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GPR120 agonism as a countermeasure against metabolic diseases
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GPR120 agonism as a countermeasure against metabolic diseases Lauren M. Cornall1, Michael L. Mathai1, Deanne H. Hryciw2 and Andrew J. McAinch1 1 2
Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, Melbourne 8001, Australia Department of Physiology, The University of Melbourne, Melbourne 3010, Australia
Obesity, type 2 diabetes mellitus and cardiovascular disease are at epidemic proportions in developed nations globally, representing major causes of ill-health and premature death. The search for drug targets to counter the growing prevalence of metabolic diseases has uncovered G-protein-coupled receptor 120 (GPR120). GPR120 agonism has been shown to improve inflammation and metabolic health on a systemic level via regulation of adiposity, gastrointestinal peptide secretion, taste preference and glucose homeostasis. Therefore, GPR120 agonists present as a novel therapeutic option that could be exploited for the treatment of impaired metabolic health. This review summarizes the current knowledge of GPR120 functionality and the potential applications of GPR120-specific agonists for the treatment of disease states such as obesity, type 2 diabetes mellitus and cardiovascular disease. Introduction The search for a panacea against metabolic diseases has identified a number of G-protein-coupled receptors (GPCRs) that are responsive to fatty acids (FAs) or their derivatives as candidates for new pharmaceutical treatments against these insidious conditions. Metabolic diseases are commonly the result of undesirable diet and lifestyle choices that lead to excessive systemic adiposity (obesity), insulin resistance, overt type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). Together, obesity, T2DM and CVD represent a major cause of morbidity and premature mortality in Westernized societies, which comes at an immense financial burden to healthcare systems globally. Therefore, significant research efforts are being directed at attenuating the increasing prevalence of these conditions. However, research into the selective manipulation of GPCRs as a treatment option for these conditions remains in its relative infancy. Of the GPCRs under investigation for their potential as drug targets, GPR120 [also known as free fatty acid receptor (FFA)4] is among those that have been progressed as a potential targeted receptor for the alleviation of metabolic diseases. GPR120 has been identified as a member of a family of free fatty acid receptors Corresponding author:. McAinch, A.J. ([email protected])
including GPR40 (also known as FFA1), GPR41 (FFA3) and GPR43 (FFA2), which have been reviewed extensively elsewhere [1–4]. As the name suggests, this family of receptors are activated by free FAs of varying chain length with GPR41 and GPR43 being activated predominantly by short-chain FAs, whereas GPR40 and GPR120 are activated by long-chain FAs (LCFAs) [4]. As a result of this, efforts to understand the explicit functions of these receptors in isolation have been clouded by nonspecific endogenous and synthetic ligands for GPR40 and GPR120. Ongoing works have been able to develop more selective chemical agonists and antagonists at these receptors, which has enhanced the current understanding of the roles of these receptors. But caution is still needed in many instances in attributing changes in function solely to one of these receptors. When looking at GPR120 specifically, this receptor has been implicated in a number of processes including release of gastrointestinal peptides, inflammation, adipogenesis, lipogenesis, glucose intolerance, insulin sensitivity and food preference [5– 10]. These factors interrelate to influence systemic metabolic function in physiological and pathophysiological conditions. Herein, we discuss the recent advances in research regarding the roles of GPR120 and how pharmaceutical agents at this receptor could be used in the prevention and treatment of metabolic diseases.
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GPR120
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GPR120 was first identified as an orphan GPCR by Fredriksson et al. [11], who determined the chromosomal location for human GPR120 to be 10q23.33. Human GPR120 was subsequently shown to exist as two splice variants, a short (361 amino acids; accession numbers: RNA – GenBank ID: BC101175 and Protein – GenBank ID: AAI01176.1) and a long (377 amino acid; accession numbers: RNA – NCBI Reference Sequence ID: NM_181745 and Protein – NCBI Reference Sequence ID: NP_859529.2) isoform [6,10,12,13] (Fig. 1). The predicted molecular weight of the long isoform is 42 kDa [11]. Of particular interest, the long GPR120 isoform appears to be human specific, being undetectable in the cynomolgus monkey [14]. Mouse GPR120 appears to correlate more closely with the short isoform present in humans having 361 amino acid residues [11].
Tissue distribution of GPR120 GPR120 is widely expressed in a number of tissue types, and is most abundantly expressed in lung and colonic tissues [6]. This diverse localization of GPR120 is likely related to the broad spectrum of effects GPR120 elicits with expression also being reported in tissues involved in homeostatic regulation of metabolic health and inflammatory and/or immune processes, including the brain, thymus, pituitary, small intestine, white adipose tissues, taste buds, skeletal muscle, heart and liver [6,7,10,15]. However, it appears that species differences exist between the distribution and density of GPR120 (Table 1). As can also be seen in Table 1, GPR120 demonstrates a divergence in tissue localization between different species so that care should be taken when extrapolating results from animal models to a potential therapeutic application in humans because the interspecies differences in expression can confound these findings. It should also be noted, however, that differences in the relative sensitivity of detection techniques used can in part account for some of the variability of expression. Moreover, studies show selective tissue-specific upregulation of GPR120 expression in the extensor digitorum longus (EDL) skeletal muscle, heart and adipose tissues following high fat feeding leading to obesity [5,7,15]. Interestingly Wu et al. [16] demonstrated that not only is GPR120 expressed in a panel of colorectal cancer cell lines and biopsies of human colorectal cancers but this receptor is significantly induced by malignancy in colorectal cancer patients. GPR120 co-localizes with ghrelin in the duodenum [17], a-gustducin in the small intestine and type II taste bud cells [18,19], neuropeptide Y centrally in the arcuate nucleus [20] and glucagon-like peptide 1 (GLP-1) in the colon and circumvallate papillae taste bud cells [6,21,22]. Interestingly GPR120 was also found to be co-expressed with other receptors for FAs including GPR43 in the proximal colon of mice [19] and GPR40 in STC-1 intestinal cells [6]. These distinct patterns of expression and colocalization are likely reflective of the functions of GPR120 discussed below.
Ligands for GPR120 GPR120 is a receptor specific for LCFAs [6]. FAs are generated during lipolysis [23]. Free FAs released into the plasma then circulate and not only provide substrate for energy production but importantly also act as endogenous ligands to modulate the 2
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expression of genes and proteins that regulate a diverse range of physiological and pathophysiogical functions including those related to energy homeostasis [24,25]. Studies to date have shown that unsaturated FAs with a carbon chain length of 16–22, including the omega 3 FAs alpha-linolenic acid (a-LA), docosahexaenoic acid (DHA) and eicosapentaenoic acid act as endogenous ligands for GPR120 [6,8]. Of these, a-LA and DHA appear most potent at GPR120 [6,8]. In the search for small molecule agonists for GPR120, initial studies identified a derivative of peroxisome-proliferator-activated receptor (PPAR) g [26], namely GW9508, as an agonist for GPR120 [27]. However, the dual specificity of GW9508 for GPR40 and GPR120 [27] presents as a confounding variable in the interpretation of results in studies using GW9508 as a result of off-target effects at the other receptor. Further research identified several other potential agonists for GPR120 including the plant-derived compound grifolic acid, which acts as a partial selective GPR120 agonist [28], NCG21 [29] and GSK137647A [22], which are reported as selective at GPR120 (Table 2). Most recently, TUG891 (4-[(4fluoro-40 -methyl[1,10 -biphenyl]-2-yl)methoxy]-benzenepropanoic acid) has been made commercially available as a GPR120 agonist by Tocris Bioscience and R&D Systems. TUG891 is reported to be potent and selective for GPR120 demonstrating greater selectivity and potency to GPR120 than GPR40 [30,31]. However, Hudson et al. [31] also demonstrate phosphorylation and desensitization of GPR120 following stimulation with TUG891, suggesting that tachyphylaxis could complicate the use of this compound therapeutically. Furthermore, the work of Hudson et al. [31] also suggests that interspecies differences in the selectivity of TUG891 to GPR120 over GPR40 exist with a substantial loss of GPR120 selectivity when cells expressing mouse GPR120 were challenged with the agonist. This limits the value of preclinical in vivo studies in mice regarding the activation of GPR120 with TUG891. Interestingly, the GPR40 antagonist GW1100 was reported as being without effect on GPR120 [31] and thus, via selectively inhibiting GPR40, GW1100 used in conjunction with TUG891 might be of benefit in attributing specific effects of TUG891 to GPR120. Because the development of a potent and selective GPR120 agonist is indispensable in the development of GPR120 as a druggable receptor, the availability of TUG891 is a promising step forward in investigating the functions of GPR120 specifically. However, given the interspecies loss of selectivity of TUG891 for GPR120, further research is needed to optimize and characterize fully the functional effects of TUG891 and other potential agonistic compounds at GPR120.
