Differential Effects of Dietary Flavonoids On Adipogenesis

European Journal of Nutrition
https://doi.org/10.1007/s00394-018-1663-8
REVIEW
Differential effects of dietary flavonoids on adipogenesis

Manizheh Khalilpourfarshbafi1 · Khadijeh Gholami2 · Dharmani Devi Murugan1 · Munavvar Zubaid Abdul Sattar3 ·
Nor Azizan Abdullah1
Received: 4 October 2017 / Accepted: 9 March 2018

© The Author(s) 2018
Abstract
Propose Obesity is a fast growing epidemic worldwide. During obesity, the increase in adipose tissue mass arise from two
different mechanisms, namely, hyperplasia and hypertrophy. Hyperplasia which is the increase in adipocyte number is char-
acteristic of severe obese patients. Recently, there has been much interest in targeting adipogenesis as therapeutic strategy
against obesity. Flavonoids have been shown to regulate several pathways and affect a number of molecular targets during
specific stages of adipocyte development.
Methods Presently, we provide a review of key studies evaluating the effects of dietary flavonoids in different stages of
adipocyte development with a particular emphasis on the investigations that explore the underlying mechanisms of action
of these compounds in human or animal cell lines as well as animal models.
Results Flavonoids have been shown to regulate several pathways and affect a number of molecular targets during specific
stages of adipocyte development. Although most of the studies reveal anti-adipogenic effect of flavonoids, some flavonoids
demonstrated proadipogenic effect in mesenchymal stem cells or preadipocytes.
Conclusion The anti-adipogenic effect of flavonoids is mainly via their effect on regulation of several pathways such as
induction of apoptosis, suppression of key adipogenic transcription factors, activation of AMPK and Wnt pathways, inhibi-
tion of clonal expansion, and cell-cycle arrest.
Keywords Adipogenesis · Flavonoids · Obesity · Hyperplasia · Adipocyte
Abbreviations C/EBP CCAT/enhancer-binding protein

FABP4 Fatty acid-binding protein 4 Cdks Cyclin-dependent kinases
hBM-MSCs Human bone marrow mesenchymal stem Rb Retinoblastoma
cells ERK Extracellular signal-regulated kinase
LPL Lipoprotein lipase KLFs Kruppel-like factors
ChREBP Carbohydrate response element-binding Pref-1 Preadipocyte factor-1
protein CREB Cyclic AMP response element-binding
EGCG Epigallocatechin gallate protein
FASN Fatty acid synthase EPAS1 Endothelial PAS domain protein 1
GPDH Glycerol-3-phosphate dehydrogenase BMAL1 Brain and muscle Arnt-like protein 1
T2DM Type 2 diabetes mellitus FOXO1 Forkhead box O1
FOXA2 Forkhead box A2
TRAP220 Thyroid receptor-associated protein com-
* Nor Azizan Abdullah plex 220
azizan@ummc.edu.my TAF8 TATA-binding protein-associated factor-8
1
Department of Pharmacology, Faculty of Medicine,
HDACs Histone deacetylases
University of Malaya, 50603 Kuala Lumpur, Malaysia NCoR Nuclear receptor co-repressors
2
Division of Human Biology, School of Medicine,
mTOR Mammalian target of rapamycin
International Medical University, 57000 Kuala Lumpur, ADD-1 Adipocyte determination and differentia-
Malaysia tion-dependent factor 1
3
Faculty of Pharmacy, MAHSA University, 42610 Jenjarum, TCF/LEF T-cell factor/lymphoid enhancer factor
Malaysia
13
Vol.:(0123456789)
TGF-β Transforming growth factorβ of these stages may serve as potential therapeutic strategy
ECG Epicatechin gallate against adipogenesis and hence obesity.
EGC Epigallocatechin Pharmaceutical approaches for weight management
LXR-alpha Liver X receptor-alpha include altering metabolism, appetite, or fat absorption.
hA-MSCs Human adipose tissue-derived mesenchy- Currently available drugs such as central nervous system
mal stem stimulants, or peripherally acting anti-obesity drugs, are
JNK C-Jun N-terminal kinase associated with several adverse effects such as hyperthyroid-
HFD High fat diet ism, palpitations, anxiety, insomnia, and diarrhea [8]. The
MAP Mitogen-activated protein development of new and safe anti-obesity agent has become
AICAR 5-Amino-imidazole-4-carboxamide riboside a necessity. Several studies have shown the potential of natu-
JAK Janus-activated kinase ral products to counteract obesity. Flavonoids represent the
miRNA MicroRNA most researched groups of phytochemicals with regards to
Wnt Wingless-type MMTV integration site their effects on weight management. Studies have shown
family fruits and vegetables rich in several flavonoid subclasses,
AMPK AMP-activated protein kinase particularly flavonols, anthocyanins, and flavones are asso-
SFRP1 Secreted frizzled-related protein 1 ciated with less weight gain. A study which assessed the
Dkk1 Dickkopf-1 associations between habitual consumption of all flavonoid
PPARG Peroxisome proliferator-activated subclasses and weight gain among 124,086 American men
receptor-gamma and women over a period of 24 years showed higher intake
SREBP1 Sterol regulatory element-binding protein 1 of foods rich in flavonols, flavan-3-ols, anthocyanins, and
FGFs Fibroblast growth factors flavonoid polymers may contribute to weight maintenance in
RUNX2 Run-related transcription factor 2 adulthood after adjustment for changes in other lifestyle fac-
PKB Protein kinase B tors such as diet, smoking status, and physical activity [9].
TNF-α Tumor necrosis factor-alpha Several other studies on human and rodents provide evidence
that flavonoids can cause suppression of appetite[10–12],
increase glucose uptake in muscle [13], decrease fat absorp-
Introduction tion [14], and inhibit adipogenesis [15, 16].
A prospective cohort study indicates that obesity is asso-
Obesity, which can be defined as increased body mass index ciated with shorten life expectancy and indeed this study
(greater than 30 kg/m2), has been identified as a risk fac- divulges that obesity in adulthood is a powerful predictor
tor for the pathogenesis of many chronic diseases includ- of death at older ages [17]. Flavonoids have been reported
ing cancer, hypertension, osteoarthritis, and cardiovascular to affect health and life span of various model organisms
diseases. It is also closely linked with metabolic disorders through different mechanisms including energy-restriction
including insulin resistance and type 2 diabetes mellitus like effects [18]. In this context, some of the molecular tar-
(T2DM) [1]. Obesity has been considered the fastest grow- gets of the anti-adipogenic effects of flavonoids which over-
ing epidemic worldwide. According to the World Health lap with some energy-restriction mimetics could be in part
Organization, in year 2014, more than 1.9 billion adults were explain their lifespan extending properties [18].
overweight of which over 600 million were obese [2]. In the This review summarizes the mechanisms of adipogenesis
United States, the prevalence of adult obesity is greater than and highlights the anti-adipogenic effect of flavonoids and
one-third (34.9%) of the population [3]. their corresponding underlying mechanisms of actions.
In obesity, the increase in adipose tissue mass arise via
two main distinct mechanisms, increasing adipocyte number Overview of adipogenesis
(hyperplasia) and/or increasing adipocyte volume (hypertro-
phy) [4, 5]. Hypertrophy occurs in overweight individuals Adipogenesis occurs in two differentiation stages in which
and prolonged period of weight gain in adulthood leads to an undifferentiated multipotent mesenchymal stem cell
hyperplasia. Hyperplasia is mostly associated with severity transforms into a ‘determined’ or ‘committed’ preadipo-
of obesity and is the characteristic of morbidly obese indi- cyte, which then undergoes a secondary differentiation
viduals [6]. Hyperplasia takes place through adipogenesis stage to become a lipid laden adipocyte [19, 20]. Dur-
that involves a cascade of transcriptional factors and cell- ing the determination stage, multipotent mesenchymal
cycle proteins which leads to development of mature adipo- stem cells (MSCs) differentiate and convert to committed
cyte [7]. This process can be divided into three main phases: preadipocytes under the influence of hormones, insulin,
growth arrest, clonal expansion, and terminal differentiation. and growth factors [19]. Subsequent stage is mitotic clonal
Inhibition of adipocyte differentiation by interrupting any expansion in which growth-arrested preadipocytes undergo
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several rounds of mitotic division which is a necessary Role of transcription factors in adipogenesis
step in the adipocyte differentiation program [21]. Follow-
ing mitotic clonal expansion, the preadipocytes leave the Adipogenesis is tightly controlled by the activity of tran-
cell cycle and undergo terminal differentiation, lose their scription factors which activate or repress each other in a
fibroblastic morphology, accumulate cytoplasmic triglyc- sequential manner. The key transcription factors that are
eride, and acquire the metabolic features of mature adipo- involved in adipogenesis include C/EBP family members
cytes. Adipocyte-specific genes are also highly expressed (C/EBPα, C/EBPβ, and C/EBPδ) and PPARG. At large, adi-
by mature adipocytes [19]. Adipocyte differentiation is pogenic program is driven by at least two waves of transcrip-
closely regulated by a cascade of transcription factors, tion factors. Adipogenic stimuli (hormones, growth factors,
amongst which peroxisome proliferator-activated recep- and cytokine) initiated the first wave which amongst others
tor gamma (PPARG) and CAAT/enhancer-binding proteins includes C/EBPβ and C/EBPβδ. These proteins subsequently
(C/EBPs) are key players of adipocyte fate. induce expression of the second wave of transcription fac-
Furthermore, to achieve successful transformation to tors of which PPARG and C/EBPα are the most important
mature adipocytes, fibroblastic preadipocytes undergo (Fig. 1). These two central adipogenic regulators positively
transformation into spherical cell shape [22, 23]. Pro- control each other and cooperate to orchestrate expression
teolytic degradation of the stromal extracellular matrix of the full adipogenic program [7].
(ECM) of preadipocyte by the plasminogen cascade is In addition to the above, an array of other important
essential for changes in cell morphology, the expression transcription factors function as regulators of adipogenesis.
of adipocyte-specific genes, and lipid accumulation [24]. Krüppel-like factors (KLFs) are expressed in adipose tissue
Following changes in ECM, C/EBPα, and PPARG are then and are either activators or repressors of transcription. KL4,
activated [25]. KLF5, KLF6, KLF9, and KLF15 are positive regulators of
adipogenesis [26]. KLF5 which is induced early during
Fig. 1 Adipogenesis network. The process of adipogenesis begin with a positive role in adipogenesis, whereas other transcriptional factors
the activation of transcription factors, C/EBPβ and C/EBPδ. These such as KLF2 and GATA2/3 suppress adipogenesis. C/EBP CCAT/
transcription factors function during the early adipogenesis program enhancer-binding protein, PPARG peroxisome proliferator-activated
to regulate the expression of the two master regulators of adipogen- receptor-gamma, ERK extracellular signal-regulated kinase, KLFs
esis, PPAR-γ and C/EBPα. The expression of adipogenic genes is Kruppel-like factors, CREB cyclic AMP response element-binding
regulated by binding of PPARG as a heterodimer with RXRα, where protein, FOXO1 forkhead box O1, TCF/LEF T-cell factor/lymphoid
C/EBPα and C/EBPβ occupy the C/EBP response elements. Several enhancer factor, MAPK mitogen-activated protein kinase, Wnt wing-
other important transcriptional factors play a role in control of adipo- less-type MMTV integration site family, PKA protein kinase A, GR
genesis. Some transcriptional factors including KLF5 and CREB have glucocorticoid receptor, DR1 direct repeat type 1 element
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adipogenesis by C/EBPβ and C/EBPδ activates the Pparg2 Cell‑cycle proteins

