Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Kristen Lednovich
 + 2446 word(s) 2446 2021-05-19 08:58:27 |
2 format correct
Nora Tang
 Meta information modification 2446 2021-05-20 03:06:16 |

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Lednovich, K. SCFA Receptors in T1D Pathology. Encyclopedia. Available online: https://encyclopedia.pub/entry/9867 (accessed on 18 November 2024).
Lednovich K. SCFA Receptors in T1D Pathology. Encyclopedia. Available at: https://encyclopedia.pub/entry/9867. Accessed November 18, 2024.
Lednovich, Kristen. "SCFA Receptors in T1D Pathology" Encyclopedia, https://encyclopedia.pub/entry/9867 (accessed November 18, 2024).
Lednovich, K. (2021, May 19). SCFA Receptors in T1D Pathology. In Encyclopedia. https://encyclopedia.pub/entry/9867
Lednovich, Kristen. "SCFA Receptors in T1D Pathology." Encyclopedia. Web. 19 May, 2021.
SCFA Receptors in T1D Pathology
Edit
This entry is adapted from the peer-reviewed paper 10.3390/metabo11050302

SCFAs, mainly acetate, butyrate, and propionate, are gut microbiota fermentation byproducts of indigestible fiber. The majority of SCFAs are readily absorbed and utilized by the colonocytes as an energy source. Remaining SCFAs are drained into the hepatic and portal venous systems before emerging into the systemic circulation. SCFAs affect host physiology in numerous ways, acting both as metabolic substrates and signaling molecules. Distinct GM and SCFA profiles in T1D versus controls provide compelling evidence for the roles of SCFA receptors in disease pathology. For a better understanding of this role, a review of known functions of FFA2 and FFA3 centering on the endocrine pancreas, immune cells, and gut is presented. Discussion of the roles of these receptors in other tissues has been covered elsewhere.

free fatty acid receptor (FFA) 2 FFA3 gut microbiome incretin insulin secretion FFA2 Type 1 Diabetes T1D fiber diet GPCR

1. SCFAs as Signaling Molecules

SCFAs act as extracellular signaling molecules by binding to their cognate G-protein-coupled receptors (GPCRs), FFA2 and FFA3, which can bind all the three SCFAs but with discrete efficacies (Table 1) and G-protein coupling profiles. Due to their coexpression in tissues, shared endogenous ligands, and lack of selective synthetic ligands, defining their physiological roles has been challenging. However, recent studies using novel rodent models have provided an increased appreciation of the roles of these receptors in various metabolic and immune states [1].

Table 1. Affinity (EC50 in μM) of SCFAs at their cognate receptors.

SCFA FFA2 FFA3
Acetate 35–431 >1000
Propionate 14–290 6–127
Butyrate 28–371 42–158
Pentanoate >1000 42–152
Hexanoate - 102–134

All values are for human receptors [2][3][4].

2. FFA2 and FFA3 Regulate β Cell Physiology

Both FFA2 and FFA3 are expressed in islets, predominantly in the β cells in both rodents and humans [5]. Pioneering work from the Layden Laboratory along with others has established the role of these receptors in the regulation of β cell function and mass [6][7][8][9][10][11][12]. Most of these effects are based upon distinct G-protein coupling preferences of FFA2 and FFA3. Upon SCFA binding, FFA2 can couple with either Gαq/11 and Gαi/o, thus exerting stimulatory or inhibitory effects on cellular function, respectively. FFA3, on the other hand, couples almost exclusively with Gαi/o, with an inhibitory tone in its signaling [3]. Accordingly, in the islet, these receptors have opposing effects on insulin secretion: in both human and mouse islets, FFA3 inhibits insulin secretion in a Gαi/o-dependent manner [6][10][13], whereas FFA2 activation may increase [7][12][14][15] or decrease insulin secretion [13], depending upon whether it couples to Gαq/11 or Gαi/o. Variance observed in FFA2 activity suggests that under any given condition, the effect of FFA2 activation on insulin secretion depends upon its preferred G-protein coupling [7][12]. This calls for the development of G-protein-biased ligands for FFA2. In fact, orthosteric FFA2 agonists SCA14, SCA15, and ZINC03832747 mediate the Gαq/11-dependent increase in mouse islets or β cell insulin secretion in contrast to the allosteric agonists CMTB and CPTB that decrease insulin secretion via Gαi/o [7][16].