GPR120 signaling GPR120 has been shown to couple to Gaq and b-arrestin 2 mediated pathways [6,8] (Fig. 2). Coupling of GPR120 induces increases in intracellular calcium transients [6,10] and is without effect on intracellular cyclic adenosine monophosphate concentration [6]. Activation of GPR120 has been shown to lead to receptor internalization [8]. Oh et al. [8] show that, in RAW 264.7 cells, DHA stimulation induced translocation of b-arrestin 2 to the plasma membrane where it co-localizes with GPR120. Further treatment with DHA led to internalization of GPR120, which was then observed to co-localize with cytosolic b-arrestin 2 [8]. This suggests that b-arrestin 2 is implicated in GPR120 internalization. Abrogation of b-arrestin 2 signaling via selective
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L
A A E T T V L L A F V L L G V C A V L V R
V V I S N L A
R
T
W
V L I A F L A C N L C A
A P I D L L A
R R R R G
A W L L G P E A V H C V L L Y F V L M T L S G S S V T L I T L L F A A V S V E L M R T V C I V
A G P L R Q P V V R F F V C
P L A L A A V S Y G I W A L L L V A A R R R G P
H L
G
R Q R G V
D Q E I
S I C T L I W P T I P G E I
S D W V S F T V L F N L P V G L I V I V S Y K S I L Q T S E H L L D A R A V V T H S E I T K A
NH2
N F K Q Q
D
I L L I I S W F F M L T L L R Q Q S V R I Q H S E S Y A L S V T L R K R S
I L I T I P M I S V L F R F
L
P F
W F
I L
V V T F A S A L P L I F N D W F P E K G A I L T D T S V K R N D L S I I S G COOH A
V S W F N N Y
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FIGURE 1
Snake-plot diagram of the human GPR120 long isoform. Amino acid residues colored in red highlight the structural difference between the long and short isoforms of GPR120 with these additional 16 amino acids being specific to the long isoform, and not present in the short isoform. Structural diagram was generated using GPCRGB Tools (http://tools.gpcr.org) from protein accession number Q5NUL3.
RNA interference was shown to attenuate DHA-mediated antiinflammatory effects [8] suggesting that, upon binding to GPR120, this LCFA exerts its effects via b-arrestin 2 signaling. However, the dual coupling of GPR120 to Gaq and b-arrestin 2 might account for the divergence in the reported functions of this receptor. Moreover, although not fully characterized at present, it is likely that GPR120-mediated signaling is different in distinct tissue types. Therefore, extrapolating findings from one tissue to another
may be fraught. Thus, further research into the tissue-specific effectors of GPR120 agonism will be important in understanding how pharmaceutical agents that target a distinct signaling pathway could be developed for the treatment of specific disease states. It is interesting to note that the long and short forms of GPR120 exist at different basal levels of phosphorylation, with the short form demonstrating a greater degree of constitutive activity [12]. Importantly, Burns and Moniri [12] showed that, upon activation,
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TABLE 1
Differential tissue distribution of GPR120
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Refs
RNA/Pro
Species
Br
Thy
Adip
Stom
SI
Col
SkM
Hrt
Liv
Kid
Spln
Lung
Panc
Tng
[2]
RNA
Mus
+
+
NR
+
+
+
NR
+
+
+
+
+
NR
NR
[2]
RNA
Hu
+
+
NR
NR
+a
+
NR
+
+
+
NR
NR
[6]
RNA
Rat
+
NR
+
+
NR
+
+
NR
[3]
RNA
Mus
+
NR
+b
+
+
+
+
+
+
+
+
+
NR
NR
[3]
RNA
Hu
NR
NR
+
NR
+
NR
NR
NR
NR
NR
NR
NR
+
NR
[11]
RNA
Rat
NR
NR
NR
NR
NR
NR
+
+
+
NR
NR
NR
NR
NR
[4]
RNA
Mus
Neg
NR
+
NR
+c
NR
Neg
Neg
NR
Neg
Neg
+
NR
NR
[10]
RNA
C-M
+
NR
NR
+
+
NR
NR
+
+
NR
NR
NR
NR
[58]
Pro
Rat
NR
NR
NR
NR
+d
NR
NR
NR
NR
NR
NR
NR
NR
NR
[59]
RNA
Hu
NR
NR
NR
+
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
[1]
RNA
Mus
NR
+e
+
+
+
+
+
NR
[1]
RNA
Hu
NR
NR
+f
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
[15]
Pro
Mus
NR
NR
+
NR
NR
+
NR
NR
NR
NR
NR
+
NR
NR
[13]
Both
Mus
NR
NR
NR
NR
NR
+
NR
NR
NR
NR
NR
NR
NR
+g
[13]
Both
Rat
NR
NR
NR
NR
NR
+h
NR
NR
NR
NR
NR
NR
NR
+i
[41]
Both
Mus
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
+j
Abbreviations: RNA, mRNA; Pro, protein; C-M, Cynomolgus monkey; Mus, mouse; Hu, human; Br, brain; Thy, thymus; Adip, adipose; Stom, stomach; SI, small intestine; Col, colon; SkM, skeletal muscle; Hrt, heart; Liv, liver; Kid, kidney; Spln, spleen; Panc, pancreas; Tng, tongue; +, present; , absent; NR, not reported, Neg, negligible. a Illeum. b Parametrial, peri-renal, epididymal, subcutaneous, mesenteric adipose tissue. c L cells. d Proximal epithelial cells from the duodenum and jejunum. e Epididymal, subcutaneous, peri-renal and brown adipose tissue. f Subcutaneous and omental adipose tissue. g Circumvallate and fungiform papillae. h Enteroendocrine and epithelial cells. i Folliate, fungiform and circumvallate papillae. j Circumvallate papillae.
the long and short isoforms of GPR120 are phosphorylated to the same extent by a-LA and DHA. It is further suggested by Watson et al. [13] that the long isoform of GPR120 exhibits preferential coupling to b-arrestin signaling. Other studies also indicate that there could be a partial loss of function associated with the long isoform of GPR120 [6,14]. Thus, it remains important to determine physiological relevance of the two isoforms and, subsequently, whether pharmaceutical agents act preferentially through the short or long isoform and their associated signaling cascades. To date, downstream effectors of GPR120 activation have been identified as the mitogen-activated kinases, extracellular regulated kinase 1/2 (ERK1/2) [6,8,32], c-Jun N-terminal kinase (JNK), inhibitor of kappa B kinase b (IKKb), inhibitor of kappa B (IkB), transforming growth factor b activated kinase 1 (TAK1) [8], caspase-3 [32] and members of the insulin signaling cascade including Akt (also known as protein kinase B), insulin receptor beta (IRb), insulin receptor substrate (IRS) 1 and 2, and the lipogenic protein stearoyl-CoA desaturase 1 [5]; all of which support a role for GPR120 in mediating inflammation and metabolic homeostasis.
Physiological functions of GPR120 and the implications for metabolic disease GPR120 is proposed as a drug candidate largely for the treatment of metabolic diseases and, in view of the current literature, agonists at this receptor are expected to be of benefit [5–8,33]. Metabolic 4
diseases are often the consequence of a chronic energy imbalance where intake exceeds requirements leading to a prolonged positive energy balance [34]. This is complicated by hedonic and hedonistic factors influencing energy intake and expenditure and, over the longer term, is reflected by an increase in body adiposity [34,35], paralleled by increased risk of co-morbid conditions such as T2DM and CVD. Here, we examine the effect of GPR120 on parameters that are known to influence metabolic health and how these might be targeted in the treatment of disease states that manifest perturbed metabolic function at the tissue-specific and systemic levels. Again, the development of chemical activators and/or inhibitors selective to GPR120 will be invaluable in determining the extent to which GPR120 is responsible for these effects. This might be especially relevant in separating the effects of GPR40 given the similar patterns of expression and dual specificity of LCFAs and chemical compounds developed to date.
Adipogenesis GPR120 is abundantly expressed in adipocyte and adipose tissue extracts [5,7,8], yet is undetectable in pre-adipocytes [7,21]. Moreover, GPR120 expression increases in parallel with lipid accumulation in the cells upon induction of differentiation in 3T3-L1 cells [7,21]. Small interference RNA against GPR120 was shown to reduce the expression of adipogenic genes and reduced lipid droplet accumulation in 3T3-L1 adipocytes [7]. Taken together,
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TABLE 2
Chemical structures of GPR120 agonists Agonist
Structure
a-Linolenic acid
H3C
Docosahexaenoic acid
H3C
[60]
COOH
[60]
COOH [23]
OH
OH COOH TUG891
[25]
Me O OH O
F [24]
NCG21
OH N
N
O
O
GSK137647A
O H N O
[16]
S O
these data support the contention that GPR120 is an adipogenic receptor. Importantly, adipocyte hypertrophy is a key pathogenic feature in the development of obesity. Interestingly, in the study by Gotoh et al. [7], GPR120 mRNA expression was increased by high fat feeding in subcutaneous, epididymal and mesenteric adipose tissues. Ichimura et al. [5] also demonstrated that the expression of GPR120 mRNA is increased in human subcutaneous and omental adipose tissues from obese compared with lean individuals. Both of these studies suggest that GPR120 activity could be augmented by a high dietary lipid load. Given the adipogenic potential of GPR120, it might be expected that augmented activity at GPR120 could promote increased adiposity. Thus, GPR120 activation might be expected to promote obesity. However, GPR120/ mice exhibited significantly greater adipocyte area (hypertrophy) than wild-type mice, an effect that persisted in mice fed a normal or high fat diet [5]. Consistent with adipocyte hypertrophy, GPR120/ mice fed a high fat diet gained significantly more fat mass than their wild-type counterparts [5]. Bodyweight was not observed to be different between GPR120/ and wild-type mice on a normal chow diet [5,8], suggesting GPR120 has an important role in regulating bodyweight in the presence of a positive energy balance and is indeed protective against diet-induced obesity.