promoter [27]. KLF6 suppresses the expression of preadipo-
cyte factor-1 (Pref-1) which is known to inhibit adipogenesis Cyclin-dependent kinases (Cdks) regulate the progression
[28]. Other proadipogenic transcription factors include sterol of preadipocytes through the cell division cycle [41]. Cdks
regulatory element-binding protein 1 (SREBP1) and cyclic when activated phosphorylate retinoblastoma family (Rb)
AMP response element-binding protein (CREB). SREBP1 members, including the retinoblastoma protein p130 and
promotes early adipocyte differentiation and can induce p107. This leads to the release of E2 promoter-binding fac-
expression of PPARG and facilitates fatty acid metabolism tors (E2Fs) from inhibitory interaction with Rb, enabling
[29], while the expression of CREB in preadipocytes is nec- E2F family to activate transcription of genes that allows the
essary to induce adipocyte differentiation. Accordingly, the cells to enter S phase [42]. Cyclins are documented to be
absence of CREB inhibits adipocytes differentiation [30, downstream targets of c-Myc protein, which has been shown
31]. to activate cell cycle and induces DNA synthesis in serum-
Signals that repress adipocyte development may have pro- starved 3T3-L1 cells [43]. Nonetheless, overexpression of
found implications for human health. Amongst the myriad c-Myc inhibits differentiation of preadipocytes possibly by
of transcription factors that are known to be repressors of inhibiting the cell to enter into a distinct predifferentiation
adipocyte differentiation are several members of the KLF stage in G0/G1[44]. During conversion from G 1 to S stage,
(KLF2 and KLF7) [32, 33], globin transcription factor p38 mitogen-activated protein kinases (MAPKs), extracel-
(GATA2 and GATA3), and forkhead (Forkhead Box O1 lular signal-regulated kinase (ERK), and glycogen synthase
(FOXO1) and Forkhead Box A2 (FOXA2)) families. GATA2 kinase-3B (GSK3B) phosphorylate and activate C/EBPβ
and GATA3 are known to inhibit terminal differentiation via which eventually leads to expression of Pparg and Cebpα
repressing transcription of PPARG [34]. [45].
Role of microRNAs in adipogenesis