Mediation of β cell function by these receptors projects a similar profile in vivo. Whole-body deletion of FFA3 improves insulin secretion and glucose tolerance both under high fat diet induced metabolic stress [10][11][13] and a regular diet [10][11]. Correspondingly, β-cell-specific FFA3 overexpression deteriorates glucose responsiveness in mice [10]. These effects appear to be a β cell secretory phenotype, as no changes in insulin sensitivity have been observed [10][11][13]. Additionally, gene expression analysis of islets from FFA3 knockout mice [7] or β-cell-specific FFA3 overexpression mice [10] revealed complementary changes (i.e., downregulation in knockout and upregulation in overexpression model) in genes related to inflammation and immune response (such as IL1β, IL1α, CD80), besides changes in genes of calcium response and glucose utilization pathways.

Evaluation of the in vivo roles of FFA2, similar to the ex vivo data, has yielded conflicting results. Mice globally lacking FFA2 exhibited fasting hyperglycemia, reduced insulin secretion, and glucose intolerance under dietary metabolic stress [7][12]. In contrast, another study has reported a phenotype of improved glucose tolerance and enhanced insulin secretion in FFA2 knockout mice [13]. Additionally, in this same study, FFA2 and FFA3 double knockout or FFA3 knockout in combination with β-cell-specific FFA2 knockout improved glucose tolerance and insulin secretion under metabolic stress. These conflicting data may arise from differences in the G-protein coupling of activated FFA2, roles of FFA2 in other metabolically active tissues, impact of gut microbiome, and/or duration of metabolic stress, besides receptor-independent effects of SCFAs [17][18][19].

SCFA receptors, specifically FFA2, also modulate β cell mass [8][9][12]. FFA2 is required for the prenatal establishment of β cell mass, as FFA2 knockout mouse neonates and 21-day-old weanlings exhibit impaired β cell mass at birth and throughout adulthood [9]. Under conditions of dietary metabolic stress [12] and pregnancy [8], when β cells are compensating for insulin resistance, this deficiency in β cell mass is magnified. FFA2 activation, as a matter of fact, increases β cell proliferation [9][12], enhances the expression of genes involved in β cell differentiation [12], and reduces cytokine- and palmitate-induced β cell apoptosis [14][15]. FFA3, on the other hand, as a Gαi/o-coupling receptor, may restrict β cell mass [20]. However, FFA3 knockout mice islets have been reported to be smaller with reduced proliferation and number of β cells [10], an effect not seen in a later study [11]. Similarly, β-cell-specific FFA3 overexpression in mice shows compensatory increased β cell proliferation and area [10]. Collectively, these data highlight the role of SCFA receptors FFA2 and FFA3 in modulating β cell function and mass. Importantly, defects in these two features are fundamental to the pathology of T1D.

3. FFA2 and FFA3 Modulate Incretin Secretion

In addition to their role within pancreatic islets, SCFA and their receptors are suggested to participate in the secretion of incretin hormones. In the upper intestine, SCFA concentrations range from 0.1 to 1 mM and are largely produced by oral microbiota [21]. By contrast, luminal SCFAs in the colon can reach levels of up to 100 mM due to the fermentation of dietary fibers via the gut microbiota. Within the intestine, SCFA receptors FFA2 and FFA3 are thought to act as sensors of these metabolites, and many important actions are carried out through this signaling.

Secreted by enteroendocrine cells (EECs) embedded within the intestinal epithelium, incretin hormones are peptide hormones that stimulate the release of insulin in response to nutrient intake, thereby lowering the level of circulating blood glucose [22]. Additionally, incretin hormones facilitate numerous postprandial metabolic functions, including lowering food intake, gastric emptying, and increasing cardiac output [23]. There are two primary incretin hormones: glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). While both hormones carry out their various functions through the binding of their specific receptors (GLP-1R and GIPR, respectively) on the surface of various tissues, they contribute to the regulation of glucose metabolism in distinct mechanisms. Although both stimulate insulin release through Gα/cAMP at β cells, in islet α cells, GLP-1 suppresses glucagon, while GIP increases it [24]. Both hormones also protect β cell mass by inhibiting apoptosis. GLP-1 and GIP play important roles in the control of glucose levels after a meal via the physiological response known as the “incretin effect.” This occurs when higher levels of glucose-stimulated insulin secretion are observed when glucose is administered orally rather than intravenously, an effect that is lost in type 2 diabetes but preserved in T1D [25].