Gastrointestinal peptides and intestinal health Gastrointestinal peptides are intimately involved in the regulation of feeding behaviors, energy metabolism and bodyweight [36–41]. GPR120 has been demonstrated to induce secretion of two such peptides: GLP-1 and cholecystokinin (CCK), from enteroendocrine STC-1 cells in vitro [6,9,10]. In both instances, transient knockdown of GPR120 ablated the effect of a-LA on secretion of GLP-1 and CCK, to confirm that GPR120 is indeed responsible for this effect [6,9]. GLP-1 is an insulinotropic, anorectic peptide that reduces gastric emptying and motility [37,38]. Like GLP-1, CCK regulates a diverse range of local and distal physiological effects including promotion of pancreatic secretions, gallbladder contractions, inhibition of gastric motility and secretions, and reduces energy intake [42]. Curiously, GPR120 has also been shown to co-localize with the orexigenic peptide, ghrelin in duodenal cells in vivo and a-LA reduces ghrelin secretion in the MGN31 ghrenlinoma cell line [43]. However, this effect persisted in cells transfected with siRNAs targeting GPR120, which indicates GPR120 was not mediating this effect. Further studies that confirm these results would be of interest given that decreased appetite, which accompanies reductions in ghrelin [44], could provide an adjunctive mechanism by which GPR120 has favorable effects on systemic energy homeostasis. As the current indication of the
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(a)
(b) 1 2 2
γ βarr2
γ
β
α
γ GDP
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α β
β
GDP P
3 P βa P rr2
Gαq GTP P 4
4
P P r2 arrr2 βa β
3
Transcriptional nscriptional re regulation gulation of downs downstream tream pathways
1
GPR120
Ligand
GDP Guanosine diphosphate
G-proteins
GTP
βarr2
β-arrestin2
Guanosine triphosphate P Phosphorylation Drug Discovery Today
FIGURE 2
Activation of GPR120 signaling. (a) GPR120 activation via Gaq signaling. (1) Inactive state; (2) ligand binds GPR120 externally leading to association with G proteins in an activated state; (3) dissociation of G proteins, activated Gaq is bound to GTP; (4) transcriptional regulation of downstream signaling cascades. (b) GPR120 activation via b-arrestin 2. (1) Inactive state; (2) ligand binds GPR120 externally leading to association with and phosphorylation of b-arrestin 2; (3) internalization of receptor–ligand complex in the activated state; (4) transcriptional regulation of downstream signaling cascades. barr2, b-arrestin2; GDP, guanosine diphosphate; GTP, guanosine triphosphate; P, phosphorylation.
cumulative effects GPR120 agonism has on the secretion of GLP-1 CCK and ghrelin levels, this could culminate in enhanced glycemia, improved appetite control and improved overall energy homeostasis. Beyond a role in mediating the secretion of gastrointestinal peptides, Fredborg et al. [45] showed that GPR120 mRNA expression is increased in intestinal Caco-2 cells by cultured medium from bacteria of the Bacteroidetes and Firmicutes phyla. Dietary composition (such as high fat and alcohol intakes) and obesity can lead to dysbiosis and alter the ratio of intestinal-bacteroidetes:firmicutes [46–49]. This suggests another mechanism whereby GPR120 expression and subsequently function could be upregulated. In contrast to these beneficial effects, Wu et al. [16] recently identified an oncogenic potential for GPR120 in promoting tumorigenesis in colorectal cancers. This study is the first to examine a role for GPR120 in cancer progression but reveals interesting findings with GPR120 mediating pro-angiogenic signaling and promoting chemotaxis in tumor cell lines in vitro, which was supported by in vivo findings showing that GPR120 activation promoted angiogenesis and tumor growth in mice [16]. 6
Although further studies are needed to investigate the effects of GPR120 in carcinogenesis, these data support GPR120 agonism as exerting a cancer-promoting effect, suggesting that applications for GPR120 agonists in intestinal tissues should be approached with caution.
Spontaneous taste preference Hedonia is a major determinant of dietary intake to which taste is intimately linked [50]. Lipid-rich foods are typically highly palatable and energy dense [50]. This palatability predisposes to excessive consumption of lipid-rich foods that, owing to the high energy density, contribute greatly to daily caloric intake. Thus, chronic overconsumption of lipid-rich foods can increase bodyweight and facilitate the development of obesity and associated co-morbidities. GPR120 is expressed in cells responsible for detecting taste including those of the circumvallate, foliate and fungiform papillae [51]. Cartoni et al. [51] provide evidence of a role for GPR120 in mediating spontaneous preference for palatable high fat foods, with GPR120/ mice exhibiting ambivalence toward dietary FAs compared with preferential intake of FAs in wild-type animals.
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Inflammation GPR120 is expressed abundantly in adipose tissues and in macrophages [8]. GPR120 has been shown to exert powerful anti-inflammatory effects [8], which is consistent with activation of GPR120 via omega 3 FAs, a-LA and DHA. These FAs have been widely validated as having anti-inflammatory effects at the tissue-specific and systemic levels [55]. In the study by Oh et al. [8], GPR120 was shown to mediate suppression of the proinflammatory markers IKKb, JNK, TNF-a, interleukin-6 and toll-like receptor-4 in vitro and reduce macrophage infiltration of adipose tissues through decreased chemotaxis in wild-type but not GPR120/ mice. Consistent with this, GPR120 is localized in macrophages with the expression of this receptor being induced by obesity, a pro-inflammatory state, in these cells [8]. In the same study Oh et al. [8] show that the expression of pro-inflammatory genes in M1 macrophages was decreased whilst the expression of M2 anti-inflammatory genes were increased in wild-type but not GPR120/ mice fed a high fat diet supplemented with omega-3 FAs. Cintra et al. [20] further show that following acute injection of omega-3 or omega-9 FAs intracerebroventricularly, GPR120 couples with b-arrestin2 to dissociate TAK1 binding protein from TAK1 and thus reduce the activity of inflammatory pathways, including those mediated by toll-like receptor-4 and tumor necrosis factor (TNF)-a. Considered together, this provides compelling evidence that GPR120 is an anti-inflammatory receptor, with macrophage GPR120 possibly being a crucial mediator of these effects.
GPR120 and insulin signaling The skeletal muscle is a major site of insulin-stimulated glucose uptake [56,57] and thus is implicit in maintaining systemic euglycaemia. Cornall et al. [15] show increased GPR120 mRNA expression in the EDL skeletal muscle which comprises predominantly glycolytic and/or fast-twitch fibers [58,59], therefore relying largely on glucose for energy production. Activity at GPR120 has been shown to have insulin-sensitizing effects [8] and protects from glucose intolerance induced by ingestion of a high fat diet [5]. Consistent with this, GPR120 knockout in mice decreases phosphorylation of IRb and IRS1 in white adipose tissues and IRS1 and IRS2 in the liver [5], all of which are important regulators of insulin-stimulated glucose uptake. This decreased phosphorylation was accompanied by increased fasting glucose and impaired responses to insulin and glucose tolerance testing in GPR120/ mice fed a high fat diet [5]. Likewise, GPR120 was shown to promote glucose transporter 4 translocation in 3T3-L1 adipocytes and directly enhanced glucose uptake via Gaq signaling [8], which is additive to improved insulin sensitivity. However this effect was not observed in L6 muscle cells, which could be explained by the lack of expression reported in these cells in this particular study [8]. The relationship between increased GPR120 expression in the EDL skeletal muscle and systemic glucose control is yet to be investigated. However, if the increased expression of GPR120 correlates with enhanced insulin-stimulated glucose uptake in skeletal muscle, particularly the EDL muscle, this might provide a mechanistic explanation behind enhanced systemic glycemic control. Similarly to the EDL muscle, GPR120 mRNA expression was also increased in cardiac tissue in response to diet-induced obesity in rats [15]. This could support a role for GPR120 in regulating cardiac muscle glucose uptake. Although the adult heart predominantly relies on FAs for energy substrate in the healthy state [60], obesity, diabetes and hypertrophic processes in the heart dysregulate the balance between glucose and FA oxidation [61–64]. The cumulative effect of this is decrements in cardiac efficiency and induction of cellular energetic stress caused by metabolic inflexibility. If activation of GPR120 can attenuate insulin resistance in cardiac muscle GPR120 agonists could also have a role in ameliorating cardiac dysfunction in metabolic disease. Furthermore, GLP-1 not only induces pancreatic insulin secretion in response to glucose but also has been shown to enhance glucose uptake directly in skeletal and cardiac muscle cells [65,66]. The consequence of these factors manifests in four separate but interrelated ways in which GPR120 agonist can: (i) enhance systemic glucose control through enhanced insulin signaling; (ii) increase GPR120 expression in muscle tissues; (iii) enhance GLP-1-mediated increase in glucose-stimulated insulin secretion from the pancreas; and (iv) enhance GLP-1-mediated muscle glucose uptake.
