GPR120: a critical role in adipogenesis, inflammation, and energy metabolism in adipose tissue

Abstract

It is well known that adipose tissue has a critical role in the development of obesity and metabolic diseases and that adipose tissue acts as an endocrine organ to regulate lipid and glucose metabolism. Accumulating in the adipose tissue, fatty acids serve as a primary source of essential nutrients and act on intracellular and cell surface receptors to regulate biological events. G protein-coupled receptor 120 (GPR120) represents a promising target for the treatment of obesity-related metabolic disorders for its involvement in the regulation of adipogenesis, inflammation, glucose uptake, and insulin resistance. In this review, we summarize recent studies and advances regarding the systemic role of GPR120 in adipose tissue, including both white and brown adipocytes. We offer a new perspective by comparing the different roles in a variety of homeostatic processes from adipogenic development to adipocyte metabolism, and we also discuss the effects of natural and synthetic agonists that may be potential agents for the treatment of metabolic diseases.

Full text

Vol.:(0123456789)
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Cell. Mol. Life Sci.
DOI 10.1007/s00018-017-2492-2
REVIEW
GPR120: acritical role inadipogenesis, inflammation, andenergy
metabolism inadipose tissue
TongxingSong1,2· YangYang1,2· YuanfeiZhou1,2· HongkuiWei1,2· JianPeng1,2
Received: 1 November 2016 / Revised: 17 February 2017 / Accepted: 21 February 2017
© Springer International Publishing 2017
Introduction
The global incidence of obesity and type 2 diabetes has
increased over the last three decades. It is well confirmed
that adipose tissues which consist of the white adipose tis-
sues and the brown adipocytes greatly contribute to obe-
sity-associated disease. As the main reservoir to store fatty
acids contain lipid droplets as a type of energy, the white
adipose tissues are to protect and insulate the body at the
physical level [1]. Brown adipocytes, on the other hand,
show high thermogenic capacity and dissipate the stored
energy in the form of heat [2, 3]. Being a remarkably com-
plex organ with significant effects on physiology, adipose
tissue also plays a pivotal role as an endocrine organ in glu-
cose metabolism and immune function through secretion
of a vast range of regulatory factors [4, 5]. Studies on the
developmental and functional roles of adipose tissue have
widely expanded after the 1990s [3]. This paper examines
the functions and regulatory mechanisms of adipose tissue
in the hope of helping to find an efficient way to decrease
the rate of obesity and metabolic diseases.
Free-fatty acids are the basic components of essential
nutrients and serve as signalling molecules that modulate
energy homeostasis [6]. In particular, beneficial effects of
n-3 polyunsaturated fatty acids (n-3 PUFAs) are clearly
observed in anti-inflammatory processes, lipid metabolism,
and glucose homeostasis, as well as in insulin-sensitizing
effects [7, 8]. Notably, the n-3 PUFAs act as ligands of G
protein-coupled receptor 120 (GPR120) [9]. A number of
studies done in the last decade have shown that GPR120
is implicated in crucial homeostatic processes, including
adipogenesis, anti-inflammatory processes, glucose uptake,
and insulin sensitivity, as well as the secretion of hormones,
prompting recent studies to thrust GPR120 into the realm
of drug discovery [10–12]. Many excellent recent reviews
Abstract It is well known that adipose tissue has a criti-
cal role in the development of obesity and metabolic dis-
eases and that adipose tissue acts as an endocrine organ to
regulate lipid and glucose metabolism. Accumulating in
the adipose tissue, fatty acids serve as a primary source of
essential nutrients and act on intracellular and cell surface
receptors to regulate biological events. G protein-coupled
receptor 120 (GPR120) represents a promising target for
the treatment of obesity-related metabolic disorders for its
involvement in the regulation of adipogenesis, inflamma-
tion, glucose uptake, and insulin resistance. In this review,
we summarize recent studies and advances regarding the
systemic role of GPR120 in adipose tissue, including both
white and brown adipocytes. We offer a new perspective
by comparing the different roles in a variety of homeo-
static processes from adipogenic development to adipocyte
metabolism, and we also discuss the effects of natural and
synthetic agonists that may be potential agents for the treat-
ment of metabolic diseases.
Keywords GPR120· Fatty acids· White adipose tissue·
Brown adipose tissue· Adipogenesis· Glucose uptake·
Metabolic homeostasis
Cellular and Molecular LifeSciences
* Hongkui Wei
weihongkui@mail.hzau.edu.cn
* Jian Peng
pengjian@mail.hzau.edu.cn
1 Department ofAnimal Nutrition andFeed Science, College
ofAnimal Science andTechnology, Huazhong Agricultural
University, Wuhan430070, China
2 The Cooperative Innovation Center forSustainable Pig
Production, Wuhan430070, China

T.Song et al.
1 3
have provided insights into the biological and physiologi-
cal roles of GPR120 [13–16]. However, the detailed role of
GPR120 in adipose tissue has not been well demonstrated
yet.
Hence, the primary goal of this review is to summarize
the most recent and seminal studies that have contributed
to our understanding of the function and regulation of
GPR120, especially in adipose tissue. We first describe the
biological characteristics of GPR120. We then expound on
the inconsistencies and certainties that have been presented
due to advances in our knowledge of the function of adi-
pose tissue. Finally, we discuss the natural and synthetic
agonists that are known to regulate the activity of GPR120
to resist obesity and diabetes.