FFA2 and FFA3 are broadly expressed within EECs throughout the gastrointestinal tract. EECs are divided into subtypes based on the peptide hormone they express and secrete [26]. Using immunohistochemical analysis and a Ffar2-red fluorescent protein (RFP) reporter mouse, FFA2 has been found to colocalize with peptide YY (PYY)/GLP-1 containing L cells in rodents and humans [27][28][29][30]. Using in situ hybridization and a Ffar3-RFP reporter mouse, FFA3 expression has been confirmed in several types of intestinal cells, including PYY-positive cells [27][31][32]. However, due to the concentrated expression of FFA3 in enteric ganglia and sympathetic ganglia, it is uncertain if its effects on EEC function arise from its expression in enterocytes or are secondary to its mediation of enteric neuronal function [27][33][34]. Further, transcriptomic analysis has found high coexpression of both receptors with gip, indicating their possible involvement in mediating GIP secretion [35].

Several studies have shown that stimulation of FFA2 by SCFA results in an increased secretion of GLP-1 from EECs in the intestine. Primary intestine cells harvested from global FFA2 knockout mice showed reduced GLP-1 release in vitro, and another study by the same group found that propionate was able to stimulate GLP-1 release in vivo only in the wild-type mice [36][37]. Besides GLP-1, studies have also documented the role of FFA2 in mediating GIP [12] and PYY secretion, with the latter in both humans and mice [12][38][39]. Controversy exists for this role of FFA2, however, with some studies reporting no difference in basal- and glucose-stimulated GLP-1 levels in FFA2 knockout mice compared to control mice [8][13].

For FFA3, while there is a paucity of data regarding its role in gut hormone secretion, FFA3 knockout mice have reduced GLP-1 and PYY secretion, and primary colonic cultures derived from these mice display impaired secretory response upon SCFA stimulation [31][37]. Predictably, FFA3-specific agonist enhances GLP-1 release from primary colonic cultures [27]. FFA3 is also implicated in the inhibition of GIP secretion, an effect more likely with the predominant Gαi/o coupling of the receptor [40].

More research is needed to ascertain the respective roles of FFA2 and FFA3 in the regulation of incretin hormones in the intestine. This includes the development of potent selective ligands and tissue-specific knockout mouse models. Some progress has already been made in this direction. Selective and potent human FFA2 inverse agonists have been developed and shown to stimulate GLP-1 secretion in the human EEC line, NCI-H716 [41]. Through a chemogenetic knock-in strategy, mice with designer receptors exclusively activated by the designer drugs (DREADD) variant of human FFAR2 replacing the mouse Ffar2 locus have been generated. DREADD activation in these mice has been shown to augment GLP-1 secretion in colonic crypt cultures and in vivo [42].

4. SCFAs, FFA2, and FFA3 Educate the Gut Immune Cells and Regulate Inflammation

SCFAs can regulate immune cell function via two major processes, either through their cognate GPCRs such as FFA2 and FFA3 or by modulating histone deacetylase (HDAC) activity [43]. Here, we emphasize the first role. With the highest SCFA concentration, a rich and diverse population of immune cells with the majority expressing FFA2 and few, such as dendritic cells expressing FFA3, the gut is an important site where SCFAs can impact the immune cells through these receptors.

FFA2 has been reported to affect neutrophil chemotaxis in gut inflammation models, where a deficiency in FFA2 increases neutrophil infiltration to sites of inflammation [44][45]. Accordingly, engagement of FFA2 with acetate mitigates such a response [44][45]. Similar FFA2-dependent neutrophil-driven responses are seen in pulmonary and joint inflammation models [45]. Neutrophil FFA2 engagement by SCFAs in the presence of allosteric modulators can also activate NADPH oxidase and enhance the production of reactive oxygen species, which is deemed necessary for phagocytic activity [45][46]. FFA2-derived neutrophil responses are required for the regulation of inflammatory responses. As recently shown, FFA2 activity promotes coordination between neutrophils and colonic group 3 innate lymphoid cells (ILC3). In neutrophils, inflammasome activation helps in pathogen clearance with the concomitant enhancement of IL1β production, where IL1β leads to IL22 production from ILC3, driving gut repair mechanisms [47]. FFA2 can also promote ILC3 expansion and function independent of neutrophils [48]. Immunomodulation by neutrophil FFA2, thus, appears to strike a balance between pro- and anti-inflammatory effects, potentially in a disease-centric manner.

SCFAs through their HDAC inhibitory activity are considered to be the main players in maintaining the regulatory T cell (Treg) pools [43]. These effects are, in part, mediated through FFA2. It is suggested that FFA2 exerts immune suppression by regulating the number, function, and differentiation of Tregs [49][50]. FFA2 also modulates gut homeostasis by modifying immunoglobulin A (IgA) production [51] and through direct effects on inflammasome activation in intestinal epithelial cells [52].

