Table 2.
Physiological function of FFAR2 in humans and mice.
| S. No. | Tissue/Organ | Research Findings | Ref. |
|---|---|---|---|
| Human | |||
| 1 | Intestinal L-cells | -Secrete GLP-1 and PYY in response to glucose via FFAR2 signaling. | [3,11,76,162] |
| 2 | Primary Neutrophils | -Cmp1 and CATPB function as an agonist and antagonist for the neutrophil FFAR2 respectively. -Cmp1 and acetate activates the phospholipase C-inositol phosphate 3 (IP3) Ca2+ signaling while CATPB inhibits it. -Cmp1 act as a potent activator of the NADPH -oxidase in TNF-α-primed neutrophils with increased release of superoxide. -Moreover, Cmp1 triggered NADPH oxidase activity was inhibited by PTX. |
[163] |
| 3 | Primary Monocytes | -Non-responders of Cmp1 shows no transient rise in intracellular Ca+2. -Human monocyte FFAR2 reduces inflammatory cytokine expression in response to acetate. -FFAR2 modulates p38-MAPK, Akt, and ERK signaling in response to acetate and FFAR2 agonist (CFMB). |
[22,163,164] |
| 4 | Primary Lymphocytes | -Non-responders to Cmp1 with no transient rise in intracellular Ca+2. | [22,163] |
| 5 | Peripheral blood mononuclear cells (PBMCs) | -mRNA expression of FFAR2 upregulate in PBMCs in Type 1 Diabetes (T1D) patient via NFκB. -Overexpression induced cell apoptosis through ERK signaling. -Stimulated PBMCs for cytokine production in the presence of lipopolysaccharides (LPS) with and/or without acetate along with anti-FFAR2 antibody. |
[29,42,163] |
| 6 | Primary Adipocytes | -FFAR2 expressed in the human multipotent adipose tissue-derived stem cells (hMADS). -SCFA acetate (luminal and systemic) are responsible for the antilipolytic response. -Treating with Gi-sensitive PTX inhibitors prevents anti-lipolytic response develop by acetate. -A mixture SCFA reduces plasma FFA in DIO mice along with beige adipogenesis marker. -So, colonic or systemic acetate modulation helps in improving the insulin resistance in human adipocytes via FFAR2 mediated attenuation of HSL phosphorylation. |
[15,19,29,42] |
| 7 | Colon | -Luminal propionate stimulates FFAR2 pathway through PYY mediation confirmed by Y1 and Y2 antagonist (BIBO3304 and BIIE0246). -FFAR2 signaling expressed evenly in the entire intestine mostly at colon in the presence of FFAR2 agonist PA. |
[15,19,165] |
| Mouse/Rodent | |||
| 1 | Pancreatic β-cells | -mRNA expression of FFAR2 upregulated through increase in pancreas β-cell expansion. -Increased β-cell contributes to more insulin secretion. -FFAR2 KO mice reduces gestational pancreatic β-cell expansion during pregnancy. -FFAR2 KO mice gestational glucose tolerance worsened even under antibiotic treatment and further deteriorated during second pregnancy. -Antibiotic modulation of gut microbiota does not disrupt the contribution of FFAR2 to gestational glucose tolerance. -FFAR2 acts as a novel target for β-cells adaptation to pregnancy-induced insulin resistance during to maintain normal glucose homeostasis. -FFAR2 a novel therapeutic target to stimulate β-cell growth and Proliferation. |
[25,96,166,167] |
