Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

GPR41/FFAR3

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101609

Synonyms

Historical Background

GPR41 (also known as free fatty acid receptor 3 or FFAR3) was identified as a G protein-coupled receptors (GPCRs) in 1997 (Sawzdargo et al. 1997). Sawzdargo et al. discovered GPR40–43, which were identified as tandemly encoded genes present on human chromosomal locus 19q13.1. Human GPR41 (hGPR41) had the same nucleotide length as human GPR42 (hGPR42) and differed by only six amino acids (Sawzdargo et al. 1997). Brown et al. performed similarity searches using public sequence databases to find mammalian orthologues of the hGPR41/hGPR42 pair. They found the mouse locus, which was syntenic with human 19q13.1, contained GPR40–43 orthologues. Only one orthologue of the hGPR41/hGPR42 pair was detected (72% amino acid similarity to hGPR41) (Brown et al. 2003). They also identified bovine and rat orthologues from the overlapping sequences. The amino acid sequences of the orthologues were intermediate between hGPR41 and hGPR42 but more similar to hGPR41. Although four of the six amino acid positions, which differed between hGPR41 and hGPR42, were also conserved among the orthologues, they matched hGPR41 at two or three of these positions, while only matching hGPR42 at one (Brown et al. 2003). This suggests that hGPR42 could have arisen as the result of a gene duplication of hGPR41, which occurred after the human lineage diverged from the rodent and bovine lineages. Since hGPR42 was also reported to occur infrequently in human populations as a polymorphic insert, the mouse, rat, and bovine genes have been named as Gpr41 (Brown et al. 2003).

The Ligand and Signaling of GPR41

For identification of natural ligands for GPR41, Le Poul et al. established a CHO-K1 cell line co-expressing GPR41, Gα16 (a G-protein subunit exhibiting promiscuous interactions) and apoaequorin. This was then screened in an aequorin-based functional assay against peptides, lipids, carbohydrates, and small chemical compounds. Biological activity for GPR41 expressing cells was observed for propionate (Le Poul et al. 2003). Furthermore, they investigated the natural coupling properties and the intracellular signaling pathways activated by GPR41 upon stimulation by propionate. They demonstrated that GPR41 coupled negatively to adenylyl cyclase (AC) through a Gi/o protein, which, in turn, decreased the accumulation of cyclic adenosine monophosphate (cAMP) (Le Poul et al. 2003). These results were confirmed by Brown et al. using the [35S]GTPγS binding assay in HEK293T cells (Brown et al. 2003). They showed that the rank order of potency of ligands for GPR41 was propionate (C3) ~ butyrate (C4) ~ valerate (C5) ~ caproate (C6) > acetate (C2), which are all short-chain fatty acids (SCFAs) consisting of one to six carbon atoms (Le Poul et al. 2003; Brown et al. 2003). Collectively, GPR41 couples with a Gi/o protein and prefers the longer SCFAs (C3–C6), with propionate being the most potent ligand (Table 1).
GPR41/FFAR3, Table 1

Affinity of short-chain fatty acids (SCFAs) for GPR41

Ligand

EC50 of ligand affinity (μM)

Structure

Name

GPR41/FFAR3

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Acetic acid (C2)

>1000b–d

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Propionic acid (C3)

6–127b–d

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Butyric acid (C4)

42–158b–d

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Valeric acid (C5)

42–142b–d

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Caproic acid (C6)

102–134a,c,d

Measured as induction of [Ca2+]ia and GTPγsb in GPR41-transfected HEK293 cells, or cAMPc and [Ca2+]id in GPR41-transfected CHO cells

SCFAs are produced when dietary fibers that are not completely hydrolyzed by the host enzymes during digestion and undergo fermentation by the gut microbiota (Topping and Clifton 2001). SCFAs have been reported to result in a wide range of health benefits including improvements in body composition, glucose homeostasis, blood lipid profiles, and reduced body weight (Donohoe et al. 2011; Offermanns 2014). Therefore, recent evidences have implicated a major role for these SCFAs receptors in the regulation of metabolism, inflammation, and disease. In the following sections, we summarize the recent progress in research on GPR41 and their physiological roles in the regulation of energy homeostasis.

