title: An Acetate-Specific GPCR, FFAR2, Regulates Insulin Secretion.
abstract: G protein-coupled receptors have been well described to contribute to the regulation of glucose-stimulated insulin secretion (GSIS). The short-chain fatty acid-sensing G protein-coupled receptor, free fatty acid receptor 2 (FFAR2), is expressed in pancreatic β-cells, and in rodents, its expression is altered during insulin resistance. Thus, we explored the role of FFAR2 in regulating GSIS. First, assessing the phenotype of wild-type and Ffar2(-/-) mice in vivo, we observed no differences with regard to glucose homeostasis on normal or high-fat diet, with a marginally significant defect in insulin secretion in Ffar2(-/-) mice during hyperglycemic clamps. In ex vivo insulin secretion studies, we observed diminished GSIS from Ffar2(-/-) islets relative to wild-type islets under high-glucose conditions. Further, in the presence of acetate, the primary endogenous ligand for FFAR2, we observed FFAR2-dependent potentiation of GSIS, whereas FFAR2-specific agonists resulted in either potentiation or inhibition of GSIS, which we found to result from selective signaling through either Gαq/11 or Gαi/o, respectively. Lastly, in ex vivo insulin secretion studies of human islets, we observed that acetate and FFAR2 agonists elicited different signaling properties at human FFAR2 than at mouse FFAR2. Taken together, our studies reveal that FFAR2 signaling occurs by divergent G protein pathways that can selectively potentiate or inhibit GSIS in mouse islets. Further, we have identified important differences in the response of mouse and human FFAR2 to selective agonists, and we suggest that these differences warrant consideration in the continued investigation of FFAR2 as a novel type 2 diabetes target.
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (M.P., S.R.V., M.F., B.T.L.), Northwestern University, Chicago, Illinois 60611; Kovler Diabetes Center (B.W.), The University of Chicago, Chicago, Illinois 60637; Monash University (C.R.M.), Clayton, Victoria 3800, Australia; Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and Department of Medicine (T.A., V.P.), University of Montreal, Quebec, H2X 0A9 Canada; Multispan (H.M.), Hayward, California 94545; Department of Pediatrics and the Herman B Wells Center for Pediatric Research (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 4602; Department of Biochemistry and Molecular Biology (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Medicine (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pharmaceutical Sciences (A.G.), Midwestern University, Downers Grove, Illinois 60515; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Medha
authors.initials: M
authors.lastname: Priyadarshini
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (M.P., S.R.V., M.F., B.T.L.), Northwestern University, Chicago, Illinois 60611; Kovler Diabetes Center (B.W.), The University of Chicago, Chicago, Illinois 60637; Monash University (C.R.M.), Clayton, Victoria 3800, Australia; Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and Department of Medicine (T.A., V.P.), University of Montreal, Quebec, H2X 0A9 Canada; Multispan (H.M.), Hayward, California 94545; Department of Pediatrics and the Herman B Wells Center for Pediatric Research (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 4602; Department of Biochemistry and Molecular Biology (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Medicine (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pharmaceutical Sciences (A.G.), Midwestern University, Downers Grove, Illinois 60515; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Villa
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (M.P., S.R.V., M.F., B.T.L.), Northwestern University, Chicago, Illinois 60611; Kovler Diabetes Center (B.W.), The University of Chicago, Chicago, Illinois 60637; Monash University (C.R.M.), Clayton, Victoria 3800, Australia; Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and Department of Medicine (T.A., V.P.), University of Montreal, Quebec, H2X 0A9 Canada; Multispan (H.M.), Hayward, California 94545; Department of Pediatrics and the Herman B Wells Center for Pediatric Research (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 4602; Department of Biochemistry and Molecular Biology (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Medicine (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pharmaceutical Sciences (A.G.), Midwestern University, Downers Grove, Illinois 60515; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Miles
authors.initials: M
authors.lastname: Fuller
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (M.P., S.R.V., M.F., B.T.L.), Northwestern University, Chicago, Illinois 60611; Kovler Diabetes Center (B.W.), The University of Chicago, Chicago, Illinois 60637; Monash University (C.R.M.), Clayton, Victoria 3800, Australia; Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and Department of Medicine (T.A., V.P.), University of Montreal, Quebec, H2X 0A9 Canada; Multispan (H.M.), Hayward, California 94545; Department of Pediatrics and the Herman B Wells Center for Pediatric Research (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 4602; Department of Biochemistry and Molecular Biology (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Medicine (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pharmaceutical Sciences (A.G.), Midwestern University, Downers Grove, Illinois 60515; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Barton
