Table 3.
Physiological function of FFAR3 in humans and mice/rodents.
| S.No. | Tissue/Organ | Research Findings | Ref. |
|---|---|---|---|
| Human | |||
| 1 | Intestinal L- cells | -Secrete GLP-1 and PYY in response to glucose | [3,11,76] |
| 2 | Intestinal I- cells | -Secrete Cholecystokinin (CCK) in response to glucose. | [3] |
| 3 | Intestinal K- cells | -Secrete glucose-dependent insulinotropic peptide (GIP) in response to glucose. | [3] |
| 4 | Colon | -No effect of propionate response on Intestinal Gluconeogenesis (IGN) genes (G6PC, PCK1, MUT) expression with either FFAR2 agonist such as tiglic acid (TA) or FFAR3 agonist i.e,1-methylcyclopropanecarboxylic acid (MA). -IGN gene expression increases by butyrate mediated through cAMP pathway but not via Gi- nor Gq pathway. -Neither Gi- nor Gq-sensitive inhibitors (PTX and U73122) able to reduce the IGN gene expression induced by butyrate. |
[149] |
| 5 | Monocyte | -Human monocyte FFAR3 reduces cytokine expression in response to acetate. -The receptor modulates p38-MAPK signaling in response to acetate and FFAR3 agonist (AR420626). |
[22] |
| 6 | Adipocytes | -FFAR3 expressed in the human multipotent adipose tissue-derived stem cells (hMADS). -Acetate is responsible for the antilipolytic response luminal and systemic level. -Rosiglitazone increases the expression of FFAR3. -FFAR3 stimulation develop anti-inflammatory action targeting TNFα and IL-1β. -Treating with Gi-sensitive PTX inhibitors prevents antilipolytic response develop by acetate. -Colonic or systemic acetate modulation helps in improving the insulin resistance in human adipocytes via FFAR3 mediated attenuation of hormone-sensitive lipase (HSL) phosphorylation. |
[15,202] |
| 7 | Enteric Neurons | -FFAR3 agonist, AR420626 response at colon mucusa showed monophasic reductions in short-circuit currents (Isc) and sensitive to neurotoxin tetrodotoxin (TTX). -At submucosal and myenteric neuronal plexus, the FFAR3 is colocalized with Vasoactive intestinal polypeptide (VIP). -FFAR3 antagonist AR399519 inhibits FFAR3 agonism activity in entire colonic region. |
[3,165] |
| Mouse/Rodent | |||
| 1 | Pancreatic α- and β-cells | -FFAR3 is transcribed from the promoter of the GPR40. -The expression is mediated via an internal ribosomal entry site (IRES) located in the intergenic region of a bicistronic mRNA. -Helps in proper understanding in the identification of therapeutic target. |
[16,28,73,203] |
| 2 | Primary Pancretic Islet | -FFAR3 expression in murine pancreatic islet -Leads to reduction of insulin secretion by coupling to Gi-type G Proteins in type-2 diabetic condition. -Locally to islet as well as in systemic circulation acetate concentration increases. -So, in type-2 diabetic condition FFAR3 antagonist may increase insulin secretion |
[16,28,168] |
| 3 | Primary Pancreatic Islet | -Infusion of Acetate, propionate and butyrate has no profound effect on insulin and glucagon secretion regardless of glucose level. -Whereas, FFAR3 agonist Compound 4 (N-(2,5-dichlorophenyl)-4-(furan2-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide) has significant effect in increasing the somatostatin and insulin secretion but showed no effect on glucagon synthesis. |
[168] |