GPR120 modulation of systemic metabolic health GPR120 is a ubiquitous receptor with pleiotropic functioning that supports a role for this receptor in mediating systemic metabolic health (Fig. 3). Regulation of adiposity is modulated by the propensity for adipocytes to store excess energy from ingested lipids and glucose in the form of fat. Partitioning of substrate (i.e. glucose and FAs) away from oxidative pathways predisposes to their storage in adipose tissues as an energy reserve. GPR120 is indeed
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This suggests that aberrant upregulation of GPR120 activity in taste bud cells could foster an increased intake of dietary lipid. Godinot et al. [52] also provide a role for GPR120 and GPR40 in mediating innervation of the glossopharyngeal nerve, indicating an ability to regulate taste. However this paper argues a greater role for GPR40 in mediating taste response to FAs, with GPR40 agonists provoking a ‘fatty’ taste in human subjects, whereas the GPR120 agonists did not [52]. Although further work is needed to delineate the role of GPR120 in mediating taste preference, it is interesting to note that GPR120 expression in the circumvallate papillae was unaffected by dietary lipid content and type, fasting or the diurnal state [53], suggesting that GPR120 is likely to have a relatively stable influence on dietary lipid intake. GLP-1 is known to be expressed in a subset of taste bud cells and has been shown to co-localize with GPR120 in the circumvallate papillae [22]. Local GLP-1 regulates taste preference for sucrose [54]. Analogous to intestinal mediation of GLP-1 by GPR120, Martin et al. [22] report induction of GLP-1 secretion from circumvallate papillae following stimulation with a-LA and GSK137647A. Thus, by means of increasing oral GLP-1 secretion, GPR120 might also be able to modulate preference for dietary carbohydrates as well as FAs. GPR120 could therefore be expected to act as a determinant of dietary composition and manipulation of this function could attenuate overconsumption of energy-dense foods. However it seems that GPR120 activation might promote preferential intake of foods high in FAs and sucrose, therefore modulation of spontaneous taste preference could present a unique role for GPR120 antagonism. Thus, further studies should investigate this effect in free feeding wild-type and GPR120/ mice to ascertain the impact of spontaneous taste preference in relation to bodyweight.
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GPR120
Taste buds
Taste preference for fatty acids
Energy intake
Bodyweight
Intestinal
GLP-1 & CKK release
Appetite
Insulin secretion/ sensitivity
Adipose
Adipogenesis
Bodyweight
Adipokine secretion
Antiinflammatory
Cytokine release/ macrophage infiltration
Systemic inflammatory state
Insulin signaling
Glucose uptake
Euglycemia
Inflammatory tissues
Skeletal muscle
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FIGURE 3
Metabolic effects of GPR120. Rows depict the direct effect of GPR120 in relation to the main known functions of GPR120 (solid arrows). Indirect interactions between these effects mediated by GPR120 (broken arrows) further highlight how GPR120 can be targeted to treat metabolic diseases such as obesity, type 2 diabetes mellitus and cardiovascular disease by way of regulating parameters relating to systemic inflammation, adiposity and glycemic control.
suggested to be adipogenic [5,7,8,21]. Regardless of this, GPR120 knockout mice are more susceptible to diet-induced obesity than their wild-type counterparts [5], implying that GPR120 is protective against diet-induced obesity. Induction of a negative energy balance to promote weight loss must be considered from the point of view of decreased caloric intake and increased energy expenditure. GPR120 has the capacity to modulate taste preferences and induce GLP-1 and CCK which have anorectic and/or satiating effects, both of which have the capacity to regulate gross caloric intake [38,67]. However care must be taken to establish whether GPR120 agonism in taste cells will promote increased intake of energy-dense foods. With respect to increased energy expenditure, immature GPR120/ mice (9–10 weeks of age) fed a high fat diet are also reported to have reduced energy expenditure during light phases [5]. Although this effect was not observed in mature GPR120/ mice (15–16 weeks of age), decreased energy expenditure in young animals favors early increases in body mass that without a compensatory mechanism to reduce adiposity will then persist as age increases. Indeed, in the study by Ichimura et al. [5] bodyweight increased in GPR120deficient mice from week 8 and persisted throughout the duration of the study. In line with increased adiposity, plasma levels of the adipokine leptin have been shown to be increased in GPR120/ mice fed a high fat diet [5]. Leptin is secreted from adipocytes in a manner that is directly commensurate to systemic adiposity [68]. This is consistent with findings that plasma leptin was increased in GPR120 knockout mice fed a high fat diet [5]. Given that leptin is generally considered protective of obesity and promotes glucose 8
and FA metabolism, the finding of hyperleptinemia in GPR120/ animals [5] suggests the development of leptin resistance, which often arises subsequent to obesity [69]. However this effect on plasma leptin was not replicated in the study by Oh et al. [8], who demonstrated that leptin levels were unchanged in wild-type and GPR120-deficient mice maintained on a high fat diet. This indicates that further work is needed to qualify the effects of GPR120 on leptin secretion. Interestingly, GPR120 knockout had no effect on plasma adiponectin levels [5], which is again protective against obesity but is usually expressed in lower amounts in the obese state. Excessive adiposity is also a key pathogenic factor in the development of CVD. Through reductions in bodyweight, GPR120 agonism is therefore also implicated as a potential therapy for obesity and heart and vessel disease. In addition to weight loss, when compared with their wild-type littermates, GPR120/ mice fed a high fat diet develop dyslipidemia exhibiting decreased plasma levels of the unsaturated FAs linoleic, oleic and palmitoleic acid, while exhibiting increased plasma triglycerides and levels of the proinflammatory arachidonic acid and saturated FAs palmitic acid and stearic acid, which was not seen in mice fed a chow diet [5]. Furthermore, Oh et al. [8] showed that the ability of a-LA to reduce plasma triglycerides is lost in GPR120 knockout mice. These results confirm the potential for GPR120 in protecting from dietinduced dyslipidemia. High circulating levels of saturated fats and triglycerides are a known risk factor for the development of atherosclerotic lesions and subsequent heart failure, infarct and stroke. Further to this, GLP-1 is also capable of improving cardiomyocyte glucose uptake [66], which might suggest a role in
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Concluding remarks Overall, GPR120 agonism appears likely to have positive outcomes on health and the current data suggest GPR120 activation to be a valid pharmaceutical target for the treatment of metabolic disease. However the findings of Wu et al. [16] demonstrating that GPR120 activation promoted tumor formation and angiogenesis suggest that GPR120 agonists could be contraindicated in terms of cancer promotion and progression. Thus, despite promising early findings in terms of metabolic health, it is important to note that
research into the systemic functions of GPR120 is largely in its initial stages of preclinical studies. To prescribe GPR120 agonists with confidence for the treatment of obesity, T2DM and/or CVD, it will be important that future studies examine in detail the effects of GPR120 agonists in tissues that are involved in maintaining metabolic health, such as skeletal and cardiac muscle, and also the cumulative effects on systemic parameters of metabolic health in the long term.
Acknowledgements L.M.C. was supported by a scholarship (PB 10 M 5472) from the National Heart Foundation of Australia. A.J.M. was supported by the Australian Government’s Collaborative Research Networks (CRN) program.
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enhancing cardiac metabolic function in the presence of insulin resistance and overt T2DM. Therefore GPR120 agonism could be a valid target for abrogating cardiovascular complications seen in metabolic disease.
