Nøhr, Mark Klitgaard7; Pedersen, Maria H2; Gille, Andreas3; Egerod, Kristoffer Lihme4; Engelstoft, Maja Storm5; Husted, Anna Sofie4; Sichlau, Rasmus Mais4; Grunddal, Kaare Villum4; Poulsen, Steen Seier6; Han, Sangdon3; Jones, Robert M3; Offermanns, Stefan3; Schwartz, Thue W.5
1 Department of Clinical Medicine - The Department of Endocrinology and Metabolism C, Department of Clinical Medicine, Health, Aarhus University2 Department of Atmospheric Environment, National Environmental Research Institute, Aarhus University, Aarhus University3 unknown4 Metabolic Receptology5 Molpharm6 Department of Anatomy, Faculty of Health Sciences, Aarhus University, Aarhus University7 Department of Clinical Medicine - The Department of Endocrinology and Metabolism C, Department of Clinical Medicine, Health, Aarhus University
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, gastric inhibitory peptide, 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 sorter 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 Ca(2+) 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.
Endocrinology, 2013, Vol 154, Issue 10, p. 3552-64