The role of FFA3 in immune regulation is less explored, likely due to its limited expression in immune cells. It has been suggested to be involved in the resolution of lung inflammation through effects on macrophage and dendritic cell populations [53] and in promoting thymic Treg differentiation in mouse offspring [54]. The function and expansion of CD8+ T cells can also be regulated by FFA3, and this has been suggested to aid the resolution of influenza infection [55]. Both FFA3 and FFA2 have been suggested to enhance T cell memory [56], with the engagement of both receptors by butyrate appearing to mediate this effect. However, as the mouse isoform of FFA2 shows a low affinity for butyrate [57], the use of synthetic ligands is required to further delineate the role of the two receptors in this process.

5. SCFAs, FFA2, and FFA3, and Gut Microbiome: It Takes Three to Tango

Obliterating the GM in mice wipes off some of the physiological effects discussed above. For instance, in germ-free (GF) mice, antigen-activated T cells fail to transition to memory cells [56]. As the GM does not directly interact with the host cells except at the gut mucosal surfaces, these effects are likely indirect, being mediated via GM-derived factors such as SCFAs. The GM-derived SCFAs acting through their receptors FFA2 and FFA3 project the link, GM→SCFAs→FFA2 and FFA3.

Highlighting this relationship, whole-body FFA2 and FFA3 knockout mice have different gut microbiota profiles as compared to wild-type mice [12][31][50][52][58]. As expected, differences in fecal SCFA profiles accompany these differences in GM profiles due to adaptation to receptor deficiency. More direct evidence for roles of FFA2 and FFA3 in the GM→SCFAs→Receptor link is provided by immune function and GM studies. Both GF and FFA2 knockout mice exhibit a dysregulated immune response to induced colitis, gout, and arthritis [45][59]. While this response is mitigated by acetate supplemented drinking water in GF mice [45], FFA2 knockout mice remain refractory to acetate treatment [49].

Likewise, high-fiber diets that tend to increase GM function and SCFA levels in wild-type mice fail to promote gut homeostasis, alleviate food allergy, and prevent respiratory viral infection in FFA2 knockout mice [50][52][60]. Similar findings have been reported for FFA3. High fiber diet mediated protection against allergic airway disease and influenza virus is not observed in FFA3 knockout mice [53][55].

Metabolic studies have also highlighted the importance of the GM→SCFAs→FFA2 and FFA3 relationship. Reduced adiposity and PYY levels in FFA3 knockout mice are GM dependent, with the effect being lost in GF FFA3 knockout mice [31]. Similarly, GM-derived SCFAs mediate suppression of GIP secretion in FFA3 dependent manner, an effect lost in GF, antibiotic-treated mice (pseudo-GF), and FFA3 knockout mice [40]. In mice, a low-fiber diet or GF status during pregnancy increases the vulnerability of the offspring to obesity and insulin resistance later in life [61]. This effect could be rescued by propionate treatment or high-fiber feeding but not in absence of FFA3 or FFA2. Furthermore, FFA3 and FFA2 SCFA signaling was found to be responsible for normal embryonic development of neural, pancreatic β cell and intestine tissues. Collectively, these data suggest that the GM modulates metabolic and immune features affecting health via SCFA-FFA2 and SCFA-FFA3 axes.