Role of transcription cofactors in adipogenesis
MicroRNAs (miRNAs) are small non-coding RNAs that
Transcription cofactors are proteins that interact with tran- regulate different biological processes at post-translational
scription factors and may affect transcription of specific modification state [46]. In addition, they play a role in a
genes in a positive or negative manner and thus play an variety of human diseases such as obesity and diabetes mel-
important role in adipogenesis. Amongst the transcription litus [47]. The miRNA profile of human adipose tissue has
co-activators, thyroid receptor-associated protein complex been demonstrated to be different in obese patients [48–50].
220 (TRAP220) is a known binding partner of PPARG, the One of the major functions of miRNAs in adipose tissue
absence of which prevents adipocyte differentiation [35]. is to inhibit or stimulate the differentiation of adipocytes.
Other significant co-activators include TATA-binding pro- There are numerous inhibitory and promoting miRNAs that
tein-associated factor-8 (TAF8) which is upregulated during contribute to the regulation of adipogenesis, in the com-
adipogenesis [36]. Hitherto and several other cofactors have mitment stage and in terminal differentiation (Fig. 2). The
been identified to play a role in preadipocyte differentiation expression pattern of 70 miRNAs has been shown to be
that contribute to the intricacies of adipogenesis. The cyc- either upregulated or downregulated during adipogenesis
lin D3-cyclin-dependent kinase-6 complex can bind to and in subcutaneous fat cells [49]. In mouse embryonic stem
phosphorylate PPARG, and eventually leads to induction of cells, 129 miRNAs expression are altered at distinct time
preadipocyte differentiation [37]. Cyclin-dependent kinase points during conversion of mesodermal progenitor cells
4 (CDK4) has also been reported to activate PPARG via its to mature adipocyte [51, 52]. MiR-103 is upregulated in
kinase domain [38]. rodents epididymal adipocytes during adipogenesis and its
By contrast, some cofactors may act as inhibitors of adi- ectopic expression increase triglyceride accumulation in the
pogenesis. For instance, cyclin D1 and transcriptional co- early stage of adipogenesis [53]. However, the expression of
activator with PDZ-binding motif (TAZ) suppress PPARG miR-103 remains unchanged during adipogenesis in human
activity and block adipocyte differentiation [39]. Some co- subcutaneous adipocytes [49]. The reason for the lack of
repressors recruit histone deacetylases (HDACs) to target inconsistencies between studies is not known but could be
promoters, which in turn result in blockade of transcription. due to differences in fat depots in mice and humans.
Mammalian sirtuin 1 (SIRT1) with HDAC activity interacts MiR-30 family is upregulated during adipogenesis, and it
with PPARG and therefore inhibits preadipocyte differentia- increases adipogenesis via targeting run-related transcription
tion. Furthermore, nuclear receptor co-repressors (NCoR) factor 2 (RUNX2) [54]. RUNX2 is an osteogenesis regulator
and silencing mediator of retinoid and thyroid hormone that promotes adipocytes differentiation when it is down-
receptors can also act as anti-adipogenics [40]. regulated. Similarly, miR-204 directly targets RUNX2.
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Fig. 2 MiRNAs in adipogenesis. MiRNAs influence adipogenesis cAMP response element-binding, WNT wingless and INT-1, TCF
during determination phase, which is the conversion of mesenchymal T-cell-specific transcription factor, PPAR peroxisome proliferator-
stem cell to preadipocytes, clonal expansion, and terminal differen- activated receptor, C/EBP CCAAT/enhancer-binding protein, KLF
tiation of preadipocyte to mature adipocyte. MAPK mitogen-activated Kruppel-like factor, IRS insulin receptor substrate, PKB protein
protein kinase, ERK extracellular signal-regulated kinase, MSC mes- kinase B, GSK glycogen synthase kinase 3
enchymal stem cell, cAMP cyclic adenosine monophosphate, CREB
Overexpression of miR-204 in MSCs promotes adipogen- 29 miRNAs including miR-27, miR-181, and miR-344 were
esis, whereas its inhibition favors osteogenesis [55, 56]. The identified to activate Wnt pathway and suppress adipogen-
miR 17–92 cluster is highly expressed during clonal expan- esis [46].
sion in preadipocytes and enhances adipogenesis through
inhibiting the tumor suppressor, Rb2/p130 during the early Role of circadian genes in adipogenesis
clonal expansion of preadipocytes [51, 52].
MiRNAs known to inhibit adipogenesis include miR-27, It has been documented that in human adipose tissue
miR-30, microRNA Let-7, and miR-448. Forced expression explants, the circadian genes can oscillate independently of
of miR-27 suppresses adipogenesis in multipotent adipose- the central nervous system which may regulate the timing
derived stem cells and 3T3-L1 cell line [57, 58] by directly of clock-controlled genes such as Pparg. Several proteins
targeting Pparg and Cebpα mRNA [59], whilst miR-130 including nocturnin, period circadian protein homolog 3
targets Pparg. Others such as microRNA Let-7 inhibit clonal (PER3), and brain and muscle Arnt-like protein-1 (BMAL1)
expansion and terminal differentiation in 3T3-L1 cells [60], that are involved in the regulation of circadian rhythm can
and miR-448 is reported to inhibit adipogenesis by targeting influence adipogenesis. Nocturnin, which is a circadian reg-
KLF5 [61]. ulated gene, has been reported to facilitate adipogenesis in
MiRNAs have also been demonstrated to modulate adipo- 3T3-L1 cells via stimulation of PPARG nuclear translocation
genesis by targeting Wnt pathway. Wnt proteins are factors [62], whereas PER3 was shown to have a negative role in dif-
in the external environment that can affect the differentia- ferentiation of MSCs to adipocytes; and besides, the protein
tion potential of preadipocytes. MiRNA microarray results can form a complex with PPARG which inhibits PPARG-
revealed increased expression of 18 miRNAs including miR- mediated transcriptional activation via Pparg response
148a, miR-210, miR-194, and miR-322 that repress Wnt elements [63]. Similarly, BMAL1 is a negative regulator
signaling and thus increase adipogenesis [46]. Conversely, of adipogenesis. BMAL1 deficiency in mice embryonic
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fibroblast cells results in increased expression of Cebpβ and regulator of adipocyte differentiation. TGF-β inhibits adi-
Pparg, and these adipogenic markers are increased even pogenesis through Smad3 which interacts with C/EBPβ and
before induction of adipogenesis which suggests spontane- C/EBPδ and represses C/EBP transcription activity [76].
ous differentiation of these cells with complete deficiency of Besides, it may also suppress adipogenesis via induction of
BMAL1. BMAL1 has been shown to suppress adipogenesis c-Myc expression [77]. A soluble form of preadipocyte fac-
by direct transcriptional regulation of genes of the Wnt sign- tor 1 (Pref-1) was shown to reduce adipose tissue mass and
aling pathway [64]. However, another study showed conflict- this factor negatively regulates adipogenesis via interaction
ing results, Bmal1 knockout C3H10T1/2 cells failed to be with Notch [78]. Finally, proinflammatory cytokines inhibit
differentiated into mature adipocytes [65]. adipogenesis via activation of several intracellular signal-
ing pathways. Proinflammatory cytokines were proven to
Other factors in regulation of adipogenesis decrease PPARG and C/EBPα expression in preadipocytes
and block insulin action [78–80].
In addition to the role of transcriptional factors, preadipocyte Conceivably, PPARG plays a major role in adipogenesis
differentiation may be influenced by a number of hormones, and most of the above factors that influence adipogenesis
growth factors and cytokine. Insulin, insulin-like growth fac- play their positive or negative role in adipogenesis by ulti-
tor-1 (IGF-1), thyroid hormones, mineralocorticoids, gluco- mately targeting PPARG, and hence, in the next section, we
corticoids (GCs), and PPARG agonists have important role look at PPARG more closely.
in promoting adipogenesis. Insulin is an important positive
regulator of adipogenesis [66]. Downstream molecules of PPARG as a master key of adipogenesis
the insulin signaling cascades such as phosphatidylinositol-3
kinase (PI3K), mammalian target of rapamycin (mTOR), PPARG which is abundantly expressed in adipose tissue is
and protein kinase B (PKB) are essential for preadipocyte a master key of adipogenesis [81, 82] and contributes to
differentiation [67, 68]. Thyroid hormone (T3), which plays whole-body insulin sensitivity and glucose homeostasis
a vital role in the control of metabolic homeostasis, pro- [81]. Activation of PPARG by ligands such as fatty acids and
motes adipogenesis via thyroid receptor α1-induced lipo- the antidiabetic drugs, and thiazolidinediones (TZDs) lead
genic gene expression [69]. Likewise, GCs, which are posi- to adipocyte differentiation and fatty acid storage. Therefore,
tive regulator of adipogenesis, promote differentiation of intake of high fat food exposes people to prolonged high
preadipocytes by increasing the expression of Cebpδ and level of fatty acid (PPARG ligand), which most likely results
Pparg. Fibroblast growth factors (FGFs) including FGF1, in obesity [83].
FGF2, and FGF10 have been shown to have proadipogenic Given that PPARG is an essential regulator of adipogen-
activity, since neutralization of these fibroblast growth fac- esis, it has been the target of anti-obesity research. PPARG
tors can block adipogenesis [70–72]. can be either modulated directly, or indirectly by targeting
Contrariwise, various extranuclear factors are shown to its upstream factors or pathways which ultimately affect
be negative regulators of adipogenesis. The wingless-type the activity of this crucial regulator of adipogenesis. In this
MMTV integration site family (Wnt) acts through autocrine regard, the expression or activity of PPARG can be sup-
or paracrine manner to regulate cell growth and cell fate in pressed through inhibition of C/EBPβ, the increased expres-
many cell types. Wnt signaling proceeds through canoni- sion of GATA2 and GATA3, regulation of mitogen-activated
cal (β-catenin) or non-canonical pathways. In the canonical protein kinase (MAPK), and the activation of the Wnt/β-
pathway, binding of Wnt to frizzled receptors on the cell catenin pathway. Another group of proteins that may play a
surface causes the translocation of β-catenin to the nucleus regulatory role in PPARG transcriptional activity are the sir-
where it interacts with the T-cell factor/lymphoid enhancer tuins (SIRT), especially SIRT1. SIRT1, an NAD+-dependent
factor (TCF/LEF) transcription factors to inhibit adipogen- deacetylase, impaired adipogenesis by directly acting as a
esis through blockade of C/EBPδ and PPARG [73, 74]. In PPARG co-repressor, thus, counteracting obesity [84, 85].
myometrial tissue, the absence of β-catenin leads to its con- Still, PPARG may possibly be regulated by post-translational
version to adipose tissue, which highlights the importance of modifications including phosphorylation which, in theory,
Wnt-β-catenin pathway in regulation of adipogenesis [32]. is a distinct feature that can be subjected for cell- or tissue-
Suggestion has been put forward that the receptors that ini- specific modulation of this molecule [86, 87]. Phosphoryla-
tiate the Wnt reside on primary cilia on adipocyte surface. tion of PPARG at Ser273 by CDK5 has been reported to
This is based on the fact that the increased adipogenesis selectively decrease expression of a subset of PPARG-tar-
observed in obese patients with the inherited ciliopathy Bar- get genes in adipocytes and pharmacological inhibition of
det–Biedl syndrome may be due to impaired cilia forma- Ser273 phosphorylation confers insulin sensitizing effects
tion which leads to increased expression of PPARG [75]. [88]. Nonetheless, Ser273 phosphorylation does not affect
Transforming growth factor β (TGF-β) is another negative regulation of adipogenesis by PPARG, suggesting that the
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antidiabetic and proadipogenic roles can be independently radiation and phytopathogens, signaling during nodulation,
manipulated by pharmacological agents. and auxin transport [90, 91]. Dietary flavonoids have been
shown to possess an array of pharmacological activities
including anti-inflammatory, antithrombotic, antitumor, anti-
Dietary flavonoids viral, anti-atherosclerotic, antidiabetic, and anti-adipogenic
effects [92–98].
Flavonoids are a class of plant secondary metabolites that Chemically, flavonoids have the basic structure of a
are widely distributed in a variety of vegetables and fruits 15-carbon skeleton consisting of two aromatic rings (A and
[89]. Flavonoids have a wide range of biological functions, B rings) connected through a heterocyclic pyrane ring (C
including coloration of flowers, protection against ultraviolet ring) (Fig. 3). Flavonoids encompass a number of subclasses
which are classified based on the level of oxidation and pat-
tern of substitution of the C ring. The six diet-derived flavo-
noid subclasses include isoflavones, flavan-3-ols, anthocya-
nidins, flavanones, flavones, and flavonols [99, 100]. Each
subclass consist of individual compounds, characterized
based on specific hydroxylation and conjugation patterns
[99]. The classification of dietary flavonoids, their chemi-
cal structures, individual compounds, and dietary source of
these subgroups are shown in Table 1.
The structure of flavonoids reveals useful information on
their anti-adipogenic effect. A comparative study investi-
gated the anti-adipogenic effect of 44 flavonoids in 3T3-L1
cells and concluded that flavonols with a methoxy group at
the 3-position possess the strongest anti-adipogenic effect.
In addition, the presence of methoxy groups at the B ring
Fig. 3 Basic structure of flavonoids contributes to the anti-adipogenic effect of flavonols. On the
Table 1 Flavonoid subclasses and their dietary sources