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44 Inui, A. et al. (2004) Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J. 18, 439–456 45 Fredborg, M. et al. (2012) G protein-coupled receptor120 (GPR120) transcription in intestinal epithelial cells is significantly affected by bacteria belonging to the Bacteroides, proteobacteria, and Firmicutes phyla. J. Anim. Sci. 90 (Suppl. 4), 10–12 46 Macfarlane, S. and Macfarlane, G.T. (2003) Regulation of short-chain fatty acid production. Proc. Nutr. Soc. 62, 67–72 47 de Wit, N. et al. (2012) Saturated fat stimulates obesity and hepatic steatosis and affects gut microbiota composition by an enhanced overflow of dietary fat to the distal intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 303, G589–G599 48 Siler, S.Q. et al. (1999) De novo lipogenesis, lipid kinetics, and whole-body lipid balances in humans after acute alcohol consumption. Am. J. Clin. Nutr. 70, 928–936 49 Kim, K.A. et al. (2012) High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS ONE 7, e47713 50 Nasser, J. (2001) Taste, food intake and obesity. Obes. Rev. 2, 213–218 51 Cartoni, C. et al. (2010) Taste preference for fatty acids is mediated by GPR40 and GPR120. J. Neurosci. 30, 8376–8382 52 Godinot, N. et al. (2013) Activation of tongue-expressed GPR40 and GPR120 by non caloric agonists is not sufficient to drive preference in mice. Neuroscience 250, 20–30 53 Martin, C. et al. (2011) The lipid-sensor candidates CD36 and GPR120 are differentially regulated by dietary lipids in mouse taste buds: impact on spontaneous fat preference. PLoS ONE 6, e24014 54 Shin, Y.K. et al. (2008) Modulation of taste sensitivity by GLP-1 signaling. J. Neurochem. 106, 455–463 55 Oh, D.Y. and Olefsky, J.M. (2012) Omega 3 fatty acids and GPR120. Cell Metab. 15, 564–565 56 Baron, A.D. et al. (1988) Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans. Am. J. Physiol. 255, E769–E774 57 Zurlo, F. et al. (1990) Skeletal muscle metabolism is a major determinant of resting energy expenditure. J. Clin. Invest. 86, 1423–1427
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58 Girgenrath, S. et al. (2005) Loss of myostatin expression alters fiber-type distribution and expression of myosin heavy chain isoforms in slow- and fast-type skeletal muscle. Muscle Nerve 31, 34–40 59 Ariano, M.A. et al. (1973) Hindlimb muscle fiber populations of five mammals. J. Histochem. Cytochem. 21, 51–55 60 Barger, P.M. and Kelly, D.P. (2000) PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc. Med. 10, 238–245 61 Coort, S.L. et al. (2007) Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: role of sarcolemmal substrate transporters. Mol. Cell. Biochem. 299, 5–18 62 Buchanan, J. et al. (2005) Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 146, 5341–5349 63 Duncan, J.G. (2011) Mitochondrial dysfunction in diabetic cardiomyopathy. Biochim. Biophys. Acta 1813, 1351–1359 64 Young, M.E. et al. (2002) Adaptation and maladaptation of the heart in diabetes, Part II: potential mechanisms. Circulation 105, 1861–1870 65 Chai, W. et al. (2012) Glucagon-like peptide 1 recruits microvasculature and increases glucose use in muscle via a nitric oxide-dependent mechanism. Diabetes 61, 888–896 66 Zhao, T. et al. (2006) Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts. J. Pharmacol. Exp. Ther. 317, 1106–1113 67 Beglinger, C. and Degen, L. (2004) Fat in the intestine as a regulator of appetite – role of CCK. Physiol. Behav. 83, 617–621 68 Myers, M.G., Jr et al. (2010) Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol. Metab. 21, 643–651 69 Mitterberger, M.C. et al. (2010) Adipokine profile and insulin sensitivity in formerly obese women subjected to bariatric surgery or diet-induced long-term caloric restriction. J. Gerontol. A: Biol. Sci. Med. Sci. 65, 915–923
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GPR120 agonism as a countermeasure against metabolic diseases Lauren M. Cornall1, Michael L. Mathai1, Deanne H. Hryciw2 and Andrew J. McAinch1 1 2
Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, Melbourne 8001, Australia Department of Physiology, The University of Melbourne, Melbourne 3010, Australia
Obesity, type 2 diabetes mellitus and cardiovascular disease are at epidemic proportions in developed nations globally, representing major causes of ill-health and premature death. The search for drug targets to counter the growing prevalence of metabolic diseases has uncovered G-protein-coupled receptor 120 (GPR120). GPR120 agonism has been shown to improve inflammation and metabolic health on a systemic level via regulation of adiposity, gastrointestinal peptide secretion, taste preference and glucose homeostasis. Therefore, GPR120 agonists present as a novel therapeutic option that could be exploited for the treatment of impaired metabolic health. This review summarizes the current knowledge of GPR120 functionality and the potential applications of GPR120-specific agonists for the treatment of disease states such as obesity, type 2 diabetes mellitus and cardiovascular disease. Introduction The search for a panacea against metabolic diseases has identified a number of G-protein-coupled receptors (GPCRs) that are responsive to fatty acids (FAs) or their derivatives as candidates for new pharmaceutical treatments against these insidious conditions. Metabolic diseases are commonly the result of undesirable diet and lifestyle choices that lead to excessive systemic adiposity (obesity), insulin resistance, overt type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). Together, obesity, T2DM and CVD represent a major cause of morbidity and premature mortality in Westernized societies, which comes at an immense financial burden to healthcare systems globally. Therefore, significant research efforts are being directed at attenuating the increasing prevalence of these conditions. However, research into the selective manipulation of GPCRs as a treatment option for these conditions remains in its relative infancy. Of the GPCRs under investigation for their potential as drug targets, GPR120 [also known as free fatty acid receptor (FFA)4] is among those that have been progressed as a potential targeted receptor for the alleviation of metabolic diseases. GPR120 has been identified as a member of a family of free fatty acid receptors Corresponding author:. McAinch, A.J. ([email protected])
including GPR40 (also known as FFA1), GPR41 (FFA3) and GPR43 (FFA2), which have been reviewed extensively elsewhere [1–4]. As the name suggests, this family of receptors are activated by free FAs of varying chain length with GPR41 and GPR43 being activated predominantly by short-chain FAs, whereas GPR40 and GPR120 are activated by long-chain FAs (LCFAs) [4]. As a result of this, efforts to understand the explicit functions of these receptors in isolation have been clouded by nonspecific endogenous and synthetic ligands for GPR40 and GPR120. Ongoing works have been able to develop more selective chemical agonists and antagonists at these receptors, which has enhanced the current understanding of the roles of these receptors. But caution is still needed in many instances in attributing changes in function solely to one of these receptors. When looking at GPR120 specifically, this receptor has been implicated in a number of processes including release of gastrointestinal peptides, inflammation, adipogenesis, lipogenesis, glucose intolerance, insulin sensitivity and food preference [5– 10]. These factors interrelate to influence systemic metabolic function in physiological and pathophysiological conditions. Herein, we discuss the recent advances in research regarding the roles of GPR120 and how pharmaceutical agents at this receptor could be used in the prevention and treatment of metabolic diseases.
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GPR120 was first identified as an orphan GPCR by Fredriksson et al. [11], who determined the chromosomal location for human GPR120 to be 10q23.33. Human GPR120 was subsequently shown to exist as two splice variants, a short (361 amino acids; accession numbers: RNA – GenBank ID: BC101175 and Protein – GenBank ID: AAI01176.1) and a long (377 amino acid; accession numbers: RNA – NCBI Reference Sequence ID: NM_181745 and Protein – NCBI Reference Sequence ID: NP_859529.2) isoform [6,10,12,13] (Fig. 1). The predicted molecular weight of the long isoform is 42 kDa [11]. Of particular interest, the long GPR120 isoform appears to be human specific, being undetectable in the cynomolgus monkey [14]. Mouse GPR120 appears to correlate more closely with the short isoform present in humans having 361 amino acid residues [11].
Tissue distribution of GPR120 GPR120 is widely expressed in a number of tissue types, and is most abundantly expressed in lung and colonic tissues [6]. This diverse localization of GPR120 is likely related to the broad spectrum of effects GPR120 elicits with expression also being reported in tissues involved in homeostatic regulation of metabolic health and inflammatory and/or immune processes, including the brain, thymus, pituitary, small intestine, white adipose tissues, taste buds, skeletal muscle, heart and liver [6,7,10,15]. However, it appears that species differences exist between the distribution and density of GPR120 (Table 1). As can also be seen in Table 1, GPR120 demonstrates a divergence in tissue localization between different species so that care should be taken when extrapolating results from animal models to a potential therapeutic application in humans because the interspecies differences in expression can confound these findings. It should also be noted, however, that differences in the relative sensitivity of detection techniques used can in part account for some of the variability of expression. Moreover, studies show selective tissue-specific upregulation of GPR120 expression in the extensor digitorum longus (EDL) skeletal muscle, heart and adipose tissues following high fat feeding leading to obesity [5,7,15]. Interestingly Wu et al. [16] demonstrated that not only is GPR120 expressed in a panel of colorectal cancer cell lines and biopsies of human colorectal cancers but this receptor is significantly induced by malignancy in colorectal cancer patients. GPR120 co-localizes with ghrelin in the duodenum [17], a-gustducin in the small intestine and type II taste bud cells [18,19], neuropeptide Y centrally in the arcuate nucleus [20] and glucagon-like peptide 1 (GLP-1) in the colon and circumvallate papillae taste bud cells [6,21,22]. Interestingly GPR120 was also found to be co-expressed with other receptors for FAs including GPR43 in the proximal colon of mice [19] and GPR40 in STC-1 intestinal cells [6]. These distinct patterns of expression and colocalization are likely reflective of the functions of GPR120 discussed below.
