close

Вход

Забыли?

вход по аккаунту

?

Fatty Acid Binding Receptors and Their Physiological Role in Type 2 Diabetes.

код для вставкиСкачать
Arch. Pharm. Chem. Life Sci. 2008, 341, 753 – 761
G. Swaminath
753
Review
Fatty Acid Binding Receptors and Their Physiological Role in
Type 2 Diabetes
Gayathri Swaminath
Amgen Inc., South San Francisco, CA, USA
G-protein-coupled receptors (GPCRs) respond to various physiological ligands such as photons,
ions, and small molecules that include amines, fatty acids, and amino acids to peptides, proteins
and steroids. Therefore, this family of proteins represents an attractive target for biopharmaceutical research [1]. The physiological role of fatty acids and other lipid molecules as important
signal mediators is well studied in various metabolic pathways [2]. Acute administration of free
fatty acids (FFAs) stimulates insulin release. Conversely, chronic exposure to high levels of free
fatty acids leads to impairment of b cell function and lipotoxicity. However, the receptors
through which these fatty acids and lipids act were unknown, until the identification of fatty
acid binding receptors: GPR40, GPR41, GPR43, and GPR119. Based on their tissue-expression profile, and pharmacologic analysis, the fatty acid binding receptors along with lipid binding receptor GPR119 are linked to diabetes and obesity. They play a critical role in the metabolic regulation of insulin release and glucose homeostasis. In this review, the mechanism of receptor activation, pharmacology, and the physiological functions of the fatty acid binding receptors will
be discussed.
Keywords: b cell function / free fatty acids (FFA) / G-protein-coupled receptors (GPCRs) / lipotoxicity / small-molecule
agonists and antagonists /
Received: May 22, 2008; accepted: August 11, 2008
DOI 10.1002/ardp.200800096
Introduction
Type 2 diabetes is the most common form of diabetes and
is the fourth leading cause of global death by disease.
Currently over 100 million people worldwide have type 2
diabetes and the prevalence is increasing dramatically in
both developed and developing countries. By 2010, 220
million people are projected to suffer from this debilitating disease [3]. Diabetes leads to several complications
including cardiovascular disease, diabetic retinopathy,
lipid disorders, and hypertension. Given the dramatic
Correspondence: Gayathri Swaminath, Amgen Inc., 1120 Veterans
Blvd., South San Francisco, CA 94080, USA.
E-mail: gswamina@amgen.com
Fax: +1 650 837-9423
Abbreviations: free fatty acid (FFA); G-protein-coupled receptor
(GPCR); high throughput screening (HTS); lysophosphatidyl choline
(LPC); oleoylethanolamide (OEA); pertussis-toxin (PTX); short-chain fatty
acid (SCFA); transmembrane (TM)
i
2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
rise in affected patient populations, there is an urgent
need for the development of new drugs / therapies that
would be effective alone or in combination with existing
drugs on the market. With the advancement in high
throughput screening (HTS), potential commercial
opportunities have emanated from the identification of
small-molecule agonists and antagonists of novel GPCRs.
Therefore, it is not surprising that the pharmaceutical
industry has embraced and enthusiastically pursued this
target class. Of the approx. 10 000 to 30 000 genes
encoded by the human genome, estimates of the number
of GPCRs vary widely in the human genome. Based on
their sequences as well as their known functions, A 800
GPCRs are listed in the human genome [4 – 5]. There are
around 481 odorant receptors, 28 taste receptors, and
330 receptors for endogenous ligands [6]. It is estimated
that the endogenous ligands are known for 200 GPCRs,
and approximately 50 GPCRs have been de-orphanized to
date [1]. There are, however, around 150 orphan GPCRs
for which ligands are unknown [1]. The importance of
754
G. Swaminath
FFA receptors was highlighted after the de-orphanization
of orphan GPCRs, GPR40, GPR41, GPR43, and GPR119 [7 –
13]. GPR40 is highly expressed in the insulin-secreting b
cells of the pancreas [14]. GPR43 and GPR41 have different tissue distributions and more broad expression profiles; GPR43 is abundant in leukocytes and adipose tissue,
whereas GPR41 is highly expressed in brain, lung, and
adipose tissue [9]. This kindled significant interest in the
pharmaceutical industry, leading to identification of
small molecule agonists / antagonists for treatment of
type 2 diabetes.
Homology of fatty acid binding receptors to
class A GPCRs, and their mechanism of
activation
Despite a highly diverse family with an overall low
sequence homology (20 – 30%), a number of key residues
are highly conserved within the class A receptors. Based
on the alignment of their protein sequence, all fatty acid
receptors show conserved signature motifs similar to
that observed in Class A GPCRs (Fig. 1). The glycine in the
GXXXN motif in transmembrane (TM) 1, is replaced by
leucine and the asparagine (Asn) residue is replaced by
threonine in GPR119. DRY and the NPXXY motif (where X
is any amino acid) in TM 7 are highly conserved with
slight variations in amino acids. These key residues most
likely play an essential role for structural and / or functional integrity of the receptors and tend to cluster in the
central part of the TM-7domain [15 – 16]. The arginine in
the DRY motif is known to bind to a carboxylic group of
GPR40 agonists [17]. Interestingly, the conserved aspartate in the DRY motif is replaced by glycine in GPR40. The
DRY motif is known to play an important role in maintaining the inactive state of GPCR [18].
