoids and short elimination half-life affects the absorption and efficacy
in vivo. Structural modifications have been utilized by flavonoids glycosylation to ameliorate water
solution.[285,286] Research on the nano-delivery systems of flavonoids possesses the capability to
improve the efficacy, including enhancing stability in plasma, increasing absorption, and decreasing
flavonoid metabolic degradation by intestinal microflora.[287–289] Lupinifolin-loaded nano lipid car
riers have shown long-term release in a simulated circulatory system and increased lupinifolin
absorption in everted intestinal sacs.[290] Polyamidoamine dendrimers have been extensively used in
drug delivery systems, which can enhance aqueous solubility, stability, dissolution, and drug
release.[291] Puerarin in polyamidoamine dendrimer complex improves water solubility by dendrimers
with amine-terminated surface functional groups. The Cmax and AUC0-8h are significantly higher than
the puerarin suspension solution.[292] Nanotechnology-based therapies, as a feasible strategy, have
expressed potential in improving the bioavailability and prevent obesity and its comorbidities.[293–295]
Recently, cell therapies are promising approach for treating obesity and related metabolic
disorders.[296,297] Yin et al. have developed a microencapsulated engineered cell system triggered by
oral administration of protocatechuic acid or green tea for controlling blood glucose in both diabetic
mice and monkey models. They designed a synthetic mammalian transrepressor (KRAB-PcaR) and
constructed an U6 promoter-driven gRNA expression-mediated module to control CRISPR-Cas9
gene editing, which could toggle a protocatechuic acid-responsive ON/OFF switch.[298] It has shown
that green tea-derived phenolic acid-controlled transgenic device opens opportunities for substantially
advance gene- and cell-based precision therapies.
Conclusion
Although many beneficial effects are ascribed to flavonoids preventing obesity and obesity-related
complications, and only a few flavonoids rich extracts have entered the clinical tests. The low bioavail
ability and water solubility of flavonoids and dose translation from animal to human studies might
explain the inconsistent outcomes in human studies and limit its development and usage. Flavonoids are
abundant in plant foods and drinks; therefore, dietary supplements of nutritional flavonoids could be
a strategy to maintain weight loss. On the other hand, the dosage of flavonoids needs to be taken into
account because people may take more than one flavonoid supplement at the same time. Therefore, it is
necessary to conduct more investigations and clinical trials examining flavonoid on dosage, efficacy,
bioavailability, and safety of flavonoids to develop promising therapeutic agents.
In this paper, the epidemiological studies, pharmacological action, molecular mechanism, current
clinical research trials as well as metabolism and bioavailability of beneficial flavonoids were reviewed, as
presented in Fig. 1. Taken together, dietary flavonoids could be potential candidates to combat obesity.[97,
Acknowledgments
This work was supported by the National Natural Science Fund (81872763).
Disclosure of potential conflicts of interest

The author(s) declare that there are no conflicts of interest.
Funding
This work was supported by the the National Natural Science Fund [81872763].
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Beneficial Flavonoid in Foods and Anti-obesity

Jingwen Liu, Jiaoxian Cao, Yiming Li & Fujiang Guo

To link to this article: https://doi.org/10.1080/87559129.2021.1923730

Published online: 12 May 2021.

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Beneficial Flavonoid in Foods and Anti-obesity Effect

Mechanisms of targeting anti-obesity

Table 2. Summary of flavonoid extracts with potential anti-obesity effects.

Figure 1. Antiobesity mechanisms of flavonoids.

Figure 2. Chemical structures of flavonoids with antiobesity activity.

Regulating gut microbiota

Increasing energy expenditure

Regulating lipid metabolism

Types of flavonoids with potential anti-obesity effects

transporter type 4 (GLUT4) and P38 mitogen-activated protein kinase (MAPK)/PGC1α/GLUT4

Flavonoid extracts with potential anti-obesity effects

double-blind, (n = 23) (500 g fresh strawberries) MDA, HbA1c

crossover and 73) 236.1 mg ECG

7-day, double-blind, healthy men (n = 1 g ↓ postprandial

Tea-derived flavonoids and polyphenols

Metabolism and bioavailability of flavonoids

Disclosure of potential conflicts of interest

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