Ligands for GPR120 GPR120 is a receptor specific for LCFAs [6]. FAs are generated during lipolysis [23]. Free FAs released into the plasma then circulate and not only provide substrate for energy production but importantly also act as endogenous ligands to modulate the 2
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expression of genes and proteins that regulate a diverse range of physiological and pathophysiogical functions including those related to energy homeostasis [24,25]. Studies to date have shown that unsaturated FAs with a carbon chain length of 16–22, including the omega 3 FAs alpha-linolenic acid (a-LA), docosahexaenoic acid (DHA) and eicosapentaenoic acid act as endogenous ligands for GPR120 [6,8]. Of these, a-LA and DHA appear most potent at GPR120 [6,8]. In the search for small molecule agonists for GPR120, initial studies identified a derivative of peroxisome-proliferator-activated receptor (PPAR) g [26], namely GW9508, as an agonist for GPR120 [27]. However, the dual specificity of GW9508 for GPR40 and GPR120 [27] presents as a confounding variable in the interpretation of results in studies using GW9508 as a result of off-target effects at the other receptor. Further research identified several other potential agonists for GPR120 including the plant-derived compound grifolic acid, which acts as a partial selective GPR120 agonist [28], NCG21 [29] and GSK137647A [22], which are reported as selective at GPR120 (Table 2). Most recently, TUG891 (4-[(4fluoro-40 -methyl[1,10 -biphenyl]-2-yl)methoxy]-benzenepropanoic acid) has been made commercially available as a GPR120 agonist by Tocris Bioscience and R&D Systems. TUG891 is reported to be potent and selective for GPR120 demonstrating greater selectivity and potency to GPR120 than GPR40 [30,31]. However, Hudson et al. [31] also demonstrate phosphorylation and desensitization of GPR120 following stimulation with TUG891, suggesting that tachyphylaxis could complicate the use of this compound therapeutically. Furthermore, the work of Hudson et al. [31] also suggests that interspecies differences in the selectivity of TUG891 to GPR120 over GPR40 exist with a substantial loss of GPR120 selectivity when cells expressing mouse GPR120 were challenged with the agonist. This limits the value of preclinical in vivo studies in mice regarding the activation of GPR120 with TUG891. Interestingly, the GPR40 antagonist GW1100 was reported as being without effect on GPR120 [31] and thus, via selectively inhibiting GPR40, GW1100 used in conjunction with TUG891 might be of benefit in attributing specific effects of TUG891 to GPR120. Because the development of a potent and selective GPR120 agonist is indispensable in the development of GPR120 as a druggable receptor, the availability of TUG891 is a promising step forward in investigating the functions of GPR120 specifically. However, given the interspecies loss of selectivity of TUG891 for GPR120, further research is needed to optimize and characterize fully the functional effects of TUG891 and other potential agonistic compounds at GPR120.
GPR120 signaling GPR120 has been shown to couple to Gaq and b-arrestin 2 mediated pathways [6,8] (Fig. 2). Coupling of GPR120 induces increases in intracellular calcium transients [6,10] and is without effect on intracellular cyclic adenosine monophosphate concentration [6]. Activation of GPR120 has been shown to lead to receptor internalization [8]. Oh et al. [8] show that, in RAW 264.7 cells, DHA stimulation induced translocation of b-arrestin 2 to the plasma membrane where it co-localizes with GPR120. Further treatment with DHA led to internalization of GPR120, which was then observed to co-localize with cytosolic b-arrestin 2 [8]. This suggests that b-arrestin 2 is implicated in GPR120 internalization. Abrogation of b-arrestin 2 signaling via selective
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L
A A E T T V L L A F V L L G V C A V L V R
V V I S N L A
R
T
W
V L I A F L A C N L C A
A P I D L L A
R R R R G
A W L L G P E A V H C V L L Y F V L M T L S G S S V T L I T L L F A A V S V E L M R T V C I V
A G P L R Q P V V R F F V C
P L A L A A V S Y G I W A L L L V A A R R R G P
H L
G
R Q R G V
D Q E I
S I C T L I W P T I P G E I
S D W V S F T V L F N L P V G L I V I V S Y K S I L Q T S E H L L D A R A V V T H S E I T K A
NH2
N F K Q Q
D
I L L I I S W F F M L T L L R Q Q S V R I Q H S E S Y A L S V T L R K R S
I L I T I P M I S V L F R F
L
P F
W F
I L
V V T F A S A L P L I F N D W F P E K G A I L T D T S V K R N D L S I I S G COOH A
V S W F N N Y
Drug Discovery Today
FIGURE 1
Snake-plot diagram of the human GPR120 long isoform. Amino acid residues colored in red highlight the structural difference between the long and short isoforms of GPR120 with these additional 16 amino acids being specific to the long isoform, and not present in the short isoform. Structural diagram was generated using GPCRGB Tools (http://tools.gpcr.org) from protein accession number Q5NUL3.
RNA interference was shown to attenuate DHA-mediated antiinflammatory effects [8] suggesting that, upon binding to GPR120, this LCFA exerts its effects via b-arrestin 2 signaling. However, the dual coupling of GPR120 to Gaq and b-arrestin 2 might account for the divergence in the reported functions of this receptor. Moreover, although not fully characterized at present, it is likely that GPR120-mediated signaling is different in distinct tissue types. Therefore, extrapolating findings from one tissue to another
may be fraught. Thus, further research into the tissue-specific effectors of GPR120 agonism will be important in understanding how pharmaceutical agents that target a distinct signaling pathway could be developed for the treatment of specific disease states. It is interesting to note that the long and short forms of GPR120 exist at different basal levels of phosphorylation, with the short form demonstrating a greater degree of constitutive activity [12]. Importantly, Burns and Moniri [12] showed that, upon activation,
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TABLE 1
Differential tissue distribution of GPR120
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Refs
RNA/Pro
Species
Br
Thy
Adip
Stom
SI
Col
SkM
Hrt
Liv
Kid
Spln
Lung
Panc
Tng
[2]
RNA
Mus
+
+
NR
+
+
+
NR
+
+
+
+
+
NR
NR
[2]
RNA
Hu
+
+
NR
NR
+a
+
NR
+
+
+
NR
NR
[6]
RNA
Rat
+
NR
+
+
NR
+
+
NR
[3]
RNA
Mus
+
NR
+b
+
+
+
+
+
+
+
+
+
NR
NR
[3]
RNA
Hu
NR
NR
+
NR
+
NR
NR
NR
NR
NR
NR
NR
+
NR
[11]
RNA
Rat
NR
NR
NR
NR
NR
NR
+
+
+
NR
NR
NR
NR
NR
[4]
RNA
Mus
Neg
NR
+
NR
+c
NR
Neg
Neg
NR
Neg
Neg
+
NR
NR
[10]
RNA
C-M
+
NR
NR
+
+
NR
NR
+
+
NR
NR
NR
NR
[58]
Pro
Rat
NR
NR
NR
NR
+d
NR
NR
NR
NR
NR
NR
NR
NR
NR
[59]
RNA
Hu
NR
NR
NR
+
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
[1]
RNA
Mus
NR
+e
+
+
+
+
+
NR
[1]
RNA
Hu
NR
NR
+f
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
[15]
Pro
Mus
NR
NR
+
NR
NR
+
NR
NR
NR
NR
NR
+
NR
NR
[13]
Both
Mus
NR
NR
NR
NR
NR
+
NR
NR
NR
NR
NR
NR
NR
+g
[13]
Both
Rat
NR
NR
NR
NR
NR
+h
NR
NR
NR
NR
NR
NR
NR
+i
[41]
Both
Mus
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
+j
Abbreviations: RNA, mRNA; Pro, protein; C-M, Cynomolgus monkey; Mus, mouse; Hu, human; Br, brain; Thy, thymus; Adip, adipose; Stom, stomach; SI, small intestine; Col, colon; SkM, skeletal muscle; Hrt, heart; Liv, liver; Kid, kidney; Spln, spleen; Panc, pancreas; Tng, tongue; +, present; , absent; NR, not reported, Neg, negligible. a Illeum. b Parametrial, peri-renal, epididymal, subcutaneous, mesenteric adipose tissue. c L cells. d Proximal epithelial cells from the duodenum and jejunum. e Epididymal, subcutaneous, peri-renal and brown adipose tissue. f Subcutaneous and omental adipose tissue. g Circumvallate and fungiform papillae. h Enteroendocrine and epithelial cells. i Folliate, fungiform and circumvallate papillae. j Circumvallate papillae.
the long and short isoforms of GPR120 are phosphorylated to the same extent by a-LA and DHA. It is further suggested by Watson et al. [13] that the long isoform of GPR120 exhibits preferential coupling to b-arrestin signaling. Other studies also indicate that there could be a partial loss of function associated with the long isoform of GPR120 [6,14]. Thus, it remains important to determine physiological relevance of the two isoforms and, subsequently, whether pharmaceutical agents act preferentially through the short or long isoform and their associated signaling cascades. To date, downstream effectors of GPR120 activation have been identified as the mitogen-activated kinases, extracellular regulated kinase 1/2 (ERK1/2) [6,8,32], c-Jun N-terminal kinase (JNK), inhibitor of kappa B kinase b (IKKb), inhibitor of kappa B (IkB), transforming growth factor b activated kinase 1 (TAK1) [8], caspase-3 [32] and members of the insulin signaling cascade including Akt (also known as protein kinase B), insulin receptor beta (IRb), insulin receptor substrate (IRS) 1 and 2, and the lipogenic protein stearoyl-CoA desaturase 1 [5]; all of which support a role for GPR120 in mediating inflammation and metabolic homeostasis.
Physiological functions of GPR120 and the implications for metabolic disease GPR120 is proposed as a drug candidate largely for the treatment of metabolic diseases and, in view of the current literature, agonists at this receptor are expected to be of benefit [5–8,33]. Metabolic 4
diseases are often the consequence of a chronic energy imbalance where intake exceeds requirements leading to a prolonged positive energy balance [34]. This is complicated by hedonic and hedonistic factors influencing energy intake and expenditure and, over the longer term, is reflected by an increase in body adiposity [34,35], paralleled by increased risk of co-morbid conditions such as T2DM and CVD. Here, we examine the effect of GPR120 on parameters that are known to influence metabolic health and how these might be targeted in the treatment of disease states that manifest perturbed metabolic function at the tissue-specific and systemic levels. Again, the development of chemical activators and/or inhibitors selective to GPR120 will be invaluable in determining the extent to which GPR120 is responsible for these effects. This might be especially relevant in separating the effects of GPR40 given the similar patterns of expression and dual specificity of LCFAs and chemical compounds developed to date.