Biological characteristics ofGPR120
The novel fatty acid receptor GPR120, also known as free-
fatty acid receptor 4 (FFAR4), is a seven transmembrane
receptor and was deorphanised in 2005 when long chain
fatty acids were shown to respond well to it [9, 17]. Numer-
ous studies have reported the characteristics of GPR120
from specific species [18–20]. The human GPR120 exists
as two splice variants, and the short variant has a structure
similar to that of the rodent and monkey receptor. Our pre-
vious work reported the three alternatively spliced tran-
scripts of pigs, and the wild-type variant is well matched
with the human short isoform [21]. As a GPCR, GPR120
shares the ability to activate heterotrimeric G proteins and
induces downstream second messenger pathways in the
context of ligand treatment. Hirasawa et al. reported that
the activation of GPR120 by fatty acids augment intracel-
lular calcium (Ca2+) and extracellular signal-regulated
kinase 1/2 (ERK1/2) without affecting the level of cyclic
AMP [17]. Furthermore, Oh et al. showed that GPR120
can effectively respond to n-3 fatty acids by activating
Gαq/11 in adipocytes and by recruiting cytosolic β-arrestin
2 to the cell membrane in macrophages [11]. Hence, we
infer that the various events induced by the two pathways
may involve one of the two coupled proteins, Gαq/11 and
β-arrestin 2. However, other biological roles of GPR120
remain to be explored.
GPR120 has been shown in recent studies to be impli-
cated in diverse physiological homeostasis processes,
including release of gut peptides, insulin sensitization, anti-
inflammatory processes, and regulation of appetite [11, 17,
22]. Consistent with the pleiotropic functions in biological
events, stronger expression of GPR120 is observed in tis-
sues, such as the small intestine, spleen, adipose tissue, and
taste buds. Despite the differing expression pattern from
varied species, a similarly high level of GPR120 is found to
be present in the same tissues, such as the small intestine,
which may reflect the concordant functions, for example,
glucagon-like peptide 1 (GLP-1) secretion [17]. It is worth
noting that GPR120 is found to be expressed endogenously
both in adipocytes and in adipose tissue but not in preadi-
pocytes [12], implying that the role of GPR120 may closely
be related to the development and metabolism of adipose
tissue. This special distribution might reflect the crucial
functions of GPR120.
Physiological functions ofGPR120 inadipose
tissue
The role ofGPR120 inadipose development
The expression ofGPR120 inadipose tissue
A growing number of evidences point to the key role of
GPR120 in adipose development, including both white and
brown adipocytes. As mentioned above, GPR120 cannot be
detected in preadipocytes, showing abundant expression in
mature 3T3-L1 cells (a recognized cell line for white adi-
pocyte research [23]) and human white adipocytes. The
expression of GPR120 increases with MDI treatment (the
differentiation medium containing isobutylmethylxanthine,
dexamethasone, and insulin), a typical adipogenic induc-
tion cocktail for white adipocytes in vitro [23], indicat-
ing that this receptor is probably implicated in adipogenic
differentiation. Using siRNA, Gotoh and his colleagues
reported that GPR120 knockdown inhibited adipogenesis
[12]. Moreover, the adipogenesis process is suppressed in
GPR120−/− mouse embryonic fibroblast-derived (MEF)
adipocytes [10]. Our study also showed that the adipogenic
ability was significantly inhibited in lentivirus-mediated
shGPR120 transfected 3T3-L1 cells [24]. Therefore, we
assume that GPR120 might act as an adipogenic receptor
[25].
An earlier study demonstrated that high expression
of GPR120 was detected in four types of adipose tissues,
including subcutaneous, perinephric, mesenteric, and
epididymis tissue collected from high-fat diet-fed mice
[12]. Experiments in humans showed a similar pattern
revealing a significantly higher expression of GPR120 in
obese individuals than in lean individuals [10]. Another
report, likewise, exhibited a high expression of GPR120 in
the brown adipose tissue (BAT) and the inducement of pro-
tein level in the BAT after cold exposure. It has also been
reported that the activation of GPR120 can promote the
browning of white fat in mice [26]. Thus, it is safe to spec-
ulate that the expression of the receptor may be induced
by high lipid intake in rodents and humans. Although the
exhaustive role of GPR120 is still unclear, its indispensable
function in adipogenesis is fairly certain.

GPR120: acritical role inadipogenesis, inflammation, andenergy metabolism inadipose tissue
1 3
The effects ofGPR120 agonists inadipogenesis
As is well known, with the activation of ligand, the GPCR
couples with G proteins and β-arrestins to transduce a sig-
nal through a downstream pathway, regulating physiologi-
cal events. GPR120 showed a strong response to medium
and long chain polyunsaturated fatty acids (LCPUFA),
especially n-3 PUFAs. Our previous studies showed that
α-linolenic acids (ALA), rather than docosahexaenoic acid
(DHA), improved adipogenesis in a GPR120-dependent
pathway in 3T3L1 cells (Fig.1) [24]. However, when using
a luciferase reporter assay, we found that both DHA and
ALA can effectively activate GPR120 [21]. Despite the
finding that LCPUFA act as natural ligands of GPR120, the
effects of LCPUFA on modulation of 3T3-L1 adipogenic
differentiation are inconclusive.