Flavonoids C ring functional group Dietary source Compound Chemical formula
Anthocyanidins 3-Hydroxy Cherry, berries, and red wine Cyanidin C15H11O6+

Delphinidin C27H31O17+
Malvidin C17H15O7+
Pelargonidin C15H11O5+
Petunidin C16H13O7+(Cl−)
Peonidin C16H13O6+
Flavones 4-Oxo Carrots, olive oil, peppers, rosemary Apigenin C15H10O5
peppermint, and celery Luteolin C15H10O6
Flavan-3-ols 3-Hydroxy Tea, chocolate and cocoa (+)-Catechin C15H14O6
3-O-gallate (+)-Gallocatechin C15H14O7
(−)-Epicatechin- C22H18O10
3-gallate C22H18O11
(−)-Epigallocatechin-
3-gallate
Flavonols 3-Hydroxy, 4-Oxo Onion, olive oil, and berries Fisetin C15H10O6
Isorhamnetin C16H12O7
Kaempferol C15H10O6
Myricetin C15H10O8
Quercetin
Flavanones 4-Oxo Citrus fruits Hesperetin C16H14O6
Naringenin C16H14O5
Isoflavones 4-Oxo Soy bean and leguminous plants Daidzein C15H10O4
Genistein C15H10O5
Glycitein C16H12O5
Biochanin A C16H12O5
Formononentin C16H12O4
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contrary, flavonoids with hydroxy groups show little or no Moreover, the exposure of these cells to apigenin reduces
anti-adipogenic effect [101]. expression of PPARG and C/EBPβ [106]. The reduction
of C/EBPβ was shown to be due to upregulation of C/
EBP inhibitors such as C/EBP homologous protein and
Interventional studies in adipocyte the phospho-liver-enriched inhibitory protein isoform of
development by dietary flavonoids C/EBPβ [107]. Similarly, luteolin inhibits adipogenesis by
attenuating the expression of C/EBPα and PPARG. Nota-
Anthocyanidins bly, the PPAR agonist, rosiglitazone-induced adipogenic
differentiation in preadipocytes is inhibited by luteolin
Anthocyanidins are common plant pigments which are pre- [108].
sent in many fruits, vegetables, and red wine. To date, about
635 anthocyanin compounds have been identified [102].
Cyanidin, peonidin, malvidin, delphinidin, pelargonidin, Flavan‑3‑ols
and petunidin are the most common anthocyanidins [103].
Human and animal studies have indicated the anti-obesity Flavan-3-ols are widely distributed in human diet and have
effect of anthocyanins [92, 103] which have recently attract been shown to be the dominant flavonoid intake by the U.S.
attention as potential novel anti-adipogenic agents. Cyanidin adults compared to other flavonoid subclasses [109]. Flavan-
has been reported to reduce adipogenesis in 3T3-L1 cells 3-ols can be found in many fruits including cocoa and tea.
by interfering with extracellular matrix and also decreasing The main flavan-3-ols in fruits and cocoa are catechin and
carbohydrate response element-binding protein (ChREBP) epicatechin. Epicatechin gallate (ECG), epigallocatechin
expression level [93]. Anthocyanins derived from black (EGC), gallocatechin, and epigallocatechin gallate (EGCG)
soybean such as cyanidin-3-O-glucoside, delphinidin-3-O- are mainly present in tea [110]. Many studies demonstrated
glucoside, and petunidin-3-O-glucoside have been shown to that catechin possesses anti-adipogenic effect. Tea catechin,
reduce preadipocyte differentiation through suppression of in particular (−)-catechin 3-gallate and (−)-epigallocatechin,
PPARG [94]. Extracts from Oryza sativa L. containing cya- have been shown to suppress adipogenesis in 3T3-L1 cells
nidin-3-O-glucoside and peonidin-3-O-glucoside have been via downregulation of PPARG2, C/EBPα, and GLUT4
demonstrated to inhibit the differentiation of mesenchymal [111]. However, (−)-catechin derived from green tea has
C3H10T1/2 cells to preadipocytes [104]. However, a more been shown to induce adipocyte differentiation in human
recent study showed treatment of preadipocytes with black bone marrow mesenchymal stem cells (hBM-MSCs) via
soybean cyanidin-3-glucoside alone paradoxically increases stimulation of transcriptional activity of PPARG. In addi-
the expression of Pparg and Cebpαand induces adipogen- tion, the level of adipogenic markers such as adiponectin
esis [95]. The discrepancy may be explained by the syner- (Adipoq), fatty acid-binding protein 4 (Fabp4), and lipopro-
gistic anti-adipogenic effects of other anthocyanins present tein lipase (Lpl) are markedly increased. Nevertheless, its
in black soybean extract in the former study [105], where stereoisomer (+)-catechin does not show any proadipogenic
treatment of preadipocytes with the combination of these effect which suggests the possibility of a direct pharmaco-
compounds results in inhibition of adipogenesis. Other pos- logical target regulated by (−)-catechin [105].
sible anti-adipogenic mechanism of anthocyanidins such as EGCG, the most abundant catechin in green tea, inhib-
cyanidin-3-O-glucoside and peonidin-3-O-glucoside include its adipogenesis by reducing the expression of PPARG,
activation of Wnt-specific target genes such as Axin2, Cyclin C/EBPα, FABP4, and fatty acid synthase while increas-
d1, and Wisp2 [104]. ing the level of β-catenin in the nucleus. Knocking down
of β-catenin using siRNA recovers the expression of these
Flavones adipogenic markers and attenuates the anti-adipogenic
effect of EGCG suggesting Wnt/β-catenin pathway as the
Flavones are present in many herbs including parsley and anti-adipogenic mechanism of EGCG [112]. EGCG has
celery. Apigenin and luteolin are the main dietary flavones also been shown to increase apoptosis in mature adipocytes
[96]. Flavones have shown promising effects in inhibiting without affecting viability of preadipocytes [113]. However,
adipogenesis. For instance, apigenin suppresses adipo- contradictory result has been obtained with EGCG; Sakuri
genesis in 3T3-L1 cells via activation of AMP-activated et al. claimed that EGCG enhances the expression of the
protein kinase (AMPK) pathway [97]. Activation of this genes involved in adipocyte differentiation. The expression
pathway has been suggested to inhibit clonal expansion of Pparg1, Pparg2, Cebps, and Ppargc1a was shown to be
phase and thus adipocyte differentiation [98]. Indeed, api- increased by EGCG treatment. Nonetheless, these effects
genin arrests the cell cycle at the G0/G1 phase which is are only observed at the early and not late stages of adipo-
associated with reduced cyclin D1 and CDK4 expression. genesis [104].
13
Flavonols wherein the flavonol inhibits mTOR phosphorylation and