The substitution of the Asn residue in the NPXXY motif
in different GPCRs has been shown to affect the activation of adenylyl cyclase [19], phospholipase C [20], [21],
phospholipase D [22], and internalization pathways [23 –
24].
GW9508, a potent synthetic agonist of GPR40 binds by
interacting with H137 (4.56), R183 (5.39), N244 (6.55),
and R258 (7.35) [17]. R183 (5.39), N244 (6.55), and R258
(7.35) are directly involved in interactions with linoleate,
an endogenous ligand for GPR40 [17]. Tikhonova et al.
[25], recently has shown that R183 (5.39), and N224 (6.55)
are important residues for the carboxylate group of compound 1, a full agonist of GPR40. The full (compound 1
and 3) and partial agonist (compound 16) interact similarly with R183 (5.39) and N224 (6.55). However, there is a
distinct difference in the interaction of the full agonist 3
i
2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2008, 341, 753 – 761
with H137 (4.56) or H86 (3.32) compared to partial agonist 16. The naphthyl group of the full agonist 3 interacts
equally with either of the histidine residues, while the
partial agonist 16 forms contact with only H86 (3.32) residue. The H86 (3.32) residue is specific for GPR40 and not
shared with other members of the fatty acid receptors.
This data suggests that the binding pocket of GPR40 is
highly flexible and minor structural changes in the
ligand, will result in different ligand-binding modes.
In GPR41 and GPR43, the asparagine residue is
replaced by aspartic acid. The importance of the residues'
critical role in the activation process of these receptors is
still unexplored.
The CWXP motif in TM 6 is known to be conserved in
family A of the GPCRs [26]. The CWXP motif is preserved
in the fatty acid binding receptors except in GPR119,
where the cystine is replaced by a serine. This motif has
been suggested to be important for folding TM 6/7 and
partially involved in the activation mechanism of the
receptors. These residues are well conserved in all the
fatty acid receptors, except GPR119 indicating a common
mechanism of ligand interaction and activation (Fig. 1).
Location and tissue distribution of fatty acid
receptors
Historically, new GPCRs were identified using homologyscreening approaches, such as low-stringency hybridization [27 – 28], degenerate polymerase chain reaction
(PCR) [28], or bioinformatic analyses of the genomes. The
orphan GPCRs that were identified based on their homology screening, lack pharmacological identities and natural ligands. Reverse pharmacology strategies were used
to identify the natural ligands to the identified orphan
receptors. This was done by expressing orphan receptors
in recombinant cell lines and assaying against a library
of small molecules.
GPR119
Human GPR119 was identified by genome sequencing
efforts. It has one coding exon and shares 82% aminoacid identity with mouse GPR119. The endogenous fatty
acid ethanolamide (Oleoylethanolamide) OEA was identified as an agonist of GPR119 [5]. GPR119 is expressed primarily in the pancreas and gastrointestinal tract in
humans [29]. In rodents, GPR119 is present in brain, pancreas, and the gastrointestinal tract [29].
GPR40
Saturated and long chain unsaturated fatty acids are
known to activate GPR40 [8 – 10]. Human GPR40 receptor
www.archpharm.com
Arch. Pharm. Chem. Life Sci. 2008, 341, 753 – 761
Nutrient-sensing GPCRs as Novel Targets for Type 2 Diabetes
755
Figure 1. Amino acid sequence alignment of human fatty acid receptors. The approximate locations of the transmembrane domains
are denoted by the dashed lines. The conserved regions of the sequences are shown in bold similar to other class A GPCRs. The
amino acids that interact with GW9508 a GPR40 small agonist are shaded grey [17].
is highly expressed in the pancreas, the brain, and monocytes. Mouse GPR40 is expressed in the b and a cells of the
pancreas [14]. The most striking common feature of these
receptors is that they are activated by saturated or unsaturated fatty acids of various chain lengths.
GPR41-GPR43
Degenerate polymerase chain reaction was used in the
search for the novel galanin receptor. This search
resulted in identification of a tandemly encoded intronless gene cluster on the CD22 gene localized on human
chromosome locus 19q13.1 [7]. Subsequent sequencing
of the gene and homology revealed the four novel GPCRs
GPR40, GPR41, GPR42, and GPR43. However, these four
i
2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
GPCRs share very little homology with the galanin receptor. GPR40, GPR41, GPR42, and GPR43 are well conserved
across mammalian species. GPR42 is present adjacent to
GPR41 at the same human chromosomal locus. GPR42
may have arisen from gene duplication, and it is possible
that it is a pseudogene. GPR42 shares 92% amino acid
identity with GPR41 [30]. GPR42 differs from GPR41 at
only six amino acid positions; otherwise, the four members of this subfamily share about 30% minimum identity [30]. Several groups have reported that short-chain
fatty acids (SCFAs are defined by a carbon length of six or
fewer carbon atoms) activate GPR41 and GPR43. C3 – C5
chain length fatty acids are more potent on GPR41
whereas to C2 – C3 chain length fatty acids are more
www.archpharm.com
756
G. Swaminath
Arch. Pharm. Chem. Life Sci. 2008, 341, 753 – 761
Table 1. Summary of fatty acid receptors ligands and mechanism of activation in various tissues.