References

  1. Priyadarshini, M.; Kotlo, K.U.; Dudeja, P.K.; Layden, B.T. Role of Short Chain Fatty Acid Receptors in Intestinal Physiology and Pathophysiology. Compr. Physiol. 2018, 8, 1091–1115.
  2. Brown, A.J.; Goldsworthy, S.M.; Barnes, A.A.; Eilert, M.M.; Tcheang, L.; Daniels, D.; Muir, A.I.; Wigglesworth, M.J.; Kinghorn, I.; Fraser, N.J.; et al. The Orphan G Protein-coupled Receptors GPR41 and GPR43 Are Activated by Propionate and Other Short Chain Carboxylic Acids. J. Biol. Chem. 2003, 278, 11312–11319.
  3. Le Poul, E.; Loison, C.; Struyf, S.; Springael, J.-Y.; Lannoy, V.; Decobecq, M.-E.; Brezillon, S.; Dupriez, V.; Vassart, G.; van Damme, J.; et al. Functional Characterization of Human Receptors for Short Chain Fatty Acids and Their Role in Polymorphonuclear Cell Activation. J. Biol. Chem. 2003, 278, 25481–25489.
  4. Hudson, B.D.; Tikhonova, I.G.; Pandey, S.K.; Ulven, T.; Milligan, G. Extracellular Ionic Locks Determine Variation in Constitutive Activity and Ligand Potency between Species Orthologs of the Free Fatty Acid Receptors FFA2 and FFA3. J. Biol. Chem. 2012, 287, 41195–41209.
  5. Tang, C.; Offermanns, S. FFA2 and FFA3 in Metabolic Regulation. Handb. Exp. Pharmacol. 2016, 236, 205–220.
  6. Priyadarshini, M.; Layden, B.T. FFAR3 modulates insulin secretion and global gene expression in mouse islets. Islets 2015, 7, e1045182.
  7. Priyadarshini, M.; Villa, S.R.; Fuller, M.; Wicksteed, B.; Mackay, C.R.; Alquier, T.; Poitout, V.; Mancebo, H.; Mirmira, R.G.; Gilchrist, A.; et al. An Acetate-Specific GPCR, FFAR2, Regulates Insulin Secretion. Mol. Endocrinol. 2015, 29, 1055–1066.
  8. Fuller, M.; Priyadarshini, M.; Gibbons, S.M.; Angueira, A.R.; Brodsky, M.; Hayes, M.G.; Kovatcheva-Datchary, P.; Bäckhed, F.; Gilbert, J.A.; Lowe, W.L., Jr.; et al. The short-chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis. Am. J. Physiol. Endocrinol. Metab. 2015, 309, E840–E851.
  9. Villa, S.R.; Priyadarshini, M.; Fuller, M.H.; Bhardwaj, T.; Brodsky, M.R.; Angueira, A.R.; Mosser, R.E.; Carboneau, B.A.; Tersey, S.A.; Mancebo, H.; et al. Loss of Free Fatty Acid Receptor 2 leads to impaired islet mass and beta cell survival. Sci. Rep. 2016, 6, 28159.
  10. Veprik, A.; Laufer, D.; Weiss, S.; Rubins, N.; Walker, M.D. GPR41 modulates insulin secretion and gene expression in pancreatic β-cells and modifies metabolic homeostasis in fed and fasting states. FASEB J. 2016, 30, 3860–3869.
  11. Priyadarshini, M.; Cole, C.; Oroskar, G.; Ludvik, A.E.; Wicksteed, B.; He, C.; Layden, B.T. Free fatty acid receptor 3 differentially contributes to β-cell compensation under high-fat diet and streptozotocin stress. Am. J. Physiol. Integr. Comp. Physiol. 2020, 318, R691–R700.
  12. McNelis, J.C.; Lee, Y.S.; Mayoral, R.; van der Kant, R.; Johnson, A.M.F.; Wollam, J.; Olefsky, J.M. GPR43 Potentiates β-Cell Function in Obesity. Diabetes 2015, 64, 3203–3217.
  13. Tang, C.; Ahmed, K.; Gille, A.; Lu, S.; Gröne, H.-J.; Tunaru, S.; Offermanns, S. Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat. Med. 2015, 21, 173–177.
  14. Pingitore, A.; Chambers, E.S.; Hill, T.; Maldonado, I.R.; Liu, B.; Bewick, G.; Morrison, D.J.; Preston, T.; Wallis, G.A.; Tedford, C.; et al. The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro. Diabetes Obes. Metab. 2016, 19, 257–265.
  15. Pingitore, A.; Gonzalez-Abuin, N.; Ruz-Maldonado, I.; Huang, G.C.; Frost, G.; Persaud, S.J. Short chain fatty acids stimulate insulin secretion and reduce apoptosis in mouse and human islets in vitro: Role of free fatty acid receptor 2. Diabetes Obes. Metab. 2019, 21, 330–339.
