GPR119 and GPR131: Functional Difference?-Juniper Publishers
Abstract
Recently, two strategies are generally applied in
clinical practice to treat diabetes, namely, glucagon like peptide-1
(GLP-1) analogs and inhibitors of the enzyme dipeptidylpeptidase-IV
(DPP-4) that degrades both GLP-1 and glucose dependent insulin tropic
polypeptide (GIP). Physiologically, after food ingestion,
enteroendocrine cells in the intestinal mucosa may release the
incretins, including GLP-1 and GIP, that can stimulate insulin secretion
from endocrine pancreas and thereby decrease blood glucose. GLP-1 is
produced and released mainly by L-cells located in the distal ileum
while GIP is secreted by enteroendocrine K-cells in the proximal gut.
However, GIP is not focused in clinics because diabetic patients are
mostly GIP resistant. Therefore, development of agent(s) that may
enhance GLP-1 pathway received increasing attentions in recent.
Many G protein-coupled receptors (GPCRs) expressed in
pancreatic islet and GLP-1 is known to be released in response to
activation of two GPCRs, GPCR119 (GPR119) and GPCR 131 (GPR131).
Physiologically, GPR119 regulates fatty acid while GPR131 also named as
TGR5 is mainly activated by bile acid. Both receptors possess the
ability to induce GLP-1 secretion and alleviate diabetes and obesity in
animal studies. Interestingly, both receptors coupled Gs protein to
activate cAMP signaling pathway. However, many functional variations are
observed between GPR119 and GPR131. Therefore, clarification of the
difference may help the reduction of adverse effect(s) during
development of agent(s).
Herein, we cited the published reports showing the
effects of GPR119 or GPR131 activation to conduct the difference between
them. Also, we mentioned our opinions to call the attention(s) for
avoiding the possible side effects during activation of each receptor.
Keywords: GPR119; GPR131; GLP-1; Diabetes; ObesityIntroduction
Diabetes mellitus (DM) is known as metabolic
disorders showing hyperglycemia and hyperlipidemia due to the
dysfunction of pancreatic islets [1]. The prevalence of DM in clinics is
markedly increased and it will reach approximately 439 million in 2030
[2]. Generally, DM is mentioned to include two main subtypes, Type 1
(Insulin dependent diabetes) and Type 2 (Non-insulin dependent diabetes)
subtypes, in addition to others. Clinically, type 2 DM (T2DM)
characterized by insulin resistance in addition to hyperglycemia and/or
hyperlipidemia is widely considered as metabolic disorder [3]. Many
factors, such as reduced insulin secretion from pancreatic dysfunction,
inadequate hepatic glucose production and peripheral insulin resistance,
are introduced to involve in the development of T2DM [4]. Therefore,
therapeutic approaches have been the hot projects to develop critically.
After food ingestion, enteroendocrine cells in the
intestinal mucosa may release the hormones that can stimulate insulin
secretion from endocrine pancreas and thereby lower blood glucose; known
as incretin effect [5]. Two types of incretins were identified in
human, including glucose dependent insulinotropic polypeptide (GIP) and
glucagon like peptide-1 (GLP-1). Physiologically, GLP-1 is produced and
released mainly by L-cells located in the distal ileum while GIP is
secreted by enteroendocrine K-cells in the proximal gut [6]. In recent,
GLP-1 has become a new target for therapeutics of T2DM due to its
insulinotropic activity [5]. However, GIP is not focused in clinics
because patients with T2DM are mostly GIP resistant [7]. Two
strategies have then been applied in clinical practice to treat
T2DM, namely, GLP-1 analogs and inhibitors of the enzyme
dipeptidylpeptidase-IV (DPP-4) that degrades both GLP-1 and
GIP [5]. However, clinical practice meets some limitations,
such as GLP-1 analogs shall be treated by injection only, and
the effectiveness of DPP-4 inhibitors is mild [8]. Therefore,
development of agent(s) that may enhance GLP-1 pathway
received increasing attentions in recent.