Fatty acids
Type of coupling
Tissue distribution
Mechanism of action
Endogenous ligand Small molecule
agonists/antagonists
GPR119
Gs
Pancreas, gastrointestinal tract
Glucose-dependent insulin
release, GLP secretion, food
intake, body weight
Oleoylethanolamide AR231453
PSN632408
PSN375693
GPR40
Gq
Pancreas, gastrointestinal tract,
brain, monocytes
Glucose-dependent insulin
release
C12-C16 long-chain GW9508
fatty acids
GW1100
GPR41
Gi/o
Immune cells
Leptin regulationa), anti-inflammatory response
C3-C5 short-chain
fatty acids
GPR43
Gi/Gq
Immune cells, spleen,
bone marrow, adipose
tissue
Lipid accumulation, inhibits C2 – C3 short-chain No small molecule
lipolysis, immune functiona) fatty acids
ligands
a)
Mechanism is not fully explored.
potent on GPR43 [31]. In GPR41, the arginine at position
174 forms a salt bridge with the carboxylate group of
ligands. GPR42 is not activated by carboxylate ligands
due to the substitution of tryptophan at the same position 174. Mutation of the W174R in GPR42 restores
ligand binding, indicating that this residue plays an
important role in receptor response [9]. GPR41 is highly
expressed in adipose tissue while GPR43 is expressed
highest in immune cells, the spleen, and bone marrow.
RT-PCR experiments showed a low level of expression of
GPR43 in several non-immune tissues such as placenta,
lung, liver, and adipose tissues. [9]. Low levels of GPR41
expression were also detected in the spleen, peripheral
blood mononuclear cells, the pancreas, and the lung [12].
The identification of these receptors as nutrient sensors of fatty acids makes them valuable as therapeutic
targets in the treatment of type 2 diabetes (Table 1).
Pharmacology and lead optimization
GPR119
The synthesis of the anandamide precursor N-acylphosphatidyl ethanolamine is catalyzed by the enzyme N-acyl
transferase. This reaction is followed by cleavage of the Nacyl phosphatidyl ethanolamine to yield anandamide
such as OEA, hydrolyzed by phospholipase D [32]. The
pharmacological concentration of OEA reaching the cell
surface to activate the GPR119 receptor is unknown. Little is known about the signal transduction mechanism of
GPR119 except that it couples primarily through Gs and
increases cAMP [33]. Overton et al. [29] reported that the
small molecule agonist PSN375693 had a potency of
i
No small molecule
ligands
2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
8.2 lM similar to OEA with an EC50 of 3.2 lM on
hGPR119. The same group showed that further optimization of the series resulted in PSN632408 and improved PK
properties. Treatment with PSN632408 showed reduced
food intake and body weight in rat models after oral dosing at 100 mg/kg. However, no effect of insulin release
was studied with this agonist [29]. HTS and lead optimization resulted in identification of AR231453 as a selective
small molecule agonist for GPR119 in a cAMP assay with
a reported EC50 of 5.7 nM [34]. The agonist AR231453 also
stimulated insulin release in a glucose-dependent manner in isolated rat and mouse islets [34]. The GPR119 agonist AR231453 exhibited good oral bioavailability properties and a dose of 20 mg/kg markedly improved oral glucose tolerance in a dose-dependent fashion [34]. Recently,
Chu et al. [35], demonstrated that AR231453 activating
GPR119, stimulates GLP secretion providing an additional mechanism by which GPR119 regulates glucose
homeostasis. The role of insulin release and GLP secretion by Arena compound AR231453 reportedly resulted
in improved glucose tolerance, reduced body weight
gain, and improved food intake. These results further
highlight the importance of GPR119 as a potential target
for diabetes and obesity.
GPR40
The fatty acid regulation in insulin release by GPR40 was
first reported by Itoh et al. [10]. Of all the fatty acids tested
on the human GPR40 receptor, docosahexaenoic acid,
and 14, 15 dihydroxyeicosa-trienoic acid were the most
potent ligands with an EC50 of around 1 lM [10]. Activation of GPR40 by fatty acids was tested in MIN6 and CHO
cells. Fatty acids were reported to induce calcium
www.archpharm.com
Arch. Pharm. Chem. Life Sci. 2008, 341, 753 – 761
Nutrient-sensing GPCRs as Novel Targets for Type 2 Diabetes
increase and activated the MAPK pathway in MIN6 and
CHO cells. Fatty acids did not induce cAMP production in
MIN6 cells. The increase in calcium response was not attenuated by pertussis-toxin (PTX) treatment in CHO cells
expressing GPR40. The toxin catalyses the ADP-ribosylation of specific G-protein a subunits of the Gi family, and
this modification prevents the coupling of the receptor
to the Gi protein. These findings support the hypothesis
that GPR40 couples primarily through Gq. Among the
fatty acid ligands examined, methyl linoleate did not
show any stimulatory activity, indicating the importance
of the carboxyl moiety in GPR40 activation [10]. Briscoe et
al. [8] reported that 8, 11-eicosatriynoic acid was the most
potent fatty acid with respect to GPR40, and reported a
EC50 of lM. A potent, selective, nM-affinity, small molecule GPR40 agonist was reported by Garrido et al. [36] and
the structure activity relationship (SAR) was explored.