DHA, similar to other fatty acids, has multifunctional
roles: it may accelerate, inhibit, or do not influence adipo-
genic processes. However, ALA was found to be more sen-
sitive to this receptor in adipogenesis as well as other events
[17]. Therefore, we chose the selective synthetic agonist
TUG-891 to clarify the downstream signalling mediated by
GPR120 and, to some extent, avoiding potential GPR120-
independent mechanisms [27]. Our previous study showed
that pig GPR120 was well activated by TUG-891, and the
stromal vascular fraction cells from porcine adipose tissue,
as well as 3T3-L1 preadipocytes, were promoted through
adipogenesis [24]. Gao etal. reported that TUG-891, at a
low concentration range, functions as a positive enhancer
in the adipogenic process, and higher concentrations induce
the opposite developmental direction, osteogenesis [28].
The different cell types and characteristics and the distinct
expression of GPR120 in the two cells may be the cause of
the diverse mechanisms. On the other hand, GPR120 which
can be definitely stimulated by GW9508, another selective
agonist for GPR120 may induce BAT activity as well as the
n-3 PUFAs [26, 29]. Both the eicosapentaenoic acid (EPA)
and GW9508 were found to have accelerated the adipo-
genesis of brown and beige adipocyte and upregulated
the expression pf key thermogenic genes (Fig.2). On the
whole, GPR120 activation may induce adipogenesis in two
different types of adipocytes, which implies the distinct
roles of this receptor in the two biological events.
What are thecellular effectors ofGPR120 inadipogenesis
During differentiation of 3T3-L1 cells, mRNA expres-
sion of GPR120 closely coincides with the master adipo-
genic regulator, peroxisome proliferator-activated receptor
γ (PPARγ). Interestingly, GPR120 knockdown was found
to reduce the mRNA level of PPARγ and the adipogenic
marker gene, fatty acid binding protein 4 (FABP4) [12].
Moreover, adipogenesis-related genes, including PPARγ
and FABP4, are decreased in adipocytes induced from
GPR120−/− MEF cells [10]. On the other hand, it has been
demonstrated that the PPARγ agonist troglitazone increased
the mRNA expression of GPR120 [12]. These results may
imply that PPARγ is regulated by GPR120 or that GPR120
can interact with PPARγ during adipocyte differentiation.
How is the signal transduced from the membrane recep-
tor to the nuclear receptor? It should be noted that both
GPR120 and PPARγ have similar ligand binding pock-
ets and both bind with DHA [30–32]. DHA and ALA are
shown as PPARγ ligands that activate the receptor. In addi-
tion, they can also combine with GPR120 [24]. Therefore,
a selective agonist is necessary for activation of PPARγ.
Although TUG-891 is a potent agonist for pig and mouse
GPR120, less evidence is available regarding the function
of TUG-891 on PPARγ. Using a luciferase reporter system,
Song et al. reported that TUG-891 could activate PPARγ
in a GPR120-dependent manner [24]. This illustrates that
with TUG-891 treatment, activated GPR120 may transduce
the intracellular signal into the nucleus to activate PPARγ.
We speculate that the GPR120-PPARγ pathway may be one
of the main regulation mechanisms to modulate adipogen-
esis in 3T3L1 cells (as shown is Fig. 1). However, using
GW9662 (an inhibitor of PPARγ) in differentiating brown
adipocyte did not dramatically alter the effects of EPA or
Fig. 1 Schematic diagram
of adipogenesis mediated by
GPR120 activation in 3T3L1
cells. With the treatment of n-3
PUFAs or GPR120 synthetic
agonist, TUG-891, GPR120
promotes adipogenesis by acti-
vating PPARγ and elevating the
expression of key adipogenic
gene via [Ca2+]i and ERK1/2
signal pathway in 3T3L1 cells

T.Song et al.
1 3
GW9508 on the phenotype of differentiation, indicating
that PPARγ may be not essential for the EPA- or GW9508-
induced brown adipocyte differentiation in some extent,
and other key downstream regulators, such as uncoupling
protein-1 (UCP1), may play a role consistent with GPR120
in this event [26, 29]. All these suggest that the targets of
the white and brown fat adipogenesis induced by GPR120
are quite different and need to be well examined further.