Adipogenesis GPR120 is abundantly expressed in adipocyte and adipose tissue extracts [5,7,8], yet is undetectable in pre-adipocytes [7,21]. Moreover, GPR120 expression increases in parallel with lipid accumulation in the cells upon induction of differentiation in 3T3-L1 cells [7,21]. Small interference RNA against GPR120 was shown to reduce the expression of adipogenic genes and reduced lipid droplet accumulation in 3T3-L1 adipocytes [7]. Taken together,
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TABLE 2
Chemical structures of GPR120 agonists Agonist
Structure
a-Linolenic acid
H3C
Docosahexaenoic acid
H3C
[60]
COOH
[60]
COOH [23]
OH
OH COOH TUG891
[25]
Me O OH O
F [24]
NCG21
OH N
N
O
O
GSK137647A
O H N O
[16]
S O
these data support the contention that GPR120 is an adipogenic receptor. Importantly, adipocyte hypertrophy is a key pathogenic feature in the development of obesity. Interestingly, in the study by Gotoh et al. [7], GPR120 mRNA expression was increased by high fat feeding in subcutaneous, epididymal and mesenteric adipose tissues. Ichimura et al. [5] also demonstrated that the expression of GPR120 mRNA is increased in human subcutaneous and omental adipose tissues from obese compared with lean individuals. Both of these studies suggest that GPR120 activity could be augmented by a high dietary lipid load. Given the adipogenic potential of GPR120, it might be expected that augmented activity at GPR120 could promote increased adiposity. Thus, GPR120 activation might be expected to promote obesity. However, GPR120/ mice exhibited significantly greater adipocyte area (hypertrophy) than wild-type mice, an effect that persisted in mice fed a normal or high fat diet [5]. Consistent with adipocyte hypertrophy, GPR120/ mice fed a high fat diet gained significantly more fat mass than their wild-type counterparts [5]. Bodyweight was not observed to be different between GPR120/ and wild-type mice on a normal chow diet [5,8], suggesting GPR120 has an important role in regulating bodyweight in the presence of a positive energy balance and is indeed protective against diet-induced obesity.
Gastrointestinal peptides and intestinal health Gastrointestinal peptides are intimately involved in the regulation of feeding behaviors, energy metabolism and bodyweight [36–41]. GPR120 has been demonstrated to induce secretion of two such peptides: GLP-1 and cholecystokinin (CCK), from enteroendocrine STC-1 cells in vitro [6,9,10]. In both instances, transient knockdown of GPR120 ablated the effect of a-LA on secretion of GLP-1 and CCK, to confirm that GPR120 is indeed responsible for this effect [6,9]. GLP-1 is an insulinotropic, anorectic peptide that reduces gastric emptying and motility [37,38]. Like GLP-1, CCK regulates a diverse range of local and distal physiological effects including promotion of pancreatic secretions, gallbladder contractions, inhibition of gastric motility and secretions, and reduces energy intake [42]. Curiously, GPR120 has also been shown to co-localize with the orexigenic peptide, ghrelin in duodenal cells in vivo and a-LA reduces ghrelin secretion in the MGN31 ghrenlinoma cell line [43]. However, this effect persisted in cells transfected with siRNAs targeting GPR120, which indicates GPR120 was not mediating this effect. Further studies that confirm these results would be of interest given that decreased appetite, which accompanies reductions in ghrelin [44], could provide an adjunctive mechanism by which GPR120 has favorable effects on systemic energy homeostasis. As the current indication of the
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Grifolic acid
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(a)
(b) 1 2 2
γ βarr2
γ
β
α
γ GDP
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GTP
α β
β
GDP P
3 P βa P rr2
Gαq GTP P 4
4
P P r2 arrr2 βa β
3
Transcriptional nscriptional re regulation gulation of downs downstream tream pathways
1
GPR120
Ligand
GDP Guanosine diphosphate
G-proteins
GTP
βarr2
β-arrestin2
Guanosine triphosphate P Phosphorylation Drug Discovery Today
FIGURE 2
Activation of GPR120 signaling. (a) GPR120 activation via Gaq signaling. (1) Inactive state; (2) ligand binds GPR120 externally leading to association with G proteins in an activated state; (3) dissociation of G proteins, activated Gaq is bound to GTP; (4) transcriptional regulation of downstream signaling cascades. (b) GPR120 activation via b-arrestin 2. (1) Inactive state; (2) ligand binds GPR120 externally leading to association with and phosphorylation of b-arrestin 2; (3) internalization of receptor–ligand complex in the activated state; (4) transcriptional regulation of downstream signaling cascades. barr2, b-arrestin2; GDP, guanosine diphosphate; GTP, guanosine triphosphate; P, phosphorylation.
cumulative effects GPR120 agonism has on the secretion of GLP-1 CCK and ghrelin levels, this could culminate in enhanced glycemia, improved appetite control and improved overall energy homeostasis. Beyond a role in mediating the secretion of gastrointestinal peptides, Fredborg et al. [45] showed that GPR120 mRNA expression is increased in intestinal Caco-2 cells by cultured medium from bacteria of the Bacteroidetes and Firmicutes phyla. Dietary composition (such as high fat and alcohol intakes) and obesity can lead to dysbiosis and alter the ratio of intestinal-bacteroidetes:firmicutes [46–49]. This suggests another mechanism whereby GPR120 expression and subsequently function could be upregulated. In contrast to these beneficial effects, Wu et al. [16] recently identified an oncogenic potential for GPR120 in promoting tumorigenesis in colorectal cancers. This study is the first to examine a role for GPR120 in cancer progression but reveals interesting findings with GPR120 mediating pro-angiogenic signaling and promoting chemotaxis in tumor cell lines in vitro, which was supported by in vivo findings showing that GPR120 activation promoted angiogenesis and tumor growth in mice [16]. 6
Although further studies are needed to investigate the effects of GPR120 in carcinogenesis, these data support GPR120 agonism as exerting a cancer-promoting effect, suggesting that applications for GPR120 agonists in intestinal tissues should be approached with caution.
Spontaneous taste preference Hedonia is a major determinant of dietary intake to which taste is intimately linked [50]. Lipid-rich foods are typically highly palatable and energy dense [50]. This palatability predisposes to excessive consumption of lipid-rich foods that, owing to the high energy density, contribute greatly to daily caloric intake. Thus, chronic overconsumption of lipid-rich foods can increase bodyweight and facilitate the development of obesity and associated co-morbidities. GPR120 is expressed in cells responsible for detecting taste including those of the circumvallate, foliate and fungiform papillae [51]. Cartoni et al. [51] provide evidence of a role for GPR120 in mediating spontaneous preference for palatable high fat foods, with GPR120/ mice exhibiting ambivalence toward dietary FAs compared with preferential intake of FAs in wild-type animals.
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Inflammation GPR120 is expressed abundantly in adipose tissues and in macrophages [8]. GPR120 has been shown to exert powerful anti-inflammatory effects [8], which is consistent with activation of GPR120 via omega 3 FAs, a-LA and DHA. These FAs have been widely validated as having anti-inflammatory effects at the tissue-specific and systemic levels [55]. In the study by Oh et al. [8], GPR120 was shown to mediate suppression of the proinflammatory markers IKKb, JNK, TNF-a, interleukin-6 and toll-like receptor-4 in vitro and reduce macrophage infiltration of adipose tissues through decreased chemotaxis in wild-type but not GPR120/ mice. Consistent with this, GPR120 is localized in macrophages with the expression of this receptor being induced by obesity, a pro-inflammatory state, in these cells [8]. In the same study Oh et al. [8] show that the expression of pro-inflammatory genes in M1 macrophages was decreased whilst the expression of M2 anti-inflammatory genes were increased in wild-type but not GPR120/ mice fed a high fat diet supplemented with omega-3 FAs. Cintra et al. [20] further show that following acute injection of omega-3 or omega-9 FAs intracerebroventricularly, GPR120 couples with b-arrestin2 to dissociate TAK1 binding protein from TAK1 and thus reduce the activity of inflammatory pathways, including those mediated by toll-like receptor-4 and tumor necrosis factor (TNF)-a. Considered together, this provides compelling evidence that GPR120 is an anti-inflammatory receptor, with macrophage GPR120 possibly being a crucial mediator of these effects.