Garrido et al. [36], also showed that carboxamide derivatives activate GPR40 indicating that the carboxyl group
is not an absolute requirement for a GPR40 agonist and
receptor activation. However, the carboxyl moiety does
increase agonistic efficacy more than is observed with
the carboxamide replacement analogs. GW9508 and
GW1100 were identified as potent small molecule partial
agonists and antagonists, respectively, of the GPR40
receptor [37 – 38]. GW9508 was reported to potentiate
insulin release in a glucose-dependent manner. This
effect was abolished on treatment with GPR40 antagonist
GW1100 [37]. The chronic effect of fatty acids leading to
insulin release on pancreatic islets has been a matter of
debate. Although medium and long-chain fatty acids
have been identified as ligands for GPR40, the direct
interaction of fatty acids leading to activation of the
receptor has not been well addressed. With the recent discovery of small molecule agonists and antagonists, it
should be possible to determine the chronic effects of
GPR40 on insulin release in pancreatic islets.
but also influence various functions of the gastrointestinal tract. GPR43 is found in the mucosa of the ileum
which suggests that these SCFAs may play a role in
inflammatory bowel diseases [39]. GPR41 signals through
the Gi/o family, whereas GPR43 couples through both the
Gi/o and Gq pathways. The Ca2+ response induced by
GPR41, was abolished by PTX, indicating that it couples
only through Gi/o [12]. Both the GPR41 and GPR43 receptors activate IP Ca2+ release, stimulate the ERK pathway,
and inhibit cAMP accumulation [12]. So far, no small molecule agonist or antagonists have been reported for these
two receptors. However, based on expression, the exact
physiological role of these receptors remains unknown.
GPR41 and GPR43
SCFAs are produced by bacterial fermentation of undigested carbohydrates from ingested dietary fiber. The
physiological concentrations of SCFAs, after a meal, are
typically around 100 mM in the lumen of the non-ruminant mammalian large intestine [39]. In contrast, the
plasma concentrations of SCFAs are in lM range. The
SCFAs are 2-carbon to 5-carbon weak acids, and include
acetate (C2), propionate (C3), butyrate (C4), and valerate
(C5) which have been reported as physiological ligands
for GPR41 and GPR43 [9]. The ratio of SCFA concentrations in the colonic lumen is about 60% acetate, 25% propionate, and 15% butyrate. Luminal SCFAs not only are
absorbed as nutrients across the intestinal epithelium,
i
2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
757
Metabolic regulation
GPR119
In the b cells and gastrointestinal tract of rodent and
human, the expression of GPR119 opened up avenues for
the exploration of its role in metabolic diseases. Overton
et al. [29] demonstrated that human and mouse GPR119
are activated by OEA. OEA activates peroxisome proliferator-activated receptor-a (PPAR-a), a nuclear receptor, in
nanomolar concentrations. OEA acts on GPR119 [29] and
vanilloid receptor TRP1V [40] in lM concentrations. OEA
is a natural analog of cannabiniod anandamide. The lipid
mediates a decrease in food intake and in regulation of
body weight in various rat-feeding models [41]. The satiety effects and changes in body mass induced by OEA on
GPR119 are still unknown. Lysophosphatidyl choline
(LPC) is another bioactive lipid mediator that activates
GPR119 in addition to activating several other endothelial differentiation gene (EDG) receptors. The physiological role of LPC in stimulating insulin release from pancreatic islets remained a mystery, until the deorphanization
of GPR119. The physiological concentrations of free LPC
levels in plasma are very low compared to the albuminbound form, which is in the range of 120 – 180 lM [42 –
43]. Administration of GPR119 small molecule agonist
PSN632408 was reported to reduce food intake for
18 hours in fasted and freely feeding male Sprague – Dawley rats. The hypophagic effect of the agonist did not
show any decrease in locomotory action, an effect which
has been observed with OEA. This could possibly be due
to specific effects of the synthetic agonist compared to
OEA [29].