The downstream signals mediated byGPR120
inadipogenesis
Moreover, the precise signalling mediated by GPR120 is
also worth studying. Numerous studies have shown that
GPR120 coupled with Gαq/11 induces an increase in
intracellular calcium concentration [Ca2+]i and phospho-
rylation of the ERK1/2 cascade [17, 27]. Several studies
have reported that both ERK1/2 and [Ca2+]i play a critical
role in adipogenesis. ERK1/2 facilitates the early stage of
adipogenesis, while this signal needs to be closed at later
stages, which suggests a multifunctional role for ERK1/2
[33, 34]. In addition, there is evidence suggesting that the
[Ca2+]i signal manifests to exert a biphasic function in adi-
pocyte differentiation both in mice and human preadipo-
cytes [35, 36]. In the first 2days of adipogenesis, increas-
ing [Ca2+]i levels suppress this progress but accelerate the
later maturation stage of adipogenic differentiation [35,
36]. The intracellular signal in adipogenesis mediated by
GPR120 remains largely unknown. As shown in Fig. 1,
[Ca2+]i and ERK1/2 may provide new insights to determine
the mechanism of GPR120 in adipogenesis. In 3T3-L1
preadipocytes, TUG-891 activates both of the signals. In
addition, combined treatment with TUG-891 and BAPTA-
AM (a Ca2+ chelator) or U0126 (ERK1/2 inhibitor) abol-
ished the adipogenesis process. Furthermore, PPARγ
mRNA and protein levels are also influenced by blocking
the two signals. This demonstrates that the [Ca2+]i-ERK1/2
pathway is involved in GPR120-induced processes and ulti-
mately targets PPARγ to affect adipogenesis [24]. This may
shed light on one of the possible intracellular pathways. In
BMMSCs, Gao etal. reported that 3days of treatment with
a low concentration of TUG-891 (0.5µM) promoted adipo-
genesis, shown both by the adipogenic phenotype and the
expression of PPARγ [28]. However, the ERK1/2 signal is
blocked in these events. Therefore, the precise underlying
mechanism may be different depending on the cell types
and treatment methods. Others have shown that phospho-
rylation of AKT (p-AKT) cannot be detected in white adi-
pose tissue separated from GPR120−/− mice [10]. Perhaps
p-AKT is also related to GPR120-mediated adipogenesis,
but this association has not been identified. Overall, the
question is how these mentioned signals can be transduced
Fig. 2 Schematic diagram of the role of GPR120 activation in adi-
pose tissues related to the metabolic homeostasis. With the treatment
of n-3 PUFAs or GPR120 synthetic agonists, GPR120 promotes adi-
pogenesis in both white and brown preadipocytes. In white adipose
tissue, GPR120 mediates anti-inflammation and insulin sensitization
effects and GPR120 activation also induces the browning of white
adipocytes. The pleiotropic functions of GPR120 in adipose tissue
will contribute to the whole-body metabolic homeostasis

GPR120: acritical role inadipogenesis, inflammation, andenergy metabolism inadipose tissue
1 3
into nuclear signals to activate PPARγ, and the answer
still needs to be clarified. Given the relationship between
GPR120 and PPARγ in adipogenesis, it will be interest-
ing to demonstrate whether the GPR120-PPARγ pathway
functions in white adipose metabolism and even in other
tissues. In comparison, the down signaling modulated by
GPR120 is somewhat complicated in the brown and beige
adipocytes. It seems that GPR120 activation upregulates
the microRNA 30b/microRNA 378 and the cyclic AMP
(cAMP), in turn, and both microRNAs and cAMP can
affect the level of GPR120 [26, 29].
Considering the especially high expression of GPR120
in adipocytes and adipose tissue, the precise mechanism of
GPR120 in both WAT and BAT is being explored. It is rea-
sonable to say that the role of GPR120 in adipogenesis is
clear, while the important functions in brown/beige adipo-
cytes adipogenesis still need to be clarified.
The metabolic regulation ofGPR120 inadipose tissue
Anti‑inflammatory effects
Obesity gives rise to chronic low-grade inflammation,
which can trigger insulin resistance and type 2 diabetes
[37]. White adipose tissue acts as an important endocrine
organ and releases numerous adipokines that can contrib-
ute to pro- or anti-inflammation states [38]. Adipose tissue
inflammation is a process characterized by an inflammatory
response mediated by adipose tissue macrophages [39].
There is increasing interest focused on the role of adipose
tissue macrophages (ATMs) in obesity and in ATM func-
tions in the inflammatory pathways activated in adipose
tissue, which change the characteristics of obesity in obese
individuals [40, 41]. Moreover, ATMs are highly responsi-
ble for the expression of tumour necrosis factor α (TNFα)
and interleukin-6 (IL-6), which can block normal activity
in adipocytes [42, 43]. Thus, ATMs provide a potential and
pivotal function in the metabolic role of adipose tissue.
Oh etal. analysed the ATMs from wild-type (WT) and
GPR120-deficient mice invivo. The HFD induced the total
number of F4/80 marked M1 macrophages separated from
adipose tissues [11]. In context of n-3 PUFA treatment, the
number of M1 macrophages decreased, while the number
of macrophage galactose-type C-type lectin 1 (MGL1)
marked M2 macrophages strikingly increased in the WT
mice but not in the GPR120-deficient mice [11]. Moreover,
GPR120 also accelerated the M2 macrophage polarization,
which facilitated the formation of an anti-inflammatory sta-
tus in adipose tissue [11]. In addition, adding n-3 PUFA to
the normal diet resulted in decreased macrophage chemo-
taxis capacity in a GPR120-dependent manner. Further-
more, using the synthetic GPR120 agonist cpdA, the posi-
tive effect of GPR120 in the ATMs was confirmed [44].
In view of the above studies, GPR120 functions as an n-3
PUFA sensor in adipose tissue that triggers beneficial anti-
inflammatory effects. In an invitro model, the mechanism
of the anti-inflammatory role has also been elucidated in
RAW 264.7 cells (a type of mouse macrophage). Ligand-
activated GPR120 binds to β-arrestin2, and the complex
interacts with transforming growth factor-β-activated
kinase binding protein 1 (TAB1), in turn, blocking down-
stream key pro-inflammatory signalling molecules, includ-
ing nuclear factor-κB (NFκB) and c-Jun N-terminal kinase
(JNK), and inhibiting inflammation [11]. Other studies
have shown different GPR120-dependent pathways that are
involved with cyclooxygenase 2 (COX-2) expression and
prostaglandin E2 (PGE2) synthesis [45, 46]. These data are
referred in another excellent review [13].