| 2 | Primary Pancreatic Islet | -SCFAs such as Acetate, propionate, and butyrate administration have no effect on insulin and glucagon secretion regardless of glucose level. -CFMB (FFAR2 agonist) has a significant effect in increasing the somatostatin and insulin secretion whereas no effect was observed in glucagon synthesis. -Mediate an inhibition of insulin secretion by coupling to Gi-type G Proteins -Under type 2 diabetic condition acetate concentration increases in pancreatic islet and systemic circulation -FFAR2 antagonist might increase insulin secretion in type 2 diabetes -Double knock-out of FFAR2 and FFAR3 altered the glucose tolerance in diabetic condition. |
[28,168] |
| 3 | Ileum | -Bacterial metabolites, propionate, activate ileal mucosal FFAR2 to decrease hepatic glucose production. -Propionate stimulate GLP-1r dependent neuronal network to regulate glucose production activated through ileal FFAR2 signaling. -Regulate glucose homeostasis. |
[28,169] |
| 4 | Macrophages | -Inducing apoptosis of infiltrated macrophages to pancrease through upregulation of FFAR2. -Improved glucose homeostasis in diabetic mice by treating with FFAR2 agonist, acetate and phenylacetamide 1. |
[29,169] |
| 5 | Peripheral blood mononuclear cells (PBMCs) | -Dextran sodium Sulphate (DSS) -induced colon shortening, mucosal thickness, inflammatory cell infiltration, and crypt damage were ameliorated by acetate treatment in C57BL/6 mice. -Stimulated PBMCs in FFAR2 KO mice for cytokine production in the presence of lipopolysaccharides (LPS) with and/or without acetate. -DSS-induced colitis is exaberated in FFAR2 KO mice through increase in pro-inflammatory cytokines such as TNF-α and IL-17 with decrease of anti-inflammatory cytokine IL-10 in the colonic mucusa. |
[29,42] |
| 6 | Neutrophil | -FFAR2 recognizes propionate and butyrate and expressed abundantly in polymorphonuclear (PMN) leukocytes. -FFAR2 mediated SCFA-induced chemotaxis through p38 MAPK signaling pathway. -Inhibiting FFAR2 mediated signaling a promising way for inhibiting the migration of PMN at the site of intestinal inflammation. -Under influenza infection, in FFAR2 KO along with wild type mice showed decrease neutrophil infiltration to airway. |
[43,114] |
| 7 | Immune Cells | -FFAR2 KO mice develops unresolving or exaberated inflammation in colitis, arthritis and asthma mice model. -FFAR2 KO mice shows inflammatory action related to increase in the production of inflammatory mediators by increased in immune cell recruitment. -Germ-free mice, which are devoid of bacteria and express little or no SCFAs, showed similar dysregulation of certain inflammatory response. -SCFA-FFAR2 interaction has profound effect on normal resolution of certain inflammatory response with a molecular link between diet, gastrointestinal bacterial metabolism and immune response. |
[35,40,43] |
| 8 | Monocytes | -Mice monocyte showed increased in IL-1α and IL-1β cytokine expression in response to acetate. -Even in FFAR2/3 KO mouse monocyte display elevate cytokine response on treatment with SCFAs. -SCFA does not act through FFAR2 to modulate mice monocyte inflammatory responses. |
[22,35] |
| 9 | L-cells | -GLP-1 synthesis was enhanced in the presence of phosphodiesterase inhibitor isobutyl methyl xanthine (IBMX). -FFAR2 expression in small intestine and colonic L-cells as compare to non-L-cell population. -Induces GLP-1 and PYY secretion via glucose dependent mechanism. -SCFAs triggered Ca2+ elevation in L-cells with enhanced GLP-1 and PYY secretion through Gq-mediated pathway, implicating FFAR2 signaling involvement. -Synthetic phenylacetamide agonist of FFAR2, CFMB, mobilizes more intracellular Ca2+ in L-cells and elevates GLP-1 hormone secretion, in the presence of DPPIVi but not in its absence in mice. |