  16. Villa, S.R.; Mishra, R.K.; Zapater, J.L.; Priyadarshini, M.; Gilchrist, A.; Mancebo, H.; E Schiltz, G.; Layden, B.T. Homology modeling of FFA2 identifies novel agonists that potentiate insulin secretion. J. Investig. Med. 2017, 65, 1116–1124.
  17. Tan, J.K.; McKenzie, C.; Mariño, E.; Macia, L.; Mackay, C.R. Metabolite-Sensing G Protein–Coupled Receptors—Facilitators of Diet-Related Immune Regulation. Annu. Rev. Immunol. 2017, 35, 371–402.
  18. Perry, R.J.; Peng, L.; Barry, N.A.; Cline, G.W.; Zhang, D.; Cardone, R.L.; Petersen, K.F.; Kibbey, R.G.; Goodman, N.A.B.A.L.; Shulman, R.J. Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome. Nature 2016, 534, 213–217.
  19. Kimura, I.; Ozawa, K.; Inoue, D.; Imamura, T.; Kimura, K.; Maeda, T.; Terasawa, K.; Kashihara, D.; Hirano, K.; Tani, T.; et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat. Commun. 2013, 4, 1829.
  20. Ahrén, B. Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes. Nat. Rev. Drug Discov. 2009, 8, 369–385.
  21. Høverstad, T.; Bjørneklett, A.; Midtvedt, T.; Fausa, O.; Bøhmer, T. Short-chain fatty acids in the proximal gastrointestinal tract of healthy subjects. Scand. J. Gastroenterol. 1984, 19, 1053–1058.
  22. Nauck, M.A.; Meier, J.J. Incretin hormones: Their role in health and disease. Diabetes Obes. Metab. 2018, 20 (Suppl. 1), 5–21.
  23. Seino, Y.; Fukushima, M.; Yabe, D. GIP and GLP-1, the two incretin hormones: Similarities and differences. J. Diabetes Investig. 2010, 1, 8–23.
  24. El, K.; Campbell, J.E. The role of GIP in α-cells and glucagon secretion. Peptides 2020, 125, 170213.
  25. Greenbaum, C.J.; Prigeon, R.L.; D’Alessio, D.A. Impaired -Cell Function, Incretin Effect, and Glucagon Suppression in Patients with Type 1 Diabetes Who Have Normal Fasting Glucose. Diabetes 2002, 51, 951–957.
  26. Gribble, F.M.; Reimann, F. Enteroendocrine Cells: Chemosensors in the Intestinal Epithelium. Annu. Rev. Physiol. 2016, 78, 277–299.
  27. Nøhr, M.K.; Pedersen, M.H.; Gille, A.; Egerod, K.L.; Engelstoft, M.S.; Husted, A.S.; Sichlau, R.M.; Grunddal, K.V.; Poulsen, S.S.; Han, S.; et al. GPR41/FFAR3 and GPR43/FFAR2 as Cosensors for Short-Chain Fatty Acids in Enteroendocrine Cells vs. FFAR3 in Enteric Neurons and FFAR2 in Enteric Leukocytes. Endocrinology 2013, 154, 3552–3564.
  28. Kaji, I.; Karaki, S.-I.; Tanaka, R.; Kuwahara, A. Density distribution of free fatty acid receptor 2 (FFA2)-expressing and GLP-1-producing enteroendocrine L cells in human and rat lower intestine, and increased cell numbers after ingestion of fructo-oligosaccharide. J. Mol. Histol. 2011, 42, 27–38.
  29. Karaki, S.-I.; Tazoe, H.; Hayashi, H.; Kashiwabara, H.; Tooyama, K.; Suzuki, Y.; Kuwahara, A. Expression of the short-chain fatty acid receptor, GPR43, in the human colon. J. Mol. Histol. 2008, 39, 135–142.
  30. Karaki, S.-I.; Mitsui, R.; Hayashi, H.; Kato, I.; Sugiya, H.; Iwanaga, T.; Furness, J.B.; Kuwahara, A. Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res. 2006, 324, 353–360.
  31. Samuel, B.S.; Shaito, A.; Motoike, T.; Rey, F.E.; Backhed, F.; Manchester, J.K.; Hammer, R.E.; Williams, S.C.; Crowley, J.; Yanagisawa, M.; et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl. Acad. Sci. USA 2008, 105, 16767–16772.
  32. Tazoe, H.; Otomo, Y.; Karaki, S.-I.; Kato, I.; Fukami, Y.; Terasaki, M.; Kuwahara, A. Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed. Res. 2009, 30, 149–156.
  33. Won, Y.-J.; Lu, V.B.; Puhl, H.L., 3rd; Ikeda, S.R. β-Hydroxybutyrate Modulates N-Type Calcium Channels in Rat Sympathetic Neurons by Acting as an Agonist for the G-Protein-Coupled Receptor FFA3. J. Neurosci. 2013, 33, 19314–19325.