Some metabolins may influence the GPR120-dependent
β-arrestin2 involved in anti-inflammation. It is worth men-
tioning that hyperhomocysteinaemia (HHcy) inhibits insu-
lin sensitivity in adipose tissue and is considered a chronic
inflammatory state by the epidemiological literature [47].
HHcy, characterized by an abnormally high level of homo-
cysteine, acts as a pro-inflammatory factor to induce the
expression and secretion of resistin [48]. Recently, it has
been reported that in rat adipocytes, GPR120 activation
by GW9508 can reverse HHcy-induced insulin resistance
by inhibiting adipose inflammation rather than endoplas-
mic reticulum (ER) stress [49]. GPR120 prevents HHcy-
induced JNK activation and inflammation. Meanwhile, the
downstream signal β-arrestin2 mediated by GPR120 can be
repressed by homocysteine [50]. Thus, it may be interest-
ing to clarify the precise mechanism of the expression and
activation of GPR120-dependent β-arrestin2 involved in
anti-inflammation.
Moreover, it cannot be ignored that the WAT depots,
in the form of triglycerides (TG), store fatty acids derived
from diets, and endogenous synthesis [51]. The lipoly-
sis of TG provides the serum with varying chains FFAs
to influence the macrophage activity [52]. Several excel-
lent reviews focus on the variety of FFAs which modify
the macrophages and other inflammatory cells [52–54].
Recently, Rodriguez-Pacheco et al. have reported that
FFAs have different effects on the inflammatory profile
of the adipocytes from the visceral adipocytes tissue and
the pro-inflammatory effects of different fatty acids in the
GPR120 knockdown visceral adipocytes can be weakened
[55]. This is because GPR120 act partially as an inflamma-
tory mediator to regulate the inflammatory effects induced
by the FFAs [55]. In addition, different fatty acids show the
varying degrees of the promotion function on the expres-
sion of GPR120 in both nonobese and morbidly obese
subjects [56]. Perhaps, GPR120 in adipocytes tissues from
different location shows various roles which are based on
the character of the native adipocytes [57]. The observation

T.Song et al.
1 3
of Rodriguez-Pacheco etal. may need to be well dissected
further, especially invivo test [55].
In addition, during adipose tissue remodelling in obesity,
another key factor that we focus on is the role of hypoxia.
Although adipose tissue can recruit new blood vessels dur-
ing expansion, even elevating the oxygen tension in the fat
pads, hypoxia may develop [58]. Moreover, hypoxia-induc-
ible factor 1 (HIF-1) becomes activated in obese adipocytes
[59]. Vascular endothelial grow factor-A (VEGF-A) plays
a critical role in promoting local vascular development in
the growing adipose tissue [60]. Hansan et al. reported
that EPA could increase the release of VEGF-A through
GPR120-dependent and independent pathways in 3T3-
L1 adipocytes [61]. This suggests that the activation of
GPR120 could act in another role to partly promote angi-
ogenesis, which may have an anti-inflammatory func-
tion in adipose tissue [60]. Indeed, given the functions in
both adipocytes and macrophages in the adipose tissue, it
seems possible that GPR120 can act in an anti-diabetic role
through an anti-inflammatory effect in adipose tissue [11,
60]. Currently, several precise mechanisms regarding the
anti-inflammation function of GPR120 in adipose tissue are
being dissected, as well as the interactions among different
cell types [3].
Glucose uptake andenergy metabolism
Consistent with the basic function of fatty acids in energy
metabolism in adipose tissue, the fatty acids receptor,
GPR120, seems to have a pivotal role in regulating adi-
pose metabolism. As described before, GPR120 is found
to be highly expressed in adipocytes and adipose tissue.
With a high-fat diet (HFD) treatment, GPR120-deficient
mice show a notable decrease in adipogenic and lipo-
genic genes, while these genes increased in the liver [10].
Seminal work by Oh etal. has shown that GPR120 acti-
vated by n-3 PUFA and GW9508 leads to insulin sensiti-
zation in vivo and strongly alleviates glucose intolerance
in HFD-induced obesity [11]. In both 3T3-L1 adipocytes
and primary adipose tissue, activated GPR120 signifi-
cantly enhances the activation of the PI3K/Akt pathway,
triggering GLUT4 translocation to the cell membrane and
increasing glucose uptake in a manner dependent on cou-
pling to Gαq/11 not β-arrestin [11]. It is worth mentioning
that Gαq/11 and IRS1 are independent signals that activate
the PI3K-Akt-GLUT4 pathway [11]. One group also devel-
oped a type of GPR120 agonist, compound A (cpdA), that
responded well to insulin sensitivity and improved glucose
tolerance and decreased hyperinsulinemia [44]. Another
small molecule agonist, TUG-891, and members of the
new fatty acid ester of hydroxy fatty acid (9-PAHSA) lipid
class have been designed to activate GPR120 and enhance
glucose uptake [27, 62, 63]. Intriguingly, Liu etal. reported
that in GPR120 knockdown 3T3-L1 cells, the expression of
GLUT4 and insulin receptor substrate 1(IRS1) is decreased
[64]. Ichimura et al. found that insulin signalling-related
genes are remarkably decreased in adipose tissue of HFD-
fed GPR120 −/− mice, especially IRS1 [10]. When the IRS1
level was lower than a specific amount, insulin signalling
was abolished. Therefore, based on the abnormal insulin
signal in adipose tissue and the liver, the GPR120-deficient
mice fed with an HFD diet develop hyperglycaemia, glu-
cose intolerance, and insulin resistance when compared
with the control group. This suggests that dysfunction
of GPR120 may impair normal insulin signalling and
adversely impact glucose uptake in adipose tissue [16].