Metabolic Functions of GPR41

GPR41 is expressed in intestinal endocrine L cells, where it stimulates the release of peptide YY (PYY) and glucagon-like peptide (GLP)-1, indicating its involvement in energy homeostasis (Tazoe et al. 2009). The secretion of PYY and GLP-1 was shown to decrease in primary cultured endocrine cells derived from Gpr41-deficient mice (Tolhurst et al. 2012; Samuel et al. 2008). Colonization of human gut-derived microbiota in germ-free mice led to significantly increased circulating levels of PYY, which was suppressed in their Gpr41 knockout littermates (Samuel et al. 2008). Intestinal transit rate was significantly faster in Gpr41 knockout mice compared with wild-type littermates; this phenotype was abolished in germ-free conditions. Moreover, the SCFAs content in feces of Gpr41 knockout mice was significantly higher than in wild-type mice (Samuel et al. 2008). These results suggest that the secretion of PYY from intestinal L cells is due to activation of GPR41 by SCFAs produced by the gut microbes, and the decreased PYY level in Gpr41 knockout mice increases gut motility, which leads to reduced SCFA absorption. In addition, Tolhurst et al. suggested that SCFAs could directly enhance the release of GLP-1 from L cells in the gut. Following an oral glucose load, they pronounced that impairments of plasma GLP-1 responses were observed in Gpr41 knockout mice compared with wild-type mice (Tolhurst et al. 2012); this was confirmed by Nøhr et al. by using the GPR41-selective agonist, AR420626 (Nøhr et al. 2013). Consistent with these findings, oral glucose tolerance was impaired in Gpr41 knockout mice (Tolhurst et al. 2012). In addition, propionate-stimulated activation of GPR41 increased plasma leptin levels, a polypeptide hormone with pleiotropic effects on appetite and energy metabolism. Leptin secretion was increased according to the overexpression of exogenous GPR41 and was decreased by siRNA-mediated knockdown of GPR41 (Xiong et al. 2004). GPR41 is also expressed in mouse and human pancreatic β cells as well as MIN6 and EndoC-βH1 cells, suggesting that it may directly regulate insulin secretion (Tang et al. 2015). These results indicate that regulating GPR41 activation has potential therapeutic targets for the treatment of obesity and type 2 diabetes.

GPR41 is also expressed in the smooth muscle cells in blood vessels, and recent studies have demonstrated that blood pressure regulation is influenced by the gut microbiota (Ahrén et al. 2015; Lye et al. 2009). Oral administration of propionate to wild-type mice promoted a hypotensive response, but this effect was not shown in Gpr41-deficient mice, suggesting that the hypotensive effect of propionate is involved in GPR41 activity (Pluznick et al. 2013). Furthermore, olfactory receptor 78 (OLFR78, which is another SCFAs receptor) could also play an important role in SCFA-mediated renin secretion and blood pressure regulation (Pluznick et al. 2013). Stimulation of GPR41 by SCFAs resulted in a drop in blood pressure, while OLFR78 activation raised the blood pressure (Pluznick et al. 2013, Pluznick 2014). Collectively, SCFAs produced by gut microbiota regulate blood pressure via OLFR78 and GPR41, and these findings provide an opportunity to develop novel therapeutic approaches to treat hypertension.

Peripheral Nervous System by GPR41

Kimura et al. reported that Gpr41 mRNA was abundantly expressed in the mouse sympathetic ganglion, by using in situ hybridization and quantitative RT-PCR analysis (Kimura et al. 2011). They indicated that energy expenditure and heart rate were increased by propionate administration; these effects were not exhibited in Gpr41 knockout mice (Kimura et al. 2011). In addition, treatment with a ganglion blocker hexamethonium had little effect on this propionate-induced increase in heart rate, whereas the β-adrenergic receptor blocker propranolol abolished the response. These results indicate that propionate activates the sympathetic nervous system (SNS) via GPR41 at the ganglionic level (Kimura et al. 2011). This function of GPR41 in sympathetic ganglia is consistent with the lower energy expenditure and obese phenotype of Gpr41 knockout mice reported by Bellahcene et al. (2013). Moreover, sympathetic activation by GPR41 directly leads to noradrenalin release from the sympathetic neurons (Kimura et al. 2011; Inoue et al. 2012). In contrast, β-hydroxybutyrate (β-HB) showed a potent antagonistic effect on GPR41 (Kimura et al. 2011). β-HB, a ketone body produced in the liver during ketogenic conditions such as starvation or diabetes, suppressed propionate-induced sympathetic activation by antagonizing GPR41. However, acetoacetate, another major ketone body, had no significant effect (Kimura et al. 2011). Thus, GPR41 regulates sympathetic activity by sensing the nutritional state, thereby maintaining body energy homeostasis.