  34. Kimura, I.; Inoue, D.; Maeda, T.; Hara, T.; Ichimura, A.; Miyauchi, S.; Kobayashi, M.; Hirasawa, A.; Tsujimoto, G. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl. Acad. Sci. USA 2011, 108, 8030–8035.
  35. Iwasaki, K.; Harada, N.; Sasaki, K.; Yamane, S.; Iida, K.; Suzuki, K.; Hamasaki, A.; Nasteska, D.; Shibue, K.; Joo, E.; et al. Free Fatty Acid Receptor GPR120 Is Highly Expressed in Enteroendocrine K Cells of the Upper Small Intestine and Has a Critical Role in GIP Secretion After Fat Ingestion. Endocrinology 2015, 156, 837–846.
  36. Psichas, A.; Sleeth, M.L.; Murphy, K.G.; Brooks, L.; Bewick, G.A.; Hanyaloglu, A.C.; Ghatei, M.A.; Bloom, S.R.; Frost, G. The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int. J. Obes. 2015, 39, 424–429.
  37. Tolhurst, G.; Heffron, H.; Lam, Y.S.; Parker, H.E.; Habib, A.M.; Diakogiannaki, E.; Cameron, J.; Grosse, J.; Reimann, F.; Gribble, F.M. Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein-Coupled Receptor FFAR2. Diabetes 2011, 61, 364–371.
  38. Forbes, S.; Stafford, S.; Coope, G.; Heffron, H.; Real, K.; Newman, R.; Davenport, R.; Barnes, M.; Grosse, J.; Cox, H. Selective FFA2 Agonism Appears to Act via Intestinal PYY to Reduce Transit and Food Intake but Does Not Improve Glucose Tolerance in Mouse Models. Diabetes 2015, 64, 3763–3771.
  39. Larraufie, P.; Martin-Gallausiaux, C.; Lapaque, N.; Dore, J.; Gribble, F.M.; Reimann, F.; Blottiere, H.M. SCFAs strongly stimulate PYY production in human enteroendocrine cells. Sci. Rep. 2018, 8, 74.
  40. Lee, E.-Y.; Zhang, X.; Miyamoto, J.; Kimura, I.; Taknaka, T.; Furusawa, K.; Jomori, T.; Fujimoto, K.; Uematsu, S.; Miki, T. Gut carbohydrate inhibits GIP secretion via a microbiota/SCFA/FFAR3 pathway. J. Endocrinol. 2018, 239, 267–276.
  41. Park, B.-O.; Kim, S.H.; Kong, G.Y.; Kim, D.H.; Kwon, M.S.; Lee, S.U.; Kim, M.-O.; Cho, S.; Lee, S.; Lee, H.-J.; et al. Selective novel inverse agonists for human GPR43 augment GLP-1 secretion. Eur. J. Pharmacol. 2016, 771, 1–9.
  42. Bolognini, D.; Barki, N.; Butcher, A.J.; Hudson, B.D.; Sergeev, E.; Molloy, C.; Moss, C.E.; Bradley, S.J.; le Gouill, C.; Bouvier, M.; et al. Chemogenetics defines receptor-mediated functions of short chain free fatty acids. Nat. Chem. Biol. 2019, 15, 489–498.
  43. Kim, C.H. Immune regulation by microbiome metabolites. Immunology 2018, 154, 220–229.
  44. Kamp, M.E.; Shim, R.; Nicholls, A.J.; Oliveira, A.C.; Mason, L.J.; Binge, L.; Mackay, C.R.; Wong, C.H.Y. G Protein-Coupled Receptor 43 Modulates Neutrophil Recruitment during Acute Inflammation. PLoS ONE 2016, 11, e0163750.
  45. Maslowski, K.M.; Vieira, A.T.; Ng, A.; Kranich, J.; Sierro, F.; Yu, D.; Schilter, H.C.; Rolph, M.S.; Mackay, F.; Artis, D.; et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009, 461, 1282–1286.
  46. Dahlgren, C.; Holdfeldt, A.; Lind, S.; Mårtensson, J.; Gabl, M.; Björkman, L.; Sundqvist, M.; Forsman, H. Neutrophil Signaling That Challenges Dogmata of G Protein-Coupled Receptor Regulated Functions. ACS Pharmacol. Transl. Sci. 2020, 3, 203–220.
  47. Fachi, J.L.; Sécca, C.; Rodrigues, P.B.; de Mato, F.C.P.; di Luccia, B.; Felipe, J.D.S.; Pral, L.P.; Rungue, M.; Rocha, V.D.M.; Sato, F.T.; et al. Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2. J. Exp. Med. 2020, 217.
  48. Chun, E.; Lavoie, S.; Fonseca-Pereira, D.; Bae, S.; Michaud, M.; Hoveyda, H.R.; Fraser, G.L.; Comeau, C.A.G.; Glickman, J.N.; Fuller, M.H.; et al. Metabolite-Sensing Receptor Ffar2 Regulates Colonic Group 3 Innate Lymphoid Cells and Gut Immunity. Immunity 2019, 51, 871–884.e6.