On the other hand, when mice are challenged by an
HFD, the expression of GPR120 increased higher than
reported in the previous work [12]. Some researchers,
such as Chen et al., have reported an upstream mecha-
nism to regulate GPR120 [65]. In context of the HFD, the
mRNA and protein expression of GPR120 and PPARγ
was increased and the binding of CCAAT/enhancer bind-
ing protein β (C/EBPβ) on the GPR120 core promoter was
accelerated [65]. They speculate that the C/EBPβ-GPR120-
PPARγ pathway might provide a way to regulate energy
metabolism [65]. In addition, another group reported that
EPA upregulated VEGF-A through GPR120-PPARγ or in
a GPR120-independent manner in 3T3-L1 adipocytes [61].
Overexpression of VEGF-A in adipose tissue ameliorated
glucose intolerance and showed an insulin-sensitizing
effect under the challenge of HFD in mice [60]. Thus, this
may demonstrate that in the HFD diet treatment, expres-
sion of GPR120 will be upregulated and activated GPR120
induced by an agonist will improve the metabolic status of
adipose tissue. However, the interaction between GPR120
and PPARγ implicated in energy metabolism needs to be
addressed in the white adipocyte.
Unlike the white adipocytes, the brown and beige adi-
pocytes transfer stored chemical energy in the form of heat
in response to cold or overfeeding [3]. Thus, we can con-
firm that the brown adipocytes thermogenic activity and
the browning of white adipocytes are the key and promis-
ing mechanism to protect body from obesity and metabolic
diseases. Notably, the BAT also contributes as an endocrine
organ [66]. As recently reported, GPR120 may be the cru-
cial mediator in the energy metabolism of brown adipo-
cytes, since n-3 PUFAs- and synthetic agonists-mediated
GPR120 activation induce the release of the hormonal fac-
tor fibroblast growth factor-21 (FGF21), resulting in the
promotion of BAT activity and WAT browning [26].
These data indicate that GPR120 plays a role as a lipid
sensor invivo and senses the dietary fat to regulate glucose
uptake and energy metabolism in adipose tissue, thus trig-
gering a novel pathway of BAT activation and browning of
WAT.

GPR120: acritical role inadipogenesis, inflammation, andenergy metabolism inadipose tissue
1 3
Taken together, the role of GPR120 in anti-inflamma-
tion, glucose uptake, energy metabolism, and other related
biological events, such as angiogenesis, has so far seemed
clear in some extent, although the precise mechanism of
GPR120 needs to be further explored.
What are theinconsistencies duringadipogenesis
andadipocyte metabolism?
The normal expression ofGPR120 may contribute
tothenormal functions
Several studies have reported that GPR120 is required for
normal adipogenesis both in vivo and in vitro. As Gotoh
et al. has shown, GPR120 was increased in four different
adipose tissues from HFD-fed mice [12]. In addition, the
expression of GPR120 was notably increased in subcutane-
ous and visceral adipose tissue from obese individuals [10].
In contrast, another group reported that morbidly obese
individuals have lower mRNA and protein expression of
GPR120 in visceral adipose tissue than lean humans, and
the expression was reduced 3 h after a high-fat meal in
obese people [56]. This is the first inconsistency between
studies. As described above, GPR120 plays an important
role in systemic homeostasis. In GPR120−/− mice, it is easy
to develop obesity, but decreased adipocyte differentiation
with lower PPARγ level and lower content of triglyceride
also occurs [10]. That means the adipogenesis process in
GPR120-deficient mice is abnormal, which is consistent
with the vitro experiment from the Gotoh group [10, 12].
Furthermore, hepatic lipogenesis is higher than in wild-type
mice, which accounts for the final fat and other obesity-
related metabolic problems of GPR120−/− mice. In addi-
tion, it has been indicated that adipogenesis fails to store
all the excess nutrients, and the extra energy will be ectopi-
cally deposited into liver and muscle tissue [67]. Dysfunc-
tion of GPR120 may lead to lipid accumulation in the liver,
resulting in worse insulin resistance [11]. Morbidly obese
individuals may have an absence of functional GPR120 and
the high-fat meal treatment may worsen the dysfunction of
GPR120 and the insulin resistance. If so, the activation of
normal GPR120 can be a way to facilitate positive adipo-
genesis and may improve insulin resistance. However, a
direct method to measure the normal, functional GPR120
in obese people is still missing. Perhaps, the expression of
GPR120 acts as an indicator to assess the state of meta-
bolic homeostasis. Actually, mature adipocytes induce the
production of C16:1n7 palmitoleate, which has been pro-
posed to be a lipid hormone that modulates the interaction
among adipose, muscle, and liver tissue [68]. It seems that
dysfunction of GPR120 leads to insufficient production of
palmitoleate [11, 68].