Mouse GPR119-specific siRNA significantly blocked
insulin release by LPC in NIT-1 cells. These results indicate that LPC partly promotes insulin release secretion
via GPR119 [33]. AR231453 specific GPR119 agonist
enhanced glucose-dependent insulin release in both HITwww.archpharm.com
758
G. Swaminath
T15 cells and rodent islets. This insulin release was
observed in vivo, where it improved oral glucose tolerance and was abolished in GPR119-KO mice. Apart from
stimulating insulin release in a glucose-dependent manner, AR231453 also reportedly potentiates GLP-1 levels
when administered to mice. Conversely, GLP-1 levels
decreased when the GLP-1 receptor was blocked with
exendin (9 – 39) in the presence of AR231453. No incretin
effect was observed in GPR119 deficient mice. Co-adminstration of AR231453 and sitagliptin, a dipeptidyl peptidase-IV (DPP-4) inhibitor significantly amplified GLP-1 levels and improved glucose tolerance in wild-type mice
compared to administration of either compound alone
[35]. The combined effects of insulin release improved
glucose tolerance, incretin, and hypophagic effects,
makes GPR119 an attractive target for pharmacological
intervention in treatment of type 2 diabetes and obesity
[34].
GPR40
Fatty acids are important metabolic regulators of various
cellular signaling processes. Besides their metabolic role,
they function as energy reserves, as building blocks in
membrane structures, and as lipophilic molecules. The
role of fatty acids as signaling molecules in insulin regulation and glucose homeostasis has been extensively
studied for several years [44 – 45]. Acute and chronic exposure of b cells to fatty acids, have different effects in insulin and glucose metabolism. Acute treatment with (free
fatty acids) FFAs on b cells promotes insulin release.
Other studies have shown that chronic exposure of b cells
to FFAs results in impairment of insulin production and
leads to apoptosis, a phenomenon recognized as lipotoxicity [46]. In humans and rodents, lipid infusion leads to
an increase in plasma insulin and this occurs within
hours of FFAs elevation in the circulation. The increase in
insulin precedes a reduction in insulin sensitivity [47 –
48]. These results suggest that hyperinsulinemia contributes to insulin resistance.
The molecular events underlying the mechanism of
FFA action on glucose balance and insulin release, was
later linked to the fatty acids receptors that were
expressed on surface of b cells as nutrient sensors. However, the direct action of FFAs activating the receptors
remains elusive. The mechanism can occur in the following two ways: (a) free fatty acids can bind directly at the
binding pocket located in the TM domain of the receptors
resulting in a conformational change, leading to activation of the receptor; or (b) the esterified form of FFAs
(resulting from intracellular metabolism) could activate
the receptor. Stewart et al. [49], used fatty acid conjugated
to coenzyme A (CoA) to study the direct binding site of
i
2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2008, 341, 753 – 761
the fatty acid on the receptor. However, the fatty acidCoA and the free CoA activated the mouse GPR40 receptor in Xenopus oocytes leading to a new discovery that
CoA by itself, can activate the receptor. This resulted in
the direct effect of binding and activation of FFAs on the
receptor at cell surface difficult to further explore. FFAs
activate GPR40, causing an increase in intracellular Ca2+
levels via activation of the Gq-phospholipase C pathway.
The capacity to increase Ca2+ from intracellular stores is
dependent on the glucose activation of the L-type Ca2+
channels and the presence of extracellular Ca2+ [50 – 51].
Zhang et al. [52] have shown that oleate promoted the
activation of the MAPK pathway mainly via GPR40. This
increased the expression of the early growth response
gene-1, leading to the anti-lipoapoptotic effect on NIT-1
cells. Intriguingly, saturated fatty acids such as palmitic
acid and stearic acid are pro-apoptoic whereas unsaturated fatty acids such as oleic and linoleic acid are
reported to increase proliferation in breast cancer cells
[53]. Reduction in insulin secretion upon fatty acid stimulation was investigated by Itoh's group [10] using GPR40
siRNA (short interfering RNA) in MIN6 cells. Activation of
GPR40 by fatty acids leads to glucose stimulated release
(GSIS) in pancreatic b cells [10] and [37]. In contrast, Steneberg et al. [54], showed that transgenic over-expression of
GPR40 in b cells leads to perturbed GSIS and diabetes.
GPR40 wild type mice (fed a high fat diet for eight weeks),
developed hyperinsulinemia, hepatic steatosis, hypertriglyceridemia, increased hepatic glucose output, and glucose intolerance. While chronic treatment of FFAs did
not lead to b cell impairment in GPR40 deficient mice
[54]. All these studies demonstrate the pleiotropic effects
of FFAs on insulin secretion upon activation of GPR40.
This necessitates the development of both potent agonists and antagonists of GPR40 so that the detailed mechanism of the receptor in glucose balance may be unraveled.
GPR41 and GPR43
Although the cognate ligands for GPR41 are similar to
those of GPR43, but with differing specificity based on
carbon-chain length, the direct role of this receptor in
mediating insulin release or involvement in glucose balance is not known. Brown et al. [9] have shown that
GPR41 mRNA expression is barely detectable after in-vitro
differentiation of 3T3-L1 and 3T3-F442A fibroblasts. Moreover, only low levels of GPR41 were detected in human
adipocytes and adipose-tissue sections. These results are
consistent with findings that detection of inhibition of
isoprenaline-stimulated lipolysis in rat primary adipocytes could not be detected. Since GPR41 is also expressed
in immune cells, its role may be linked to propionic acidwww.archpharm.com
Arch. Pharm. Chem. Life Sci. 2008, 341, 753 – 761
Nutrient-sensing GPCRs as Novel Targets for Type 2 Diabetes
emia, a rare inherited disorder caused by deficiency in
the activity of propionyl-CoA carboxylase [55]. Xiong et al.