its downstream molecules such as p70 ribosomal S6 kinase
Flavonols are the most widely distributed flavonoids in which in turn decreases Cebpα gene expression [120, 121].
the plant kingdom with the exception of algae and fungi. Rhamnetin blocks adipocyte differentiation during the early
Quercetin, kaempferol, isorhamnetin, fisetin, and myricetin stage of adipogenesis program by inhibition of clonal expan-
are the main dietary flavonols that can be found in berries, sion. The expression level of adipogenic transcription factors
onions, and olive oil. A number of dietary flavonols investi- in the presence of rhamnetin also declines during the early
gated showed anti-adipogenic effects by interruption of both adipogenesis [122].
the conversion of mesenchymal cells to preadipocytes and A comparative study investigated and compared the
the differentiation of preadipocytes to mature adipocytes. inhibitory effects of flavonoids (rutin, naringenin, hesperi-
In vitro studies have indicated that isorhamnetin treatment din, quercetin, naringin, and resveratrol) on adipocyte dif-
of preadipocytes results in downregulation of Pparg and ferentiation, as indicated by the decreases in triglyceride
Cebpα without affecting regulation of Cebpβ and Cebpδ. accumulation and GPDH activity [123]. In this study, rutin,
In addition, this flavonol decreases expression of PPARG- a flavonol glycoside, exhibits the highest anti-adipogenic
target genes such as liver X receptor-alpha (Lxr-α), Lpl, and effect characterized by downregulation of adipogenic tran-
Fabp4 suggesting PPARG inhibition as a possible mecha- scription factors and leptin, and upregulation of adiponec-
nism underlying the anti-adipogenic effect of isorhamnetin tin [124]. Choi et al. investigated the anti-adipogenic effect
[114]. Another study conducted by the same group showed of rutin in preadipocytes and HFD-induced obese animals.
that isorhamnetin inhibits differentiation of human adipose The results indicates that rutin decreases the expression of
tissue-derived mesenchymal stem (hA-MSCs) cells to pread- key adipogenic transcription factors. Experimental animals
ipocytes, wherein it downregulates the mRNA levels of Wnt which received rutin gain less body weight and have lower
antagonist such as secreted frizzled-related protein 1 (Sfrp1) blood cholesterol [125]. However, rutin was shown to be
and dickkopf-1 (Dkk1). Furthermore, isorhamnetin stabi- slowly and poorly absorbed in human [126] as it has to be
lizes β-catenin which suggests Wnt signaling pathway as hydrolysed by the intestinal microflora. These findings may
the mechanism responsible for isorhamnetin anti-adipogenic limit the effectiveness of rutin as anti-adipogenic agent fol-
effect in mesenchymal stem cells [115]. Myricetin inhibits lowing dietary consumption.
hA-MSCs differentiation to preadipocytes and significantly Several mechanisms contribute to the anti-adipogenic
reduces Pparg, Cebpα, and Fabp gene expression [116]. effect of quercetin. Exposure of mouse preadipocytes to
Besides inhibiting mesenchymal stem cell differentiation, quercetin leads to activation of AMPKα and β1 and phos-
Wang et al. demonstrated the anti-adipogenic effect of myri- phorylation of their substrate, acetyl-CoA carboxylase. In
cetin on preadipocyte differentiation. Myricetin-treated 3T3- addition, quercetin reduces adipocyte differentiation by
L1 cells downregulates transcription factors such as Pparg, inhibiting clonal expansion during the early adipogenesis
Cebpα, Cebpβ, Lpl, Fabp4, Glut4, and Srebp-1c. Other anti- via suppression of cyclin A [127]. A recent study indicated
adipogenic targets of myricetin include inhibition of ERK that quercetin prevents differentiation of OP9 mouse stromal
and c-Jun N-terminal kinase (JNK) phosphorylation dur- cells into mature adipocytes through downregulation of adi-
ing the differentiation process [117]. Microarray analysis pogenic transcription factors, FABP4, LPL, and upregula-
revealed that kaemperol decreases expression of adipogenic tion of adipose triglyceride and hormone sensitive lipases
transcription factors and triglyceride synthesis-related genes [128]. Quercetin may reduce adipose tissue mass not only
and, conversely, increases gene involved in lipolysis [106]. by inhibiting adipogenesis, but this flavonol also induces
Many transcriptional factors such as C/EBPβ, KLF4, and apoptosis in mature adipocytes by modulating mitogen-
KLF5 are downregulated by kaempferol treatment, while activated protein (MAP) kinases, in particular ERKs and
negative regulators of adipogenesis such as KLF2 and Pref-1 JNK pathway [129].
are upregulated during the early adipogenesis [118]. As with
many flavonoids, the anti-adipogenic mechanisms of kaemp- Flavanones
ferol are several. Kaempferol also prevents adipocyte differ-
entiation by inhibiting cell-cycle progression via regulation Flavanones are a subclass of dietary flavonoids that are
of cyclins. In addition, kaempferol treatment during early found to be rich in citrus fruits. The major dietary flavanones
adipogenesis inhibits phosphorylation of AKT and mTOR are naringin and hesperidin [110]. Although naringin and
signaling pathways. Fisetin was reported to induce cell-cycle hesperidin have shown promising effects in preventing obe-
arrest in preadipocytes by suppressing cell-cycle regulatory sity, limited studies have been conducted to investigate the
proteins such as cyclin A, cyclin D1, and CDK4 expres- anti-adipogenic effect of these flavanones.
sion [119]. Nonetheless, another study reported that fisetin Hesperetin, an aglycone of hesperidin, inhibits adipo-
reduces adipogenesis by suppression of mTORC1 activity, genesis in hBM-MSCs by reducing resistin (Retn), Adipoq,
13
Fabp4, Pparg, Stat5a, Lpl, and tumor necrosis factor-alpha Recently, SIRTs, specifically SIRT1, have become a focus
(Tnf-α) expression, while increasing proapoptotic genes of intense anti-obesity research [134]. The NAD+-depend-
such as Bcl and Bax in preadipocytes. This study suggests ent deacetylase SIRT1 has been shown to maintain proper
inhibition of adipocyte differentiation in hBM-MSCs and metabolic functions in many tissues to protect against obe-
induction of apoptosis in preadipocytes responsible for the sity [84]. As a matter of fact, SIRT1 inhibits adipogenesis
anti-adipogenic effect of hesperetin [130]. by repressing the transcriptional activity of PPARG [85].
Furthermore, mice with adipose tissue-specific SIRT1 dele-
tion exhibit greater adiposity and metabolic dysregulation,
Isoflavones including insulin resistance [135]. Other study investigated
the role of SIRT1 in curbing adipocyte hyperplasia; SIRT1
Dietary isoflavones are present in legumes, soy bean, and knockdown results in hyperplastic, small, and inflamed adi-
soy foods. As with many natural products, isoflavones such pocytes that appear to be dysfunctional metabolically and
as genistein and daidzein can target more than one pathways physiologically [136]. This study demonstrated that reduced
in the development of adipocytes. Cultured human adipose- levels of SIRT1 cause c-Myc to become hyperacetylated,
derived mesenchymal cells (hAD-MSCs) treated with gen- which leads to higher preadipocyte proliferation potential
istein or daidzein maintain their fibroblast-like appearance and enhanced adipocyte mitotic clonal expansion during
and express Oct-4, the stem cell marker indicating the dif- differentiation, which eventually results in dysfunctional
ferentiation of these cells into preadipocytes is interrupted. hyperplastic adipocytes. Indeed, SIRT1 levels are reduced
Once the cells become committed to adipose lineage, genin mice-fed high fat diet which triggers inflammation-
istein demonstrates anti-adipogenic effect by inhibition of induced cleavage and inactivation of SIRT1 [135]. In this
Pparg, Srebp-1c, and Glut 4 during intermediate phase of context, some of the anti-adipogenic effects of flavonoids
the adipogenesis program. Microarray result indicated that mentioned above may very well be due to their actions on
activation of Wnt pathway through estrogen receptor (ER)- SIRT1; quercetin and apigenin have been shown to increase
dependent pathways including ERK/JNK signaling and LEF/ NAD + levels which leads to activation of SIRT1 [137]. It
TCF4 co-activators are amongst the mechanisms underlying has been reported that resveratrol inhibits human preadipo-
the anti-adipogenic effect of genistein [131]. Recent studies cyte proliferation and adipogenesis in a SIRT1-dependent
have shown that hypoxic suppressions of adipocyte differen- manner [116]. Fisetin suppresses the early stages of adipo-
tiation are associated with AMPK activation which, in turn, genesis through SIRT1-mediated deacetylation of PPARγ
can impair mitotic clonal expansion during the early adi- and FoxO1, and enhances the association of SIRT1 with the
pogenesis. In this context, genistein has been demonstrated PPARγ promoter, leading to suppression of PPARγ tran-
to induce reactive oxygen species (ROS), which eventually scriptional activity [117].
leads to activation of AMPK and inhibition of mitotic clonal Collectively, flavonoids exert their beneficial effects
expansion. Furthermore, genistein was shown to activate against adipogenesis through multiple pathways (Table 2).
AMPK comparable to 5-amino-imidazole-4-carboxamide Although these findings are encouraging, most of their anti-
riboside (AICAR), a known activator of AMPK. Both gen- adipogenic effects are identified from cellular models of adi-
istein and daidzein also stimulate lipolysis [131]. Another pogenesis and remains to be validated in vivo or in human
study investigated the underlying mechanisms responsible cells. We must also keep in mind that much of these data
for the anti-adipogenic effect of genistein. Genestein has are based on rodent models which cannot always be directly
been demonstrated to stimulate lipolysis by preventing the extrapolated to clinical effects. However, such studies elu-
inhibitory effect of dexamethasone on eNOS expression cidate different molecular mechanisms by which flavonoids,
and NO release in 3T3-L1 cells. In addition, pretreatment either as individual treatments or in combination, might be
of preadipocytes with genistein has been reported to inhibit effective in prevention of adipocyte differentiation and ulti-
fatty acid synthase and suppress p38; expression of fatty acid mately obesity.
synthase is associated with activation of p38 [119]. Indeed,
phosphorylation of p38 mitogen-activated protein kinase is
required for adipocyte differentiation during the early adipo- Final remarks and conclusion
genesis, wherein treatment of preadipocytes with p38 inhibi-
tors suppressed adipogenesis [120]. Genistein also affects Prolonged excessive energy intake without an increase in
other pathway during adipocyte development; this flavonoid energy expenditure promotes the increase in adipocyte size
inhibits janus-activated kinase (JAK) 2 to attenuate the effect and number. Hyperplasia is triggered by a network of signal-
of growth hormones in promoting adipogenesis [121]. In ing factors that induce conversion of MSCs to preadipocytes
addition, genistein was shown to suppress adipogenesis by which then differentiate into mature adipocytes. Interrupting
induction of apoptosis in mature adipocytes [132, 133]. adipogenesis at any stage of adipocyte differentiation may
13
Table 2 List of flavonoids and their underlying mechanisms of action in adipogenesis
Flavonoids Stages of adipogenesis Effect Pathways/target molecules Experimental model and dose Comments References
applied
Anthocyanidins
Cyanidin Terminal differentiation Anti-adipogenic Upregulation of ChREBP and Preadipocytes obtained from Reduces adipogenesis via [93]
interfering with the extracel- subcutaneous and visceral interfering with extracel-
lular matrix human adipose explant tissue lular matrix and decreasing
ChREBP expression level

