title: 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.
abstract: The expression of short-chain fatty acid receptors GPR41/FFAR3 and GPR43/ free fatty acid receptor 2 (FFAR2) was studied in the gastrointestinal tract of transgenic monomeric red fluorescent protein (mRFP) reporter mice. In the stomach free fatty acid receptor 3 (FFAR3)-mRFP was expressed in a subpopulation of ghrelin and gastrin cells. In contrast, strong expression of FFAR3-mRFP was observed in all cholecystokinin, glucose-dependent insulinotropic peptide (GIP), and secretin cells of the proximal small intestine and in all glucagon-like peptide-1 (GLP-1), peptide YY, and neurotensin cells of the distal small intestine. Throughout the colon and rectum, FFAR3-mRFP was strongly expressed in the large population of peptide YY and GLP-1 cells and in the neurotensin cells of the proximal colon. A gradient of expression of FFAR3-mRFP was observed in the somatostatin cells from less than 5% in the stomach to more than 95% in the rectum. Substance P-containing enterochromaffin cells displayed a similar gradient of FFAR3-mRFP expression throughout the small intestine. Surprisingly, FFAR3-mRFP was also expressed in the neuronal cells of the submucosal and myenteric ganglia. Quantitative PCR analysis of fluorescence-activated cell sorting (FACS) purified FFAR3-mRFP positive cells confirmed the coexpression with the various peptide hormones as well as key neuronal marker proteins. The FFAR2-mRFP reporter was strongly expressed in a large population of leukocytes in the lamina propria of in particular the small intestine but surprisingly only weakly in a subpopulation of enteroendocrine cells. Nevertheless, synthetic ligands specific for either FFAR3 or FFAR2 each released GLP-1 from colonic crypt cultures and the FFAR2 agonist mobilized intracellular Ca²⁺ in FFAR2 positive enteroendocrine cells. It is concluded that FFAR3-mRFP serves as a useful marker for the majority of enteroendocrine cells of the small and large intestine and that FFAR3 and FFAR2 both act as sensors for short-chain fatty acids in enteroendocrine cells, whereas FFAR3 apparently has this role alone in enteric neurons and FFAR2 in enteric leukocytes.
authors.affiliation: MD, DMSci, Laboratory for Molecular Pharmacology, The Panum Institute, Building 18.5, University of Copenhagen, Blegdamsvej 3, Copenhagen DK-2200, Denmark. tws@sund.ku.dk.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Nøhr
authors.forename: Maria H
authors.initials: MH
authors.lastname: Pedersen
authors.forename: Andreas
authors.initials: A
authors.lastname: Gille
authors.forename: Kristoffer L
authors.initials: KL
authors.lastname: Egerod
authors.forename: Maja S
authors.initials: MS
authors.lastname: Engelstoft
authors.forename: Anna Sofie
authors.initials: AS
authors.lastname: Husted
authors.forename: Rasmus M
authors.initials: RM
authors.lastname: Sichlau
authors.forename: Kaare V
authors.initials: KV
authors.lastname: Grunddal
authors.forename: Steen Seier
authors.initials: SS
authors.lastname: Poulsen
authors.forename: Sangdon
authors.initials: S
authors.lastname: Han
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jones
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D017615:Enteric Nervous System / Q000378:metabolism*; D019858:Enteroendocrine Cells / Q000166:cytology / Q000378:metabolism*; D005232:Fatty Acids, Volatile / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000166:cytology / Q000276:immunology / Q000294:innervation / Q000378:metabolism; D017930:Genes, Reporter; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology / Q000294:innervation / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009928:Organ Specificity; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000097573:Red Fluorescent Protein
chemical_list: D015415:Biomarkers; D005232:Fatty Acids, Volatile; D008024:Ligands; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D000097573:Red Fluorescent Protein; C506481:Ffar2 protein, mouse; C506482:Gpcr41 protein, mouse