[56] demonstrated the expression of GPR41 in mouse adipose tissue and a mouse adipogenic cell line. Leptin production was observed upon stimulation by propionate in
mouse adipocytes and ablated by PTX indicating Gi/o-pathway involvement. Silencing the GPR41 gene using siRNA
inhibited leptin production in adipocytes, confirming
the direct involvement of the receptor. In mice, acute
oral administration of propionate has been found to
increase circulating leptin levels [56]. Since propionate is
also a ligand for GPR43, its effect on the receptor, if demonstrated, would have shed light towards a deeper understanding of both GPR41 and GPR43 receptors. Consistent
with the findings of Brown et al. [9] and Hong et al. [57],
GPR41 mRNA was undetectable in the four different
types of adipose tissues. The results of these discrepancies
are not known. Leptin is a anorexigenic hormone inhibiting food intake through receptors in the brain [58]. It is
possible that GPR41 may be influenced by appetite control mechanisms through action of SCFAs. Thus far, the
functions and direct physiological role of the receptor in
obesity and adipogenesis have not been clearly established.
Generally, the fasting and postprandial serum concentration of acetate is around 100 lM, and 4 to 5 lM for propionate in humans [59]. Ethanol administration
increases acetate concentration 10-fold compared to
basal values. Acetate and propionate reduce isoproterenol-stimulated lipolysis in a dose-dependent manner in
vitro. The role of SCFAs in inhibiting lipolysis in fat cells
is similar to the insulin action. Knock-down of GPR43 by
siRNA reportedly does not lead to anti-lipolysis in 3T3-L
cells [57]. Acetate and propionate were reported to
increase the mRNA expression level of GPR43 in differentiated adipocytes and administration increased fat accumulation. Treatment with GPR43 specific siRNA in 3T3-L
cells was found to reduce lipid accumulation. Mice fed
on a high-fat diet also showed enhanced expression of
GPR43, indicating its role in lipid accumulation [57].
Taken together, these studies further emphasize the role
of GPR43 in lipid accumulation, adipocyte differentiation, stimulating anti-lipolysis activity, and validating
the importance of GPR43 in adipogenesis. GPR43 is also
expressed in immune cells and in the colon of the rat
intestine [39]. The effects of SCFAs in the intestinal lumen
are considered to be induced via specific receptors and /
or absorption by epithelial cells. However, the specific
sensing mechanism in the intestinal lumen is currently
unclear. It is reported that SCFAs potentiate an antiinflammatory response in the immune cells [60]. The
exact physiological roles of GPR41 or GPR43 can be eluci-
dated by generation of KO mice and examining their phenotypes with respect to lipid accumulation and adipogenesis. Development of specific synthetic agonists for
these receptors would also be helpful in understanding
GPR43's role as a valuable therapeutic target.
i
2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
759
Pathophysiology and treatment of type 2
diabetes
GPR119
Lauffer et al. [61] have shown that GPR119 stimulates
insulin release by two complementary mechanisms: activation of adenylyl cyclase with increase in the cAMP levels and by induction of GLP-1 secretion. The small molecule agonists of GPR119 with its dual mechanism of
action awaits clinical trials in humans to demonstrate its
utility as a novel incretin agent in treatment of type 2 diabetes.
GPR40
The etiology of type 2 diabetes is governed by several factors including, beta cell dysfunction, impaired insulin
secretion, glucose intolerance, and inappropriate glucagon secretion. However, the effects of nutrients on insulin secretion are often underappreciated. It is known that
the amino acids are effective stimulators of insulin secretion. What is unknown and is a matter of debate, is the
effective role of fatty acids and their receptors in insulin
secretion and glucose balance. Nutrient-induced insulin
secretion is involved to correct the loss of the first phase
of insulin secretion. This is the point at which glucose
intolerance develops. Restoration of the first phase of
insulin response improves blood glucose immediately
after eating and few hours later. It is known that fatty
acids are released during this first phase of insulin. Based
on this observation, one can speculate that the fatty acids
released, can activate the GPR40 receptor and stimulate
calcium release. This, in turn, would trigger insulin
release from ß cells. GPR40 receptor is expressed in L-cell,
but the role of this receptor in GLP-1 secretion is still
unknown.
GPR43
It hss been shown that GPR43 is expressed in adipocytes
and inhibits lipolysis thereby reducing plasma FFA levels.
The reduction in plasma FFA levels can control plasma
lipid parameters, which, in turn, are linked to diabetes
and obesity [62].
Based on these interesting pharmacological data and
tissue expression, there is still a potential need for a
deeper understanding of the biology of novel orphan
www.archpharm.com
760
G. Swaminath
islet GPCR targets. Such an improved understanding may
pave a way towards the development of potent small molecule drugs with greater efficacy and safety for treating
type 2 diabetes patients.
I would like to thank Richard Lindberg, Bei Shan, Barry Friedrichsen, William Simonet, and David Lacey for reviewing the
manuscript.