Recently, De Vadder et al. demonstrated that propionate-mediated GPR41 activation induced intestinal gluconeogenesis (IGN) via a gut-brain neural circuit and improved insulin resistance (De Vadder et al. 2014). They found the Gpr41 mRNA in the nerve fibers of the portal vein. The SCFA-fed rats exhibited improved glucose tolerance compared with standard-diet-fed rats. This effect from the SCFAs was abolished in mice deficient for IGN, despite similar modifications in gut microbiota composition (De Vadder et al. 2014). This implies that GPR41 stimulation by SCFAs exhibit beneficial effects on the host metabolism via the peripheral nervous system and hormone secretion in the gut.

Immune Functions of GPR41

GPR41 is also expressed in peripheral blood mononuclear cells, monocytes, and macrophages. Although it was reported that GPR41 expression was correlated with inflammatory markers (Pivovarova et al. 2015), the effects of GPR41 in inflammation have not been widely recognized. Trompette et al. reported that mice fed a high-fiber diet showed changes in intestinal and lung microbial populations, in particular by altering the ratio of Firmicutes to Bacteroidetes, followed by an increase in both cecal and serum SCFA levels, resulting in protection against allergic inflammation in the lungs. In contrast, mice that fed a low-fiber diet showed decreased levels of SCFAs and exacerbated symptoms of allergic airway disease. Treatment of mice with propionate led to a protective effect against allergic airway inflammation via GPR41 (Trompette et al. 2014). Propionate also enhanced bone marrow hematopoiesis in a GPR41-dependent manner, by inducing an enhanced generation of macrophage and dendritic cell (DC) precursors. These DCs exhibited an impaired ability to promote T helper type 2 (TH2) cell effector cells in the lungs (Trompette et al. 2014). These results highlight the importance of dietary fermentable fibers and provide a cellular mechanism for an intestinal-bone marrow-lung axis in controlling allergic airway inflammation. In contrast, Kim et al. reported that Gpr41 knockout mice had reduced inflammatory responses after administration of ethanol or TNBS compared with control mice and had a slower immune response against Citrobacter rodentium infection, resulting in the bacteria being cleared more slowly. After administration of ethanol, TNBS, or C. rodentium, SCFAs activated intestinal epithelial cells to produce chemokines and cytokines in vitro and in vivo; this effect was dependent on GPR41 (Kim et al. 2013). Moreover, they showed that GPR41 expressed in immune cells was not important for this phenotype because the clearance of C. rodentium was not improved in Gpr41-deficient mice transplanted with bone marrow cells from wild-type mice. GPR41 in intestinal epithelial cells promoted the expression of pro-inflammatory markers through extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase (Kim et al. 2013). These results suggest that the immune response through GPR41 activation by SCFAs is required for effective clearance of pathogens in the intestine. Collectively, GPR41 may be involved in the beneficial effects of SCFAs on host metabolism through the regulation of immune responses.

Summary

In recent years, many metabolic and immune response pathways have been reported in relation to nutrient-sensing systems. Several studies have provided evidence that GPR41 is a dietary sensors expressed in both metabolic tissues and immune cells that regulates both energy metabolism and inflammatory responses (Fig. 1). These results indicate that GPR41 stimulation by SCFAs has beneficial effects on host metabolism. Thus, GPR41 agonists may serve as a novel therapy for metabolic disorders. Several synthetic compounds have been reported as GPR41 agonists or antagonists, with structural analysis revealing that the presence of small carboxylic acids, including cyclopropanecarboxylic acid, in the structure enhanced GPR41 selectivity (Leonard et al. 2006). Moreover, Hudson et al. reported that these synthetic ligands were allosteric GPR41 modulators with complex and diverse pharmacology (Hudson et al. 2014). A further understanding of the regulation of energy metabolism and inflammatory responses by GPR41 represents an important path for future research in drug development for the treatment of disease such as obesity and type 2 diabetes.
GPR41/FFAR3, Fig. 1

Effects of dietary gut microbial short-chain fatty acids (SCFAs) in energy utilization mediated by GPR41. SCFAs act as ligands for GPR41 and affect host homeostasis through the stimulation of GPR41

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Applied Biological Science, Graduate School of AgricultureTokyo University of Agriculture and TechnologyTokyoJapan