Many G protein-coupled receptors (GPCRs) expressed in
pancreatic islet and GLP-1 is known to be released in response
to activation of two GPCRs, GPCR119 (GPR119) and GPCR 131
(GPR131), in addition to others such as GPR40 and GPR120. All
of these GPCRs with a similar genomic sequence were coupled
to G-protein while Taq Man Gene Expression Assays showed
GPR119, mouse- Mm00731497, rat - Rn01648212 and GPR131,
mouse -Mm04212121, rat - Rn00710093 for gene expression
[9].
The GPR119 receptor for regulation of fatty acid was
described as a class 1 (rhodopsin-type) orphan G-proteincoupled
receptor [10]. The oleoylethanolamide (OEA) is
identified as a potential endogenous ligand for GPR119
receptor that has been suggested as novel target for treatment
of diabetes and obesity [11]. Activation of GPR119 by agonists
showed an elevation of cAMP levels to stimulate GLP-1 secretion
from cells. Similarly, activation of GPR 131 can result in same
changes. GPR131 also named as Takeda G-protein-coupled
receptor 5 (TGR5) or G-protein-coupled bile acid receptor 1
(GPBAR1) to bind bile acid in main [12]. Activation of GPR131
(TGR5) receptor may also promote the secretion of GLP-1 [13].
Knockout of GPR131 (TGR5) decreases energy expenditure and
elicits obesity in female mice [14]. Similar to GPR119, GPR131
(TGR5) is also suggested as an attractive target for the treatment
of diabetes and obesity [15]. However, functional difference
between GPR119 and GPR131 remained obscure.
In intestinal L-cells, both GPR119 and GPR131 participated
in GLP-1 secretion through cAMP signaling pathway. Gene of
GPR119 or GPR131 from L-cells can be identified in pancreatic
α-cell line while GLP-1 secretion was stimulated by the activation
of GPR131 (TGR5) but not by GPR119 [9]. Selective secretion
of GLP-1 by GPR131 (TGR5) agonist for glucose homeostasis
has also been demonstrated [16]. Merit of GPR131 (TGR5)
activation from basic research to clinical applications has been
summarized [17]. However, GPR131 (TGR5) agonist may cause
gallbladder filling in mice [18] probably due to the co-released
peptide YY (PYY) while GLP-1 and PYY have been shown to act
synergistically to slow gastric emptying and inhibit food intake
[19]. Interestingly, the recently developed new compound OL3 is
a low-absorbed TGR5 agonist that lowers blood glucose without
inducing gallbladder filling [20]. But, similar effect from GPR119
agonist is still not reported.
For obesity, GPR119 activation by agonist OEA showed the
merits in reduction of feeding behavior [21]. Similar results
were observed during activation of GPR131 [15]. The effect on
obesity is easily to link with GLP-1 because GLP-1 is known to
cause gastric deceleration and increase satiety [22]. However, it
has been reported that OEA is able to suppress the food intake
to a similar level in both wild-type and GPR119-knockout mice
[23]. Additionally, homology clustering analysis showed the
closest relatives of GPR119 to be the cannabinoid receptors [24].
Otherwise, GPR131 agonist bile acids induce energy expenditure
by promoting intracellular thyroid hormone activation [25].
Therefore, treatment of obesity by GPR119 agonist seems not
the same as that induced by GPR131 (TGR5) agonist.
High mRNA levels of GPR131 (TGR5) were detected in human
many organs with a gene located on chromosome position
2q35 and the open reading frame of 993 base pairs, encoding
330 amino acids [26]. Recently, functions of GPR131 (TGR5)
have been extended to more than the metabolic regulation
and included the inflammatory response, cancer and liver
regeneration Guo et al. [27]. Therefore, different to GPR119,
the agonist(s) of GPR131 (TGR5) will be developed to involve in
many functional regulations in the future.
Conclusion
GPR119 and GPR131 (TGR5) have been identified in metabolic
regulation for a long time. However, both receptors possess
different role in another functional regulation. Development
of the ligand(s) both agonist(s) and/or antagonist(s) shall be
concerned the difference to avoid the adverse effect(s).
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