The author has declared no conflict of interest.
References
[1] K. Lundstrom, IDrugs 2005, 8, 909 – 913.
[2] C. J. Nolan, M. S. R. Madiraju, V. Delghingaro-Augusto, M.
L. Peyot, M. Prentki, Diabetes 2006, 55, 16 – 23.
[3] A. F. Amos, D. J. McCarty, P. Zimmet, Diabet. Med. 1997, 14,
S1 – 85.
[4] D. K. Vassilatis, J. G. Hohmann, H. Zeng, F. Li, et al., Proc.
Natl. Acad. Sci. U. S. A. 2003, 100, 4903 – 4908.
[5] R. Fredriksson, M. C. Lagerstrom, L. G. Lundin, H. B.
Schioth, Mol. Pharmacol. 2003, 63, 1256 – 1272.
[6] S. Takeda, S. Kadowaki, T. Haga, H. Takaesu, S. Mitaku,
FEBS Lett. 2002, 520, 97 – 101.
[7] M. Sawzdargo, S. R. George, T. Nguyen, S. Xu, et al., Biochem. Biophys. Res. Commun. 1997, 239, 543 – 547.
[8] C. P. Briscoe, M. Tadayyon, J. L. Andrews, W. G. Benson, et
al., J. Biol. Chem. 2003, 278, 11303 – 11311.
[9] A. J. Brown, S. M. Goldsworthy, A. A. Barnes, M. M. Eilert, et
al., J. Biol. Chem. 2003, 278, 11312 – 11319.
[10] Y. Itoh, Y. Kawamata, M. Harada, M. Kobayashi, et al.,
Nature, 2003, 422, 173 – 176.
[11] K. Kotarsky, N. E. Nilsson, E. Flodgren, C. Owman, B. Olde,
Biochem. Biophys. Res. Commun. 2003, 301, 406 – 410.
[12] E. Le Poul, C. Loison, S. Struyf, J. Y. Springael, et al., J. Biol.
Chem. 2003, 278, 25481 – 25489.
[13] N. E. Nilsson, K. Kotarsky, C. Owman, B. Olde, Biochem. Biophys. Res. Commun. 2003, 303, 1047 – 1052.
[14] R. Bartoov-Shifman, G. Ridner, K. Bahar, N. Rubins, M. D.
Walker, J. Biol. Chem. 2007, 282, 23561 – 23571.
[15] S. G. Rasmussen, H. J. Choi, D. M. Rosenbaum, T. S. Kobilka,
et al., Nature 2007, 450, 383 – 387.
[16] S. Yohannan, S. Faham, D. Yang, J. P. Whitelegge, J. U.
Bowie, Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 959 – 963.
[17] C. S. Sum, I. G. Tikhonova, S. Neumann, S. Engel, et al., J.
Biol. Chem. 2007, 282, 29248 – 29255.
[18] G. E. Rovati, V. Capra, R. R. Neubig, Mol. Pharmacol. 2007,
71, 959 – 964.
[19] L. S. Barak, L. Menard, S. S. Ferguson, A. M. Colapietro, M.
G. Caron, Biochemistry 1995, 34, 15407 – 15414.
[20] J. H. Perlman, A. O. Colson, W. Wang, K. Bence, et al., J. Biol.
Chem. 1997, 272, 11937 – 11942.
[21] S. C. Sealfon, L. Chi, B. J. Ebersole, V. Rodic, et al., J. Biol.
Chem. 1995, 270, 16683 – 16688.
i
2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2008, 341, 753 – 761
[22] R. Mitchell, D. McCulloch, E. Lutz, M. Johnson, et al.,
Nature 1998, 392, 411 – 414.
[23] C. Gales, A. Kowalski-Chauvel, M. N. Dufour, C. Seva, et al.,
J. Biol. Chem. 2000, 275, 17321 – 17327.
[24] R. He, D. D. Browning, R. D. Ye, J. Immunol. 2001, 166,
4099 – 4105.
[25] I. G. Tikhonova, C. S. Sum, S. Neumann, S. Engel, et al., J.
Med. Chem. 2008, 51, 625 – 633.
[26] F. Boeckler, H. Lanig, P. Gmeiner, J. Med. Chem. 2005, 48,
694 – 709.
[27] J. R. Bunzow, H. H. van Tol, D. K. Grandy, P. Albert, et al.,
Nature 1988, 336, 783 – 787.
[28] F. Libert, M. Parmentier, A. Lefort, C. Dinsart, et al., Science
1989, 244, 569 – 572.
[29] H. A. Overton, A. J. Babbs, S. M. Doel, M. C. Fyfe, et al., Cell
Metab. 2006, 3, 167 – 175.
[30] A. J. Brown, S. Jupe, C. P. Briscoe, DNA Cell Biol. 2005, 24,
54 – 61.
[31] D. K. Covington, C. A. Briscoe, A. J. Brown, C. K. Jayawickreme, Biochem. Soc. Trans. 2006, 34, 770 – 773.
[32] D. Piomelli, Nat. Rev. Neurosci. 2003, 4, 873 – 884.