Cyanidin-3-O-glucoside Terminal differentiation Proadipogenic Upregulation of Pparg and 3T3-L1 cells (20 and Increases Pparg and Cebpα [95]
Cebpα 100 µM)/db/db mice (black expression, adiponectin
soy bean extract 30 mg/kg, secretion and activates insu-
orally) lin signaling cascade
Determination Anti-adipogenic Activation of Wnt pathway C3H10T1/2 cells (black rice Inhibits differentiation of [138]
extract 10, 20, 40, and 80 µg/ mesenchymal cells to
ml)/HFD mice (black rice preadipocytes and induces
extract, 100 mg/kg, orally) Wnt-specific target genes
such as Axin2, Wisp2, and
Cyclin d1
Terminal differentiation Anti-adipogenic Suppression of PPARG 3T3-L1 cells (black soybean Reduces lipid accumulation [94]
extract 12.5 and 50 µg/ml) and suppresses PPARG
expression
Delphinidin-3-O-glucoside Terminal differentiation Anti-adipogenic Suppression of PPARG 3T3-L1 cells (black soybean Reduces lipid accumulation [94]
extract 12.5 and 50 µg/ml) and suppresses PPARG
expression
Peonidin-3-O-glucoside Determination Anti-adipogenic Activation of Wnt pathway C3H10T1/2 cells (black rice Inhibits differentiation of [138]
extract 10, 20, 40, and 80 µg/ mesenchymal cells to
ml)/HFD mice (black rice preadipocytes and induces
extract, 100 mg/kg, orally) Wnt-specific target genes
such as Axin2, Wisp2, and
Cyclin D1
Flavones
Apigenin Clonal expansion Anti-adipogenic Inhibition of mitotic clonal 3T3-L1 cells (30 and 70 µM) Inhibits clonal expansion, [107]
expansion and cell-cycle arrests cell cycle at the G
0/G1
arrest phase and decreases PPARG
and C/EBPβ levels
Terminal differentiation Anti-adipogenic Activation of AMPK 3T3-L1 cells (10, 50 µM) Induces activation of AMPK [97]
and decreases expression
of adipogenic and lipolytic
genes
Luteolin Terminal differentiation Anti-adipogenic Inhibition of the transactiva- 3T3-L1 cells Attenuates PPARG and C/ [108]
tion of PPARG EBPα expression
Baicalein Clonal expansion Anti-adipogenic Suppression of Akt-C/EBPα- 3T3-L1 cells (50 µM) Decreases the intracellular [133]
GLUT4 signaling lipid accumulation by down-
regulation of glucose uptake
via repression of Akt-C/
13
EBPα-GLUT4 signaling