[11,22,162,170] |
| 10 | Colonic Mucosa | -FFAR2 express in the colonic mucosa -Withdrawal of ceftriaxone antibiotic leads to reduction in SCFA concentration and increase in increased number of conditionally pathogenic Enterobacteria, E. coli, Clostridium, Staphylococcus spp., and hemolytic bacteria in colonic gut. -FFAR2 immune regulation mechanism get hamper with increase in cytokine concentration in colonic mucosa. -Increase histopathology condition of colitis with goblet cell dysfunction, colonic dilatation and wall thickening, ultimate leads to IBD. |
[78] |
| 11 | Enterochromaffin cells | -FFAR2 agonist PA1 (Phenylacetamide 1) in a dose-dependent manner stimulate HCO3- secretion, even prior exposed to DPPIV inhibitor NVP728. -HCO3- secretion stimulate by activated FFAR2 through muscarinic and 5-HT4 receptor signaling rather than through VIP, CCK and GLP-2 pathway. -Moreover, SCFAs (mostly acetate) activate FFAR2 and FFAR3 followed by 5-HT and GLP-2 release. |
[171] |
| 12 | Mast cell | -Rat intestinal lamina propria mast cells expressed FFAR2 along with 5-hydroxytryptophan (5-HT). -The activated mucosal FFAR2 act on the nearby nerve endings at 5-HT3 serotogenic receptors. -SCFAs stimulate PYY and 5-HT secretion from ileum and colonic endocrine cells by activating FFAR2 receptor. |
[76,171] |
| 13 | Stomach | -The villi and microvilli of gastric brush cells reveal expression of FFAR2 (at gene and protein level) in the mice stomach. | [7,76,172] |
| 14 | Lungs | -Expressed in the mice lungs. -SCFAs modulate allergy airway inflammation in mice lungs via FFAR2 signaling. |
[6,7,152,172] |
| 15 | Muscle | -Expressed FFAR2 in smooth muscle cells of small resistance vessels. -SCFAs produced from gut microbiota modulate the blood glucose level. |
[6,20] |
FFAR2: Free fatty acid receptor 2; GLP-1: Glucagon-like peptide 1; PYY: Peptide YY; Cmp1: Compound 1 (3-benzyl-4-(cyclopropyl-(4-(2,5-dichlorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid; ERK: Extracellular signal-regulated kinase); CATPB: (S)-3-(2-(3-chlorophenyl)acetamido)-4-(4-(trifluoromethyl)phenyl)butanoic acid; GLPG0974: 4-[[(2R)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid; IP3: Inositol phosphate 3; NADPH: Nicotinamide adenine dinucleotide phosphate; TNFα: Tumor Necrosis Factor alpha; PTX: Pertussis toxin; MAPK: Mitogen-activated protein kinase; Akt: Protein Kinase B; ERK: Extracellular signal-regulated kinase; CFMB: [( S)-2-(4-chlorophenyl)-3,3-dimethyl- N-(5-phenylthiazol-2-yl)butamide; PBMCs: Peripheral blood mononuclear cells; T1D: Type-1 Diabetes; LPS: Lipopolysaccharides; hMADS: human multipotent adipose tissue-derived stem cells; SCFA: Short chain fatty acids; FFA: Free fatty acids; DIO: Diet induced obesity; HSL: Hormone-sensitive lipase; FFAR3: Free fatty acid receptor 3; GLP-1r: Glucagon-like peptide 1 receptor; DSS: Dextran sodium Sulphate; KO: Knock out; LPS: Lipopolysaccharides; IL: Immunoglobulin; PMN: Polymorphonuclear; SCFA: Short chain fatty acid; IBMX: Isobutyl methyl xanthine; DPPIVi: Dipeptidyl peptidase 4 inhibitor; PA1: Phenylacetamide 1; ACh: Acetylcholine; 5-HT: 5-Hydroxytryptophan; 5-HT3: 5-Hydroxytryptophan type 3; HCO3-: Bicarbonate: VIP: Vasoactive intestinal peptide; CCK: Cholecystokinin; GIP: Glucose-dependent insulinotropic peptide; IGN: Intestinal Gluconeogenesis.