[33] T. Soga, T. Ohishi, T. Matsui, T. Saito, et al., Biochem. Biophys. Res. Commun. 2005, 326, 744 – 751.
[34] Z. L. Chu, R. M. Jones, H. He, C. Carroll, et al., Endocrinology
2007, 148, 2601 – 2609.
[35] Z. L. Chu, C. Carroll, J. Alfonso, V. Gutierrez, et al., Endocrinology 2008, 149 (5), 2038 – 2047.
[36] D. M. Garrido, D. F. Corbett, K. A. Dwornik, A. S. Goetz, et
al., Bioorg. Med. Chem. Lett. 2006, 16, 1840 – 1845.
[37] C. P. Briscoe, A. J. Peat, S. C. McKeown, D. F. Corbett, et al.,
Br. J. Pharmacol. 2006, 148, 619 – 628.
[38] S. C. McKeown, D. F. Corbett, A. S. Goetz, T. R. Littleton, et
al., Bioorg. Med. Chem. Lett. 2007, 17, 1584 – 1589.
[39] S. Karaki, R. Mitsui, H. Hayashi, I. Kato, et al., Cell Tissue Res.
2006, 324, 353 – 360.
[40] X. Wang, R. L. Miyares, G. P. Ahern, J. Physiol. 2005, 564,
541 – 547.
[41] F. Rodriguez de Fonseca, M. Navarro, R. Gomez, L. Escuredo, Nature 2001, 414, 209 – 212.
[42] W. Y. Fujimoto, S. A. Metz, Endocrinology 1987, 120, 1750 –
1757.
[43] W. Y. Fujimoto, J. Teague, Diabetes 1989, 38, 625 – 628.
[44] W. A. Seyffert Jr., L. L. Madison, Diabetes 1967, 16, 765 – 776.
[45] W. B. Greenough 3rd, S. R. Crespin, D. Steinberg, Lancet
1967, 2, 1334 – 1336.
[46] J. D. McGarry, R. L. Dobbins, Diabetologia 1999, 42, 128 –
138.
[47] G. Boden, X. Chen, J. Rosner, M. Barton, Diabetes 1995, 44,
1239 – 1242.
[48] G. Boden, Endocr. Pract. 2001, 7, 44 – 51.
[49] G. Stewart, T. Hira, A. Higgins, C. P. Smith, J. T. McLaughlin, Am. J. Physiol. Cell. Physiol. 2006, 290, C785 – 792.
[50] K. Fujiwara, F. Maekawa, T. Yada, Am. J. Physiol. Endocrinol.
Metab. 2005, 289, 670 – 677.
[51] H. Shapiro, S. Shachar, I. Sekler, M. Hershfinkel, M. D.
Walker, Biochem. Biophys. Res. Commun. 2005, 335, 97 – 104.
www.archpharm.com
Arch. Pharm. Chem. Life Sci. 2008, 341, 753 – 761
Nutrient-sensing GPCRs as Novel Targets for Type 2 Diabetes
[52] Y. Zhang, M. Xu, S. Zhang, L. Yan, et al., J. Mol. Endocrinol.
2007, 38, 651 – 661.
[57] Y. H. Hong, Y. Nishimura, D. Hishikawa, H. Tsuzuki, et al.,
Endocrinology 2005, 146, 5092 – 5099.
[53] S. Hardy, W. El – Assaad, E. Przybytkowski, E. Joly, et al., J.
Biol. Chem. 2003, 278, 31861 – 31870.
[58] P. Cohen, C. Zhao, X. Cai, J. M. Montez, et al., J. Clin. Invest.
2001, 108, 1113 – 1121.
[54] P. Steneberg, N. Rubins, R. Bartoov-Shifman, M. D. Walker,
H. Edlund, Cell Metab. 2005, 1, 245 – 258.
[59] T. M. Wolever, R. G. Josse, L. A. Leiter, J. L. Chiasson, Metabolism 1997, 46, 805 – 811.
[55] W. A. Fenton, R. A. Gravel, D. S. Rosenblatt in The Metabolic
and Molecular Bases of Inherited Disease (Eds.: C. R. Scriver, A.
L. Beaudet, D. Valle, W. S. Sly), McGraw-Hill Book Co, New
York, 2000, pp. 2165 – 2193.
[60] A. Andoh, T. Tsujikawa, Y. Fujiyama, Curr. Pharm. Des.
2003, 9, 347 – 358.
[61] L. Lauffer, R. Iakoubov, P. L. Brubaker, Endocrinology 2008,
149, 2035 – 2037.
[56] Y. Xiong, N. Miyamoto, K. Shibata, M. A. Valasek, et al.,
Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 1045 – 1050.
[62] H. Ge, X. Li, J. Weiszmann, P. Wang, et al., Endocrinology
2008, 149, 4519 – 4526.
i
2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
761
www.archpharm.com
Документ
Категория
Без категории
Просмотров
9
Размер файла
1 074 Кб
Теги
acid, physiological, thein, diabetes, role, receptors, typed, fatty, binding
1/--страниц
Пожаловаться на содержимое документа