Free fatty acid receptor 3 activation suppresses neurogenic motility in rat proximal colon

Kaji, Izumi; Akiba, Yasutada; Furuyama, Takafumi; Adelson, David; Iwamoto, Kenji; Watanabe, Masahiko; Kuwahara, Atsukazu; Kaunitz, Jonathan D.

doi:10.1111/nmo.13157

Cited by 40 publications

(45 citation statements)

References 43 publications

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“…Ffar3 expression has been demonstrated in cholinergic and nitrergic neurons of the myenteric plexus of the rat colon and in the myenteric plexus of the mouse small intestine . The inhibitory effect of SCFAs was observed in the presence of L‐NAME and MRS 2500, indicating that it is not mediated via the release of nitric oxide (NO) or purines acting on the P2Y 1 receptor.…”

Section: Discussionmentioning

confidence: 99%

The circadian clock regulates the diurnal levels of microbial short‐chain fatty acids and their rhythmic effects on colon contractility in mice

et al. 2018

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Aim: The microbiota shows diurnal oscillations that are synchronized by the host's circadian clock and feeding rhythms. Short-chain fatty acids (SCFAs) produced by the microbiota are possible synchronizers of peripheral circadian clocks.We aimed to investigate whether faecal SCFAs show a diurnal rhythm that regulates the rhythm of SCFA receptor expression (FFAR2/3, OLFR78, HCAR2) and SCFA-induced colonic contractility. The role of the circadian clock was studied in mice lacking the core clock gene Bmal1. Methods: Mice were sacrificed at 4-hour intervals. Faecal SCFA concentrations and SCFA receptor expression were determined. The effect of increasing concentrations of a SCFA mix on electrical field-induced neural responses in colon strips was measured isometrically. Results: Diurnal fluctuations in faecal SCFA concentrations (peak 4 hours after lights on) were observed that were in phase with the rhythm of Ffar2/3 expression in the colonic muscle layer. Olfr78 expression was not diurnal and Hcar2 was not detectable. The inhibitory effect of a SCFA mix on neural contractions in colonic smooth muscle strips showed a diurnal rhythm and oscillated in phase with faecal SCFA concentrations and Ffar2/3 expression. In contrast, neither excitatory neural responses nor acetylcholine-induced smooth muscle contractions showed a diurnal rhythm. In Bmal1 −/− mice, no fluctuations in faecal SCFA levels, Ffar3 expression and neural responses to SCFAs were observed. Conclusion: Diurnal microbial SCFA levels regulate the rhythm of Ffar3 expression in the colonic myenteric plexus, which causes rhythmicity in SCFA-induced colonic motility. Deletion of Bmal1 abolishes rhythmicity of SCFA levels and their downstream effects. K E Y W O R D Scircadian clock, colon contractility, short-chain fatty acids | INTRODUCTIONThe circadian clock coordinates the timing of physiological processes with solar time. The circadian system consists of a master clock, located in the suprachiasmatic nuclei of the anterior hypothalamus, and several peripheral clocks in different organs that are synchronized by the master clock. 1

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Section: Discussionmentioning

confidence: 99%

The circadian clock regulates the diurnal levels of microbial short‐chain fatty acids and their rhythmic effects on colon contractility in mice

et al. 2018

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“…In fact, this selective FFA2 agonist suppressed insulin levels in vivo, so we concluded that FFA2 could be a therapeutic target for obesity rather than type 2 diabetes . In contrast, FFA3 signaling appears to be primarily neural and in the GI tract may involve cholinergic nicotinic (in the rat ascending colon) and 5‐hydroxytryptamine (5‐HT) mechanisms and possibly vasoactive intestinal polypeptide (VIP), although FFA3 expression has also been observed in human colon epithelia . Species variations in the signaling bias of FFA2 and FFA3 agonists have presented significant challenges for their translation .…”

Section: Introductionmentioning

confidence: 91%

Signaling of free fatty acid receptors 2 and 3 differs in colonic mucosa following selective agonism or coagonism by luminal propionate