Table 2 (continued)
applied
13
Flavan-3-ols
Catechin Terminal differentiation Anti-adipogenic Suppression of PPARG2, C/ 3T3-L1 cells (50, 75, 100 µM) Inhibits adipogenesis via [111, 139]
EBPα& GLUT4 3T3-L1 cells (30 µM) suppression of PPARG2, C/
EBPα, and GLUT4
(−)-Catechin Determination Proadipogenic Upregulation of Pparg hBM-MSCs (1 and 100 µM) Upregulates the mRNA levels [105]
of adipogenic markers, such
as Adipoq, Pparg, Fabp4,
and Lpl in hBM-MSCs
(−)-Epigallocatechin gallate Terminal differentiation Proadipogenic Upregulation of Pparg and 3T3-L1 cells (0.5, 5, or 10 µM) Increases expression of [104]
Cebps Pparg1, Pparg2, and Cebps
(−)Epigallocatechin gallate Terminal differentiation Anti-adipogenic Activation of Wnt/β-catenin 3T3-L1 cells (100, 150, Reduces expression of [112]
pathway 200 µM) adipogenic markers such as
PPARG, C/EBPα, FABP4
and fatty acid synthase while
increases β-catenin in the
nucleus
Terminal differentiation Anti-adipogenic Apoptosis 3T3-L1 cells (50–200 µM) Increases apoptosis in mature [113]
adipocytes without affecting
viability of preadipocytes
Flavonols
Fisetin Terminal differentiation Anti-adipogenic Inhibition of mTORC1 signal- 3T3-L1 cells (50 µM) /HFD Reduces adipogenesis by [140]
ing mice (HFD supplemented suppression of mTORC1
with 0.2% or 0.5% (w/w) activity
fisetin)
Clonal expansion Anti-adipogenic Inhibition of mitotic clonal 3T3-L1 cells (10, 30 µM) Suppresses cell cycle regula- [141]
expansion tory proteins such as cyclin
A, cyclin D1 and CDK4
expression and inhibits cell
proliferation
Terminal differentiation Anti-adipogenic Inhibition of mTOR-C/EBPα 3T3-L1 cells (10 µM) Downregulates Pparg and [142]
Signaling Cebpαexpression during
adipogenesis
Isorhamnetin Terminal differentiation Anti-adipogenic Suppression of Pparg 3T3-L1 cells (50 µM) Reduces Pparg and Cebpα [114]
expression. However Cebpβ
and Cebpδ expression
remains unchanged
Determination/terminal dif- Anti-adipogenic Stabilization of β-catenin hA-MSCs/3T3-L1 cells (1, Inhibits Wnt receptor and co- [115]
ferentiation protein 25 µM) receptor genes expression,
increases β-catenin, but no
effect on β-catenin mRNA
levels
applied
Kaempferol Clonal expansion Anti-adipogenic Inhibition of cell-cycle pro- 3T3-L1 cells (30 µM)/zebra Inhibits cell-cycle progression [118]
gression, AKT and mTOR fish (5, 10, 20 µM) via regulation of cyclins. In
signaling pathway addition, inhibits phos-
phorylation of AKT and
mTOR signaling pathway.
Many transcriptional factors

such as C/EBPβ, KLF4 and
KLF5 are downregulated,
while nKLF2 and Pref-1 are
upregulated
Terminal differentiation Anti-adipogenic Suppression of Pparg 3T3-L1 cells (40, 80 µM) Downregulates expression [106, 143]
of Pparg, Cebpβ, Srebp1,
Rxrβ, Lxrβ, Rorα and also
genes involved in triglyceride
biosynthesis such as Gpd1,
Agpat2, Dgat2
Myricetin Terminal differentiation Anti-adipogenic Suppression of Pparg 3T3-L1 cells (100 µM) Reduces expression of Cebpα, [144]
Pparg, Cebpβ, Sreb1c,
Fabp4, Lpl and Glut4. Also,
inhibits phosphorylation of
ERK and JNK during differ-
entiation of adipocytes
Determination Anti-adipogenic Suppression of Pparg hA-MSCs (30 µM) Reduces expression of Cebpα, [145]
Pparg, Lpl and Fabp
Rhamnetin Clonal expansion/terminal dif- Anti-adipogenic Inhibition of mitotic clonal 3T3-L1 cells Decreases expression of [122]
ferentiation expansion, and suppression Pparg,Cebpα, and perilipin
of Pparg (Plin) Also completely inhib-
its triglyceride biosynthesis
and clonal expansion
Rutin Terminal differentiation Anti-adipogenic Suppression of Pparg and 3T3-L1 cells (0.25, 0.5, Reduces mRNA expression of [125, 146]
Cebpα 1.0 mg/ml)/3T3-L1 cells (10, Pparg and Cebpα
30, 100 µM)/HFD mice (25,
50 mg/kg, orally)
13

applied
13
Quercetin Terminal differentiation Anti-adipogenic Activation of AMPK pathway 3T3-L1 cells (10, 50, 100 µM) Stimulates activation of [129]
AMPK pathway and phos-
phorylation of acetyl-CoA
carboxylase
Clonal expantion Anti-adipogenic Inhibition of mitotic clonal 3T3-L1 cells (50, 100 µM) Decreases adipocyte differen- [147]
expansion tiation by inhibition of clonal
expansion during early
adipogenesis via suppression
of cyclin A
Determination Anti-adipogenic Suppression of PPARG, C/ OP9 mouse stromal cells Downregulates mRNA and [148]
EBPα and SREBP-1c (50 µM) protein expression of C/
EBPα, PPARG, SREBP-1c,
FAS, FABP4 and mRNA
level of Hsl and Lpl
Flavanones
Hesperetin Determination Anti-adipogenic Apoptosis hBM-MSCs (10, 20, 40, 80, Decreases expression of Adi- [130]
160 µM) poq, Retn, Fabp4, Pparg, Lpl
and Tnf-α, while upregulates
proapoptotic genes
Naringenin Terminal differentiation Anti-adipogenic Suppression of PPARG 3T3-L1 cells (25, 50 µg/ml) Reduces expression of FABP4, [149]
PPARG, STAT5A, and
adiponectin
Isoflavones
Biochanin A Determination Anti-adipogenic Suppression of Pparg hA-MSCs (0.1, 0.3, and 1 µM) Decreases Pparg, Leptin [150]
(Lep), osteopontin (Opn)and
Lpl expression
Daidzein Determination Anti-adipogenic Stimulation of lipolysis hA-MSCs (0.1–100 µM) Stimulates lipolysis by cAMP- [131]
dependent protein kinase-
mediated hormone sensitive
lipase
Formononetin Terminal differentiation Proadipogenic Upregulation of PPARG C3H10T1/2 cells (1–20 µM) Upregulates PPARG and its [151]
target genes such as Fabp4
and Glut4
Terminal differentiation Proadipogenic Upregulation of PPARG 3T3-L1 cells (1–20 µM) Upregulates PPARG and its [152]
target genes such as Fabp4
and Glut4
serve as potential therapeutic strategy against adipogenesis