| 4 | Sympathetic Nervous System (SNS) | -Expressed in the rodent SNS especially at Superior cervical ganglia (SCG) and Celiac-mesenteric Ganglia (CSMG). -Induced variable ICa2+ modulation activity by sodium propionate in the FFAR3+/+ mice. -Moreover, along with acetate and propionate, ketogenic metabolites β-hydroxybutyrate (BHB) produced voltage dependent reduction of N-type Ca2+ channel in SNS. -FFAR3-expressing neurons from reporter mice expressed decrease in Cav2.2-FFAR3 inhibitory coupling variability. -FFAR3 is expressed primarily in neurons with a vasoconstrictor phenotype. |
[101,102,104] |
| 5 | Superior cervical ganglia (SCG) | -Propionate enhances the norepinephrine (NE) release from primary-cultured mice SCG. -Pretreatment with Gi/o pathway sensitive-PTX; Gβγ inhibitor-Gallin; PLC inhibitor U73122 and MEK inhibitor U0126 significantly reduces NE secretion indicating the involvement of Gi/o, Gβγ, PLCβ3 pathway in hormonal secretory function. -Treatment with Gαi/o inhibitor NF023 shows no inhibition of NE release, so FFAR3 response is independent of Gαi/o pathway. -Further, treatment with siRNA against either PLCβ3 or ERK1/2 decreases the expression NE protein by more than 80%. -So, SCFA receptor FFAR3 is coupled with Gi/o protein, to release NE via Gβγ-PLCβ3- ERK1/2-synapsin 2 pathway. |
[103] |
| 6 | Intestine | -IGN induction is mediated by propionate through gut-brain axis. -Dietary propionate leads to c-Fos (neuronal activation marker) activation in the hypothalamic region which receives neuronal signal from both parabrachial nucleus (PBN) and dorsal vagal complex (DVC), mostly paraventricular nucleus (PVN), the lateral hypothalamus (LH) and the arcuate nucleus (ARC) of hypothalamus. |
[149] |
| 7 | Intestinal Enteroendocrine Cells | -Acetate, propionate and butyrate administration in mice protect against diet-induced obesity and insulin resistance. -Propionate and butyrate but not acetate induce gut hormones and reduces food intake. -Butyrate had minor effect in stimulation of GLP-1 through FFAR3. -FFAR3 KO mice shows normal body weight and glucose homeostasis, indicating some additional mediators are involves in these mechanism. -FFAR3 KO mice shows impair GLP-1 synthesis with altered in mRNA expression of Glucagon, PYY and active GLP-1 peptide. |
[11,121,148,204] |
| 8 | Monocytes | -Mice monocyte shows increase in IL-1α, IL-1β and GM-CSF cytokine expression in response to acetate. -Even in FFAR2/3 KO mouse monocyte displays elevate cytokine response on treatment with SCFAs. -So, SCFA does not act through FFAR2 to modulate mice monocyte inflammatory responses. |
[22] |
| 9 | Neutrophil | -FFAR3 pathway is associated with airway neutrophil response subjected to influenza infection verified in FFAR3 KO mice. | [114] |
| 10 | Bone marrow | -FFAR3 KO mice produce less monocytes and interstitial macrophages from the bone marrow in response to butyrate | [114] |
| 11 | Ileum and Colon | -Moreover, dietary (Flaxseed) fibers restructured the gut microbiota with proliferation of the genera Bifidobacterium and Akkermansia reduces fat mass and show improve tolerance to intraperitoneal and oral glucose via FFAR3. -Microbiota is associate with increase SCFA production acting through FFAR3 signaling. -Through selective FFAR3-agonist, AR420626 showed greatest efficacy of FFAR3 at distal regions of intestine to protect mice from diet induced obesity by preventing a reduction in energy expenditure induced by an HFD. |
[148,165,198] |
| 12 | Colonic Mucosa | -FFAR2 express in the colonic mucosa -Withdrawal of ceftriaxone antibiotic leads to reduction in SCFA concentration and increase number of conditionally pathogenic Enterobacteria, E. coli, Clostridium, Staphylococcus spp. and hemolytic bacteria in colonic gut. -FFAR2 immune regulation mechanism get hampered with increase in cytokine concentration in colonic mucosa. -Increased histopathology condition of colitis with goblet cell dysfunction, colonic dilatation and wall thickening, ultimate leads to IBD. |