  49. Smith, P.M.; Howitt, M.R.; Panikov, N.; Michaud, M.; Gallini, C.A.; Bohlooly-Y, M.; Glickman, J.N.; Garrett, W.S. The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis. Science 2013, 341, 569–573.
  50. Tan, J.; McKenzie, C.; Vuillermin, P.J.; Goverse, G.; Vinuesa, C.G.; Mebius, R.E.; Macia, L.; Mackay, C.R. Dietary Fiber and Bacterial SCFA Enhance Oral Tolerance and Protect against Food Allergy through Diverse Cellular Pathways. Cell Rep. 2016, 15, 2809–2824.
  51. Wu, W.; Sun, M.; Chen, F.; Cao, A.T.; Liu, H.; Zhao, Y.; Huang, X.; Xiao, Y.; Yao, S.; Zhao, Q.; et al. Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43. Mucosal Immunol. 2017, 10, 946–956.
  52. Macia, L.; Tan, J.; Vieira, A.T.; Leach, K.; Stanley, D.; Luong, S.; Maruya, M.; McKenzie, C.I.; Hijikata, A.; Wong, C.; et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 2015, 6, 6734.
  53. Trompette, A.; Gollwitzer, E.S.; Yadava, K.; Sichelstiel, A.K.; Sprenger, N.; Ngom-Bru, C.; Blanchard, C.; Junt, T.; Nicod, L.P.; Harris, N.L.; et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 2014, 20, 159–166.
  54. Nakajima, A.; Kaga, N.; Nakanishi, Y.; Ohno, H.; Miyamoto, J.; Kimura, I.; Hori, S.; Sasaki, T.; Hiramatsu, K.; Okumura, K.; et al. Maternal High Fiber Diet during Pregnancy and Lactation Influences Regulatory T Cell Differentiation in Offspring in Mice. J. Immunol. 2017, 199, 3516–3524.
  55. Trompette, A.; Gollwitzer, E.S.; Pattaroni, C.; Lopez-Mejia, I.C.; Riva, E.; Pernot, J.; Ubags, N.; Fajas, L.; Nicod, L.P.; Marsland, B.J. Dietary Fiber Confers Protection against Flu by Shaping Ly6c− Patrolling Monocyte Hematopoiesis and CD8+ T Cell Metabolism. Immunity 2018, 48, 992–1005.e8.
  56. Bachem, A.; Makhlouf, C.; Binger, K.J.; de Souza, D.P.; Tull, D.; Hochheiser, K.; Whitney, P.G.; Fernandez-Ruiz, D.; Dähling, S.; Kastenmüller, W.; et al. Microbiota-Derived Short-Chain Fatty Acids Promote the Memory Potential of Antigen-Activated CD8+ T Cells. Immunity 2019, 51, 285–297.e5.
  57. Priyadarshini, M.; Wicksteed, B.; Schiltz, G.E.; Gilchrist, A.; Layden, B.T. SCFA Receptors in Pancreatic β Cells: Novel Diabetes Targets? Trends Endocrinol. Metab. 2016, 27, 653–664.
  58. Sivaprakasam, S.; Gurav, A.; Paschall, A.V.; Coe, G.L.; Chaudhary, K.; Cai, Y.; Kolhe, R.; Martin, P.; Browning, D.; Huang, L.; et al. An essential role of Ffar2 (Gpr43) in dietary fibre-mediated promotion of healthy composition of gut microbiota and suppression of intestinal carcinogenesis. Oncogenesis 2016, 5, e238.
  59. Vieira, A.T.; Macia, L.; Galvão, I.; Martins, F.S.; Canesso, M.C.C.; Amaral, F.A.; Garcia, C.C.; Maslowski, K.M.; de Leon, E.; Shim, D.; et al. A Role for Gut Microbiota and the Metabolite-Sensing Receptor GPR43 in a Murine Model of Gout. Arthritis Rheumatol. 2015, 67, 1646–1656.
  60. Antunes, K.H.; Fachi, J.L.; de Paula, R.; da Silva, E.F.; Pral, L.P.; dos Santos, A.Á.; Dias, G.B.M.; Vargas, J.E.; Puga, R.; Mayer, F.Q.; et al. Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon response. Nat. Commun. 2019, 10, 3273.
  61. Kimura, I.; Miyamoto, J.; Ohue-Kitano, R.; Watanabe, K.; Yamada, T.; Onuki, M.; Aoki, R.; Isobe, Y.; Kashihara, D.; Inoue, D.; et al. Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice. Science 2020, 367, eaaw8429.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Biology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Kristen Lednovich
View Times: 446
Entry Collection: Peptides for Health Benefits
Revisions: 2 times (View History)
Update Date: 20 May 2021
Table of Contents
    1000/1000
    Hot Most Recent
    ScholarVision Creations
    Feedback