The contrariety between“the pro‑adipogenic function”
and“anti‑inflammatory role”?
Another inconsistency is between the promoting function in
adipogenesis and the anti-inflammatory role in adipocytes.
The idea that obesity is involved in adipocyte hyperplasia
has created a false notion in our mind: adipogenesis causes
obesity [3]. However, it is worth noting that adipogenesis
occurs in the obesity process but is not the primary driver.
The root cause is the energy balance equation. Given extra
nutrition, increased adipogenesis is driven by a require-
ment to store excess calories. Moreover, the formation of
new adipocytes should be adapted to dispose of the surplus
energy safely [3]. As mentioned before, normal GPR120
may be activated by FFAs to facilitate adipogenesis and
lipogenesis in adipose tissue, thereby resulting in healthy
metabolic homeostasis. Recently, a group of people called
“metabolically healthy obese” (MHO) were identified,
who tend to show reduced visceral adiposity and inflam-
mation and improved glucose and lipid homeostasis [69].
Notably, they have smaller adipocytes than other “normal
obese” people [70]. Another alternative hypothesis is that
adipogenesis increases the number of new, smaller adipo-
cytes that have functional glucose uptake and healthy adi-
pokines to improve metabolic health [3]. Importantly, the
agonist of PPARγ, thiazolidinedione (TZD), plays a pivotal
role in regulating homeostasis and improving insulin resist-
ance. Consequently, TZD increased adipocyte cell numbers
and total adiposity [71], and unhealthy obese people had
a diminished number of preadipocytes [72]. In our previ-
ous work, we found that the expression of GPR120, syn-
chronously with PPARγ, is decreased after 6days of MDI
adipogenic induction [21]. In regard to the hypertrophy
of mature adipocytes, the bigger the adipocyte grows, the
worse their metabolic status. Thus, we speculate that the
increase of GPR120 in adipogenesis may be used for form-
ing new adipocytes, and the decrease of GPR120 in mature
adipocytes may be a response to the dysfunction of adipo-
cytes. However, it seems that making obese people more fat
with new, smaller adipocytes is not a priority for medical
research [3].
Despite some of the vital functions have been revealed,
new roles are still being discovered. The contradictory
nature of the different functions of GPR120 implies that
there is much that is not known about this receptor. The
precise underlying mechanisms of GPR120 signalling need
to be explored. On the whole, it is certain that GPR120 is
required for adipogenesis to format new adipocytes and
functions in metabolic homeostasis via its important, but
not detailed, role in maintaining normal adipose metabo-
lism. Recently, the observation that GPR120 is prominently
increased in murine brown adipose tissue in response to
exposure to cold supports its role in energy expenditure

T.Song et al.
1 3
[73]. Studies have shown that the GPR120 activated by
agonists can trigger the BAT activation and browning of
WAT [ 26, 29]. These findings indicate the importance of
GPR120 in systemic metabolic and further stir the interest
in the potential natural or synthetic agonists of GPR120 for
fighting the metabolic diseases.
The application ofGPR120 agonists inanti‑obesity
andanti‑diabetic therapeutics
As mentioned before, GPR120 is a promising pharmaceu-
tical target for anti-diabetic and anti-obesity treatments.
Hirasawa and colleagues, for the first time, deorphanised
this receptor and found that the ligand was LCFA [17].
After that, others have also identified several types of fatty
acids and have determined that n-3 PUFA is not a unique
ligand for GPR120 [11, 74]. Based on an ectopic GPR120-
overexpression system in HEK293T cells, saturated and
monounsaturated fatty acids have also been found to acti-
vate this receptor [11, 20, 75]. It needs careful considera-
tion regarding the special kind of natural agonists. In some
cell types that have high expression of GPR120, only LCP-
UFA responded well to GPR120. In mouse STC-1 cells,
LCPUFA, but not saturated LCFA, could evoke a clear
response to the secretion of glucagon-like peptide 1(GLP-1)
[17]. Surprisingly, both n-3 and n-6 PUFAs could strongly
activate GPR120 with different signalling events in human
CaCo-2 cells, which are used as an intestinal epithelial
model [76]. Thus, the conclusions should be treated with
caution. In lipidomic analysis experiments, Yore etal. iden-
tified a new class of endogenous agonist, called 9-PAHSA,
and found that it can activate GPR120 in a concentration-
dependent manner [62]. Although 9-PAHSA shares similar
properties with DHA and another agonist, GW9508, the
pharmacological characteristics of this endogenous agonist
have not been well illustrated.