References and obesity. In this context, dietary flavonoids have become
[153]
[119]
Induces ROS, activates AMPK [154]
[131]
the subject of increasing scientific interest due to their effects
on adipogenesis. The anti-adipogenic effects of flavonoids
expansion and suppression of

are mainly via their effect on a number of molecular tar-
Activates Wnt/β-catenin path-

inhibits phosphorylation of
Pparg, Srebp-1c and Glut4

inhibition of mitotic clonal
way, inhibits expression of

and inhibits mitotic clonal
Increases eNOS expression,
JAK2 and decreases FAS

gets and regulation of several pathways such as induction of
Blocks adipogenesis by
apoptosis [123], suppression of key adipogenic transcription

PPARG expression
factors [94, 95, 114, 144], activation of AMPK [97, 129],

and Wnt [115, 138] pathways, inhibition of clonal expansion
expression [147, 153, 155], cell-cycle arrest, and modulation of insulin
expansion
Comments
signaling cascade [118], suggesting flavonoids as effective

inhibitors of adipogenesis during determination and terminal
differentiation stages.
Although these data are encouraging, further investiga-
Experimental model and dose
3T3-L1 cells (5, 50, 100 µM)
tion is essential to gain insight into the molecular mecha-

hA-MSCs (0.1–100 µM)
nisms that connect extranuclear and nuclear mediators of

3T3-L1 cells (100 µM)
3T3-L1 cells (50 µM)
adipogenesis. Even though most of the studies have shown

that flavonoids suppress the key adipogenic regulators such
as PPARG and C/EBPα, the upstream mechanisms which
led to suppression of these master regulators of adipogenesis
applied
are not fully investigated. In addition, the effect of flavonoids

in areas such as microRNAs and circadian clock need to be
more explored.
via ERs-dependent pathway
inhibition of clonal expan-
induction of apoptosis and
Anti-adipogenic Activation of Wnt signaling

Anti-adipogenic Inhibition of mitotic clonal
Strategies to develop flavonoids as treatment or as sup-

Pathways/target molecules
Anti-adipogenic Activation of AMPK and

expansion and PPARG
plementary treatment of obesity will have to consider the

Anti-adipogenic Suppression of MAPK
pharmacokinetic aspects of the molecules, as well. We

have to bear in mind that the in vitro evidence of flavo-
expression
noids in suppressing adipogenesis might be somewhat of

limited impact due to the fact that in vivo flavonoids are
sion
extensively metabolized to molecules with different struc-

tures and activities and, therefore, may preclude their use in
humans [127]. Flavonoids are substrates for conjugating and
hydrolyzing enzymes in the small intestine, liver, and colon.
Conjugation of flavonoids first occurs in the small intestine
Effect
followed by the liver where they are further metabolized and

the produced glucuronides and sulfate derivatives facilitate
Clonal expansion/terminal dif-
their excretion via urine and bile. The compounds that are
not absorbed in the intestine will reach the colon and be
Terminal differentiation
subjected to structural modifications by colonic microflora.

Stages of adipogenesis
The flavonoid glucuronides that re-enter the enterohepatic

Clonal expansion
circulation through bile excretion are hydrolyzed by the

Determination
ferentiation
gut microbiota to aglycones that can further be catabolized

to low-molecular-weight compounds that can readily be
absorbed [128]. This bacterial conversion of flavonoids may
have potential health consequences for the host. Therefore,
the differences in intestinal microbiota composition among
different species may result in different profiles of flavonoid
metabolites with different bioactivity [156]. This emphasizes
the importance of studying the pharmacokinetic profile of

the various flavonoids in human subjects.
Genistein
Flavonoids
It is also important to determine the amount of flavonoids

or bioactive compounds in foods or dietary supplement as
well as their bioavailability. Despite the health benefits of
13
flavonoids, the bioavailability of flavonoids is generally low of Education, Malaysia, and the University of Malaya Postgraduate
and can vary drastically among different flavonoid classes Research Fund PG010-2016A.
as well as among compounds in a particular class. Flavo-
noids with complex structures and larger molecular weights Compliance with ethical standards
may even have lower bioavailability [128]. In human diet,
Conflict of interest The authors have declared that no competing inter-
the concentration of flavonoids may be too low to generate est exists.
adequate efficacy for their health benefits including anti-
adipogenic properties. During the past few decades, dietary Open Access This article is distributed under the terms of the Crea-
supplements have become increasingly popular as an alter- tive Commons Attribution 4.0 International License (http://creativeco
native source to flavonoid-rich fruits and vegetables [157]. mmons.org/licenses/by/4.0/), which permits unrestricted use, distribu-
tion, and reproduction in any medium, provided you give appropriate
Even though consuming supplements can ensure us that we credit to the original author(s) and the source, provide a link to the
are getting our daily dose of flavonoids, toxicity issues as Creative Commons license, and indicate if changes were made.
well as nutrient–drug interactions should be the subject of
concern. Furthermore, the health promoting effects of some
of dietary flavonoids are due to the synergistic effects of
other flavonoids or compounds present in the food. There- References
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Differential Effects of Dietary Flavonoids On Adipogenesis

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European Journal of Nutrition

Differential effects of dietary flavonoids on adipogenesis

Received: 4 October 2017 / Accepted: 9 March 2018

Keywords Adipogenesis · Flavonoids · Obesity · Hyperplasia · Adipocyte

Abbreviations C/EBP CCAT/enhancer-binding protein

adipogenesis by C/EBPβ and C/EBPδ activates the Pparg2 Cell‑cycle proteins

Role of microRNAs in adipogenesis

Table 1 Flavonoid subclasses and their dietary sources

Anthocyanidins 3-Hydroxy Cherry, berries, and red wine Cyanidin C15H11O6+

Flavonols wherein the flavonol inhibits mTOR phosphorylation and

ChREBP expression level

Many transcriptional factors

serve as potential therapeutic strategy against adipogenesis

Induces ROS, activates AMPK [154]

expansion and suppression of

Activates Wnt/β-catenin path-

Pparg, Srebp-1c and Glut4

way, inhibits expression of

JAK2 and decreases FAS

apoptosis [123], suppression of key adipogenic transcription

factors [94, 95, 114, 144], activation of AMPK [97, 129],

signaling cascade [118], suggesting flavonoids as effective

3T3-L1 cells (5, 50, 100 µM)

tion is essential to gain insight into the molecular mecha-

nisms that connect extranuclear and nuclear mediators of

adipogenesis. Even though most of the studies have shown

are not fully investigated. In addition, the effect of flavonoids

Anti-adipogenic Activation of Wnt signaling

Strategies to develop flavonoids as treatment or as sup-

Anti-adipogenic Activation of AMPK and

plementary treatment of obesity will have to consider the

pharmacokinetic aspects of the molecules, as well. We

noids in suppressing adipogenesis might be somewhat of

extensively metabolized to molecules with different struc-

followed by the liver where they are further metabolized and

subjected to structural modifications by colonic microflora.

The flavonoid glucuronides that re-enter the enterohepatic

circulation through bile excretion are hydrolyzed by the

gut microbiota to aglycones that can further be catabolized

the importance of studying the pharmacokinetic profile of

It is also important to determine the amount of flavonoids

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Abbreviations C/EBP CCAT/enhancer-binding protein

Table 1 Flavonoid subclasses and their dietary sources