GPR120 and insulin signaling The skeletal muscle is a major site of insulin-stimulated glucose uptake [56,57] and thus is implicit in maintaining systemic euglycaemia. Cornall et al. [15] show increased GPR120 mRNA expression in the EDL skeletal muscle which comprises predominantly glycolytic and/or fast-twitch fibers [58,59], therefore relying largely on glucose for energy production. Activity at GPR120 has been shown to have insulin-sensitizing effects [8] and protects from glucose intolerance induced by ingestion of a high fat diet [5]. Consistent with this, GPR120 knockout in mice decreases phosphorylation of IRb and IRS1 in white adipose tissues and IRS1 and IRS2 in the liver [5], all of which are important regulators of insulin-stimulated glucose uptake. This decreased phosphorylation was accompanied by increased fasting glucose and impaired responses to insulin and glucose tolerance testing in GPR120/ mice fed a high fat diet [5]. Likewise, GPR120 was shown to promote glucose transporter 4 translocation in 3T3-L1 adipocytes and directly enhanced glucose uptake via Gaq signaling [8], which is additive to improved insulin sensitivity. However this effect was not observed in L6 muscle cells, which could be explained by the lack of expression reported in these cells in this particular study [8]. The relationship between increased GPR120 expression in the EDL skeletal muscle and systemic glucose control is yet to be investigated. However, if the increased expression of GPR120 correlates with enhanced insulin-stimulated glucose uptake in skeletal muscle, particularly the EDL muscle, this might provide a mechanistic explanation behind enhanced systemic glycemic control. Similarly to the EDL muscle, GPR120 mRNA expression was also increased in cardiac tissue in response to diet-induced obesity in rats [15]. This could support a role for GPR120 in regulating cardiac muscle glucose uptake. Although the adult heart predominantly relies on FAs for energy substrate in the healthy state [60], obesity, diabetes and hypertrophic processes in the heart dysregulate the balance between glucose and FA oxidation [61–64]. The cumulative effect of this is decrements in cardiac efficiency and induction of cellular energetic stress caused by metabolic inflexibility. If activation of GPR120 can attenuate insulin resistance in cardiac muscle GPR120 agonists could also have a role in ameliorating cardiac dysfunction in metabolic disease. Furthermore, GLP-1 not only induces pancreatic insulin secretion in response to glucose but also has been shown to enhance glucose uptake directly in skeletal and cardiac muscle cells [65,66]. The consequence of these factors manifests in four separate but interrelated ways in which GPR120 agonist can: (i) enhance systemic glucose control through enhanced insulin signaling; (ii) increase GPR120 expression in muscle tissues; (iii) enhance GLP-1-mediated increase in glucose-stimulated insulin secretion from the pancreas; and (iv) enhance GLP-1-mediated muscle glucose uptake.
GPR120 modulation of systemic metabolic health GPR120 is a ubiquitous receptor with pleiotropic functioning that supports a role for this receptor in mediating systemic metabolic health (Fig. 3). Regulation of adiposity is modulated by the propensity for adipocytes to store excess energy from ingested lipids and glucose in the form of fat. Partitioning of substrate (i.e. glucose and FAs) away from oxidative pathways predisposes to their storage in adipose tissues as an energy reserve. GPR120 is indeed
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This suggests that aberrant upregulation of GPR120 activity in taste bud cells could foster an increased intake of dietary lipid. Godinot et al. [52] also provide a role for GPR120 and GPR40 in mediating innervation of the glossopharyngeal nerve, indicating an ability to regulate taste. However this paper argues a greater role for GPR40 in mediating taste response to FAs, with GPR40 agonists provoking a ‘fatty’ taste in human subjects, whereas the GPR120 agonists did not [52]. Although further work is needed to delineate the role of GPR120 in mediating taste preference, it is interesting to note that GPR120 expression in the circumvallate papillae was unaffected by dietary lipid content and type, fasting or the diurnal state [53], suggesting that GPR120 is likely to have a relatively stable influence on dietary lipid intake. GLP-1 is known to be expressed in a subset of taste bud cells and has been shown to co-localize with GPR120 in the circumvallate papillae [22]. Local GLP-1 regulates taste preference for sucrose [54]. Analogous to intestinal mediation of GLP-1 by GPR120, Martin et al. [22] report induction of GLP-1 secretion from circumvallate papillae following stimulation with a-LA and GSK137647A. Thus, by means of increasing oral GLP-1 secretion, GPR120 might also be able to modulate preference for dietary carbohydrates as well as FAs. GPR120 could therefore be expected to act as a determinant of dietary composition and manipulation of this function could attenuate overconsumption of energy-dense foods. However it seems that GPR120 activation might promote preferential intake of foods high in FAs and sucrose, therefore modulation of spontaneous taste preference could present a unique role for GPR120 antagonism. Thus, further studies should investigate this effect in free feeding wild-type and GPR120/ mice to ascertain the impact of spontaneous taste preference in relation to bodyweight.
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GPR120
Taste buds
Taste preference for fatty acids
Energy intake
Bodyweight
Intestinal
GLP-1 & CKK release
Appetite
Insulin secretion/ sensitivity
Adipose
Adipogenesis
Bodyweight
Adipokine secretion
Antiinflammatory
Cytokine release/ macrophage infiltration
Systemic inflammatory state
Insulin signaling
Glucose uptake
Euglycemia
Inflammatory tissues
Skeletal muscle
Drug Discovery Today
FIGURE 3
Metabolic effects of GPR120. Rows depict the direct effect of GPR120 in relation to the main known functions of GPR120 (solid arrows). Indirect interactions between these effects mediated by GPR120 (broken arrows) further highlight how GPR120 can be targeted to treat metabolic diseases such as obesity, type 2 diabetes mellitus and cardiovascular disease by way of regulating parameters relating to systemic inflammation, adiposity and glycemic control.
suggested to be adipogenic [5,7,8,21]. Regardless of this, GPR120 knockout mice are more susceptible to diet-induced obesity than their wild-type counterparts [5], implying that GPR120 is protective against diet-induced obesity. Induction of a negative energy balance to promote weight loss must be considered from the point of view of decreased caloric intake and increased energy expenditure. GPR120 has the capacity to modulate taste preferences and induce GLP-1 and CCK which have anorectic and/or satiating effects, both of which have the capacity to regulate gross caloric intake [38,67]. However care must be taken to establish whether GPR120 agonism in taste cells will promote increased intake of energy-dense foods. With respect to increased energy expenditure, immature GPR120/ mice (9–10 weeks of age) fed a high fat diet are also reported to have reduced energy expenditure during light phases [5]. Although this effect was not observed in mature GPR120/ mice (15–16 weeks of age), decreased energy expenditure in young animals favors early increases in body mass that without a compensatory mechanism to reduce adiposity will then persist as age increases. Indeed, in the study by Ichimura et al. [5] bodyweight increased in GPR120deficient mice from week 8 and persisted throughout the duration of the study. In line with increased adiposity, plasma levels of the adipokine leptin have been shown to be increased in GPR120/ mice fed a high fat diet [5]. Leptin is secreted from adipocytes in a manner that is directly commensurate to systemic adiposity [68]. This is consistent with findings that plasma leptin was increased in GPR120 knockout mice fed a high fat diet [5]. Given that leptin is generally considered protective of obesity and promotes glucose 8
and FA metabolism, the finding of hyperleptinemia in GPR120/ animals [5] suggests the development of leptin resistance, which often arises subsequent to obesity [69]. However this effect on plasma leptin was not replicated in the study by Oh et al. [8], who demonstrated that leptin levels were unchanged in wild-type and GPR120-deficient mice maintained on a high fat diet. This indicates that further work is needed to qualify the effects of GPR120 on leptin secretion. Interestingly, GPR120 knockout had no effect on plasma adiponectin levels [5], which is again protective against obesity but is usually expressed in lower amounts in the obese state. Excessive adiposity is also a key pathogenic factor in the development of CVD. Through reductions in bodyweight, GPR120 agonism is therefore also implicated as a potential therapy for obesity and heart and vessel disease. In addition to weight loss, when compared with their wild-type littermates, GPR120/ mice fed a high fat diet develop dyslipidemia exhibiting decreased plasma levels of the unsaturated FAs linoleic, oleic and palmitoleic acid, while exhibiting increased plasma triglycerides and levels of the proinflammatory arachidonic acid and saturated FAs palmitic acid and stearic acid, which was not seen in mice fed a chow diet [5]. Furthermore, Oh et al. [8] showed that the ability of a-LA to reduce plasma triglycerides is lost in GPR120 knockout mice. These results confirm the potential for GPR120 in protecting from dietinduced dyslipidemia. High circulating levels of saturated fats and triglycerides are a known risk factor for the development of atherosclerotic lesions and subsequent heart failure, infarct and stroke. Further to this, GLP-1 is also capable of improving cardiomyocyte glucose uptake [66], which might suggest a role in
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Concluding remarks Overall, GPR120 agonism appears likely to have positive outcomes on health and the current data suggest GPR120 activation to be a valid pharmaceutical target for the treatment of metabolic disease. However the findings of Wu et al. [16] demonstrating that GPR120 activation promoted tumor formation and angiogenesis suggest that GPR120 agonists could be contraindicated in terms of cancer promotion and progression. Thus, despite promising early findings in terms of metabolic health, it is important to note that
research into the systemic functions of GPR120 is largely in its initial stages of preclinical studies. To prescribe GPR120 agonists with confidence for the treatment of obesity, T2DM and/or CVD, it will be important that future studies examine in detail the effects of GPR120 agonists in tissues that are involved in maintaining metabolic health, such as skeletal and cardiac muscle, and also the cumulative effects on systemic parameters of metabolic health in the long term.
Acknowledgements L.M.C. was supported by a scholarship (PB 10 M 5472) from the National Heart Foundation of Australia. A.J.M. was supported by the Australian Government’s Collaborative Research Networks (CRN) program.
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enhancing cardiac metabolic function in the presence of insulin resistance and overt T2DM. Therefore GPR120 agonism could be a valid target for abrogating cardiovascular complications seen in metabolic disease.
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