Based on the uncertainty of the natural ligand, it is nec-
essary to explore synthetic ligands with high potency and
selectivity for GPR120. Several recent reviews have well
summarized the development progress of GPR120 ago-
nists. For instance, Briscoe et al. described GW9508, a
small molecule for both GPR120 and GPR40 [74]. In cells
expressing GPR120, but not GPR40, GW9508 can be a
specific agonist for GPR120 [11, 77]. NCG21, another ago-
nist product, was not widely used in subsequent research,
and notably, it is identified among the derivatives of PPARγ
agonists [31]. This may also show the relationship between
GPR120 and PPARγ. Noticeably, TUG-891 was recently
identified as a GPR120 agonist, which has better selective
potency on human and mice GPR120 than GW9508 and
NCG21 [27, 63]. In our previous work, using TUG-891
to activate porcine GPR120, we found that this agonist
shares the strong response to GPR120 similar to DHA and
ALA [21]. Furthermore, TUG-891 can stimulate intracel-
lular calcium release in a concentration-dependent manner
in 2-day differentiated 3T3-L1 adipocytes [24]. Both in
the ectopically expressing HEK293T cells and the endog-
enously expressing adipocytes, ERK1/2 signal can be well
phosphorylated by TUG-891 treatment [21, 24]. However,
the selectivity of TUG-891 is limited for mice and is still
unknown for rat GPR120. In addition, the orally available
and in vivo tested GPR120 agonist cpdA has been devel-
oped [44]. cpdA mimics the anti-inflammatory effects with
DHA, as Oh etal. reported, and showed a GPR120-medi-
ated anti-inflammation role invivo [44].
It is certain that GPR120 improves glucose uptake and
provides anti-inflammatory/insulin-sensitizing effects.
Uncovering the detailed mechanism of GPR120-n-3 PUFA
will lead to a more direct and potent way to guide the
proper supplementation of fish oil. Especially, in regard
to the anti-inflammatory effect, n-3 PUFA could activate
GPR120 in the hypothalamus in a diet-induced obesity
mice model, and further studies are still needed to shed
light on the role of GPR120 to alleviate inflammation in the
central nervous system (CNS) [78, 79]. As a “druggable”
GPCR, the development of a highly efficient and functional
GPR120 agonist both invitro and in vivo could lead to a
new therapeutic approach for the treatment of systemic
metabolic diseases (Fig.2) [80].
Conclusion andperspective
Over the last decade, recent studies have illustrated that
GPR120 acts as a positive regulator of adipogenesis and
improves glucose uptake in adipocytes, as well as having an
anti-inflammatory effect in ATMs. Its different roles during
the development and metabolism of adipocytes may sug-
gest that the expression and activity of GPR120 is capable
of promoting normal lipid and glucose metabolism (Fig.2).
Therefore, useful approaches to modulating GPR120 activ-
ity may be developed as promising anti-obesity and anti-
diabetic agents. Currently, highly efficient and potent drugs
targeting GPR120 are being developed, though one kind of
agonist, cpdA, shows functional effects both in vivo and
invitro in the regulation of glucose uptake, anti-inflamma-
tory activity, and insulin resistance. Although some impor-
tant issues have been solved to uncover the role of GPR120,
other questions remain to be addressed in the future.
First, some studies demonstrate that the signals trans-
duced from membrane-associated GPR120 into the cells
result in the regulation of the nuclear receptor PPARγ.
What are the specific events in this putative GPR120-
PPARγ pathway? Calcium and ERK1/2 may be two second
messengers that help transduce the signal into the cell, but

GPR120: acritical role inadipogenesis, inflammation, andenergy metabolism inadipose tissue
1 3
the subsequent mechanism that activates PPARγ needs to
be dissected. GPR120 and PPARγ exhibit a similar pocket
structure, and n-3 PUFA can activate both of them, which
means that co-activation might be a model to investigate
in further research, such as in studies of anti-inflammatory
properties. Furthermore, the precise downstream signalling
mediated by GPR120 in brown adipocytes adipogenesis is
worth being uncovered.
Second, as an important endocrine organ, adipose tis-
sue is distributed or intertwined in different organs, such as
muscle, heart, kidney, liver, or even cancer cells. The inter-
actions between adipose tissue and other organs are being
explored and show promise [3]. GPR120 maintains the nor-
mal adipose-liver-muscle interactions, and the dysfunction
of GPR120 may lead to insufficient production of palmi-
toleate (C16:1n7), leading to disorders in lipid metabolism
in the liver and muscle [10]. The systemic role of GPR120
in adipose tissue interactions with other organs needs to be
further verified.
Finally, GPR120 signals via both β-arrestin 2 and
G proteins in the reported studies. As is well known,
diverse proteins are coupled in different biological events.
β-Arrestin2 mediates the anti-inflammatory effect through
internalization with the receptor, while in lipid and glucose
metabolism, two downstream signals, intracellular calcium
mobilization, and phosphorylation of ERK1/2 are the con-
sequence of G protein coupling. However, direct evidence
for the receptor and G protein interaction is lacking. Fur-
thermore, there are few reports about the roles of other pos-
sible protein interactions in these events, such as G protein-
coupled receptor kinase 6 (GRK6) [81, 82]. Thus, it is of
great interest to clarify the precise downstream signals in
different processes. This may help us better understand the
actual function of GPR120 and better design agents for the
treatment of metabolic diseases.
Acknowledgements We apologize to those authors whose excel-
lent work we could not reference directly in this review due to lim-
ited text space. This study was jointly supported by the National
Natural Science Foundation of China (Nos. 31472075 and 31402085);
Hubei Provincial Creative Team Project of Agricultural Science
and Technology (No. 2007-620); the Key Technology Research and
Development Program of Hubei Province (Nos. 2014ABB014 and
2014ABC012).
Compliance with ethical standards
Conflict of interest The authors declare no conflicts of interest.
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