Tough

Forbes

Cox

2018

Neurogastroenterology Motil

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BackgroundPropionate exhibits affinity for free fatty acid receptor 2 (FFA2, formerly GPR43) and FFA3 (GPR41). These two G protein‐coupled receptors (GPCRs) are expressed by enteroendocrine L cells that contain anorectic peptide YY (PYY) and glucagon‐like peptide 1 (GLP‐1), while FFA3 is also expressed by enteric neurons. Few studies have investigated the individual roles of FFA2 and FFA3 in propionate's gastrointestinal (GI) effects. Here, we compared FFA2, FFA3, and propionate mucosal responses utilizing selective ligands including an FFA3 antagonist, in mouse and human colonic mucosa.MethodsVectorial ion transport was measured in native colonic preparations from normal mouse and human colon with intact submucosal innervation. Endogenous fecal pellet propulsion was monitored in colons isolated from wild‐type (WT) and PYY−/− mice.Key ResultsFFA2 and FFA3 signaling differed significantly. FFA2 agonism involved endogenous L cell‐derived PYY and was glucose dependent, while FFA3 agonism was independent of PYY and glucose, but required submucosal enteric neurons for activity. Tonic FFA3 activity was observed in mouse and human colon mucosa. Apical propionate responses were a combination of FFA2‐PYY mediation and FFA3 neuronal GLP‐1‐ and CGRP‐dependent signaling in mouse ascending colon mucosa. Propionate also slowed WT and PYY−/− colonic transit, and this effect was blocked by a GLP‐1 receptor antagonist.Conclusions & InferencesWe conclude that luminal propionate costimulates FFA2 and FFA3 pathways, reducing anion secretion and slowing colonic motility; FFA2 via PYY mediation and FFA3 signaling by activation of enteric sensory neurons.

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“…While little is known of the mechanisms of response to BCFA in the gut, the responses to SCFAs (mainly acetate, propionate, and butyrate) are mediated through the fatty acid receptor 2 (FFA2) and/or 3 (FFA3) formerly known as GPR43 and GPR41, respectively. These receptors are expressed in a variety of cells in the gut including enteroendocrine cells, adipocytes, pancreatic cells, immune cells, and enteric neurons; however, their expression in smooth muscle has not been studied [4,5,[7][8][9][10][30][31][32][33][34][35]. Similarly, their role in mediating the response to BCFA has not been studied in any of these cell types in any detail.…”

Section: Discussionmentioning

confidence: 99%

“…The effect of SCFA on mucosal health and function has been studied more extensively than the effects on motility although several studies suggest that SCFA increase colonic motility and secretion via stimulation of neural and/or serotonin mediated pathways [29][30][31][32][33][34][35]. Direct contractile effects of SCFA on rat colonic smooth muscle have been reported, however, little is known of the effects of BCFA on colonic smooth muscle [36].…”

Section: Introductionmentioning

confidence: 99%

Branched Short-Chain Fatty Acid Isovaleric Acid Causes Colonic Smooth Muscle Relaxation via cAMP/PKA Pathway

et al. 2018

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Background.-Isovaleric Acid (IVA) is a 5-carbon branched chain fatty acid present in fermented foods and produced in the colon by bacterial fermentation of leucine. We previously reported that the shorter, straight chain fatty acids acetate, propionate and butyrate, differentially affect colonic motility; however, the effect of branched chain fatty acids on gut smooth muscle and motility is unknown. Aims.-To determine the effect of IVA on contractility of colonic smooth muscle. Methods.-Murine colonic segments were placed in a longitudinal orientation in organ baths in Krebs buffer and fastened to force transducers. Segments were contracted with acetylcholine (ACh) and the effects of IVA on ACh-induced contraction were measured in the absence and presence of tetrodotoxin (TTx) or inhibitors of nitric oxide synthase (L-N-nitroarginine (L-NNA)) or adenylate cyclase (SQ22536). The effect of IVA on ACh-induced contraction was also measured in isolated muscle cells in the presence or absence of SQ22536 or protein kinase A (PKA) inhibitor (H-89). Direct activation of PKA was measured in isolated muscle cells. Results.-In colonic segments, ACh-induced contraction was inhibited by IVA in a concentration-dependent fashion; the IVA response was not affected by TTx or L-NNA but inhibited by SQ22536. Similarly, in isolated colonic muscle cells, AChinduced contraction was inhibited by IVA in a concentration-dependent fashion and the effect blocked by SQ22536 and H-89. IVA also increased PKA activity in isolated smooth muscle cells. Conclusions.-The branched chain fatty acid IVA acts directly on colonic smooth muscle and causes muscle relaxation via the PKA pathway.

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Free fatty acid receptor 3 activation suppresses neurogenic motility in rat proximal colon

Abstract: Background: Short-chain fatty acids (SCFA) are microbial fermentation products ab-

Cited by 40 publications

References 43 publications

The circadian clock regulates the diurnal levels of microbial short‐chain fatty acids and their rhythmic effects on colon contractility in mice

The circadian clock regulates the diurnal levels of microbial short‐chain fatty acids and their rhythmic effects on colon contractility in mice

Signaling of free fatty acid receptors 2 and 3 differs in colonic mucosa following selective agonism or coagonism by luminal propionate

Branched Short-Chain Fatty Acid Isovaleric Acid Causes Colonic Smooth Muscle Relaxation via cAMP/PKA Pathway

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