[78] |
| 13 | Duodenum L- cells | -FFAR3 is colocalized with GLP1 and expressed in L cells. -SCFAs (mostly acetate) activate FFAR2 and FFAR3 followed by 5-HT and GLP-2 release. |
[171] |
| 14 | Enteric Neurons | -FFAR3 agonism (by AR420626) at descending colon mucusa was inhibited by neurogenic sensitive tetrodotoxin (TTX). -FFAR3 agonist activity is sensitive to acetylcholinergic (ACh) neurotransmission in rat colon mucosa. -ACh muscarinic antagonist atropine, nicotinic sensitive hexamethonium, FFAR3 antagonist AR399519, GLP1 antagonist Ex(3-39) or calcitonin gene related peptide (CGRP) blocker BIBN4096 abolished FFAR3 agonism activity in mouse colon region. |
[3,165,197] |
| 15 | Stomach | -By qrtPCR and immunohistochemistry showed the expression of FFAR3 in villi and microvilli of gastric brush cells of mice stomach. | [3,7,172] |
| 16 | Enteric mucosal and submucosal cholinergic neurons of rat | -Suppresses carbachol (CCh)- or luminal propionate-induced Cl- secretion influenced by TTX, hexamethonium and MQC through nicotinic ACh receptor activation. -SCFA-FFAR3 pathway responsible for anti-secretory function inhibited through cholinergic neural reflexes. -Pretreatment with serosal PTX along with MQC application restored the CCh response indicating the FFAR3 anti-secretory effect is mediated through Gi/o pathway in rat proximal colon. |
[197] |
| 17 | Adipocytes | -A mixture of SCFA reduces plasma FFA in DIO mice along with beige adipogenesis marker. -Increase in adipose tissues with reduction in colon size. -Reduction in Firmicutes: Bacteroidetes ratio. -Reduces body weight by increasing mitochondrial biogenesis and reducing chronic inflammation. |
[19,199] |
| 18 | Lungs | -Expressed in the mice lungs. -Propionate minimize allergy airway inflammation in mice lungs mediated through FFAR3. |
[6] |
| 19 | Duodenal I-cells | -The receptor senses the circulating SCFA in plasma to modulate I-cell functions. -But unlike the LCFA, SCFAs are not involved in the cholecystokinin synthesis from duodenal I-cells. |
[205] |
FFAR3: Free fatty acid receptor 3; GLP-1: Glucagon-like peptide 1; PYY: Peptide YY; CCK: Cholecystokinin; GIP: Glucose-dependent insulinotropic peptide; IGN: Intestinal Gluconeogenesis; TA: Tiglic acid; MA: Methylcyclopropanecarboxylic acid; hMADS: human multipotent adipose tissue-derived stem cells; PTX: Pertussis toxin; HSL: Hormone-sensitive lipase; Isc: Short-circuit currents; TTX: Tetrodotoxin; VIP: Vasoactive intestinal polypeptide; IRES: Internal ribosomal entry site; Compound 4: (N-(2,5-dichlorophenyl)-4-(furan2-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide); SNS: Sympathetic nervous system; SCG: Superior cervical ganglia; CSMG: Celiac-mesenteric Ganglia; BHB: β-hydroxybutyrate; NE: Norepinephrine; PLC: Phospholipase C; MEK: Methyl ethyl ketone; siRNA: Small interfering ribonucleic acid; PBN: Parabrachial nucleus; DVC: Dorsal vagal complex; PVN: Paraventricular nucleus; LH: Lateral hypothalamus; ARC: Arcuate nucleus; KO: Knock-out; TTX: Tetrodotoxin; ACh: Acetylcholinergic; CGRP: Calcitonin gene related peptide; CCh: Carbachol; MQC: N-[2-methylphenyl]-[4-furan-3-yl]-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide; FFA: Free fatty acid; LCFA: Long chain fatty acid.