authors.initials: B
authors.lastname: Wicksteed
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (M.P., S.R.V., M.F., B.T.L.), Northwestern University, Chicago, Illinois 60611; Kovler Diabetes Center (B.W.), The University of Chicago, Chicago, Illinois 60637; Monash University (C.R.M.), Clayton, Victoria 3800, Australia; Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and Department of Medicine (T.A., V.P.), University of Montreal, Quebec, H2X 0A9 Canada; Multispan (H.M.), Hayward, California 94545; Department of Pediatrics and the Herman B Wells Center for Pediatric Research (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 4602; Department of Biochemistry and Molecular Biology (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Medicine (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pharmaceutical Sciences (A.G.), Midwestern University, Downers Grove, Illinois 60515; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Mackay
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (M.P., S.R.V., M.F., B.T.L.), Northwestern University, Chicago, Illinois 60611; Kovler Diabetes Center (B.W.), The University of Chicago, Chicago, Illinois 60637; Monash University (C.R.M.), Clayton, Victoria 3800, Australia; Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and Department of Medicine (T.A., V.P.), University of Montreal, Quebec, H2X 0A9 Canada; Multispan (H.M.), Hayward, California 94545; Department of Pediatrics and the Herman B Wells Center for Pediatric Research (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 4602; Department of Biochemistry and Molecular Biology (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Medicine (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pharmaceutical Sciences (A.G.), Midwestern University, Downers Grove, Illinois 60515; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Thierry
authors.initials: T
authors.lastname: Alquier
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (M.P., S.R.V., M.F., B.T.L.), Northwestern University, Chicago, Illinois 60611; Kovler Diabetes Center (B.W.), The University of Chicago, Chicago, Illinois 60637; Monash University (C.R.M.), Clayton, Victoria 3800, Australia; Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and Department of Medicine (T.A., V.P.), University of Montreal, Quebec, H2X 0A9 Canada; Multispan (H.M.), Hayward, California 94545; Department of Pediatrics and the Herman B Wells Center for Pediatric Research (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 4602; Department of Biochemistry and Molecular Biology (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Medicine (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pharmaceutical Sciences (A.G.), Midwestern University, Downers Grove, Illinois 60515; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Vincent
authors.initials: V
authors.lastname: Poitout
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (M.P., S.R.V., M.F., B.T.L.), Northwestern University, Chicago, Illinois 60611; Kovler Diabetes Center (B.W.), The University of Chicago, Chicago, Illinois 60637; Monash University (C.R.M.), Clayton, Victoria 3800, Australia; Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and Department of Medicine (T.A., V.P.), University of Montreal, Quebec, H2X 0A9 Canada; Multispan (H.M.), Hayward, California 94545; Department of Pediatrics and the Herman B Wells Center for Pediatric Research (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 4602; Department of Biochemistry and Molecular Biology (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Medicine (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pharmaceutical Sciences (A.G.), Midwestern University, Downers Grove, Illinois 60515; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Helena
authors.initials: H
authors.lastname: Mancebo
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (M.P., S.R.V., M.F., B.T.L.), Northwestern University, Chicago, Illinois 60611; Kovler Diabetes Center (B.W.), The University of Chicago, Chicago, Illinois 60637; Monash University (C.R.M.), Clayton, Victoria 3800, Australia; Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and Department of Medicine (T.A., V.P.), University of Montreal, Quebec, H2X 0A9 Canada; Multispan (H.M.), Hayward, California 94545; Department of Pediatrics and the Herman B Wells Center for Pediatric Research (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 4602; Department of Biochemistry and Molecular Biology (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Medicine (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pharmaceutical Sciences (A.G.), Midwestern University, Downers Grove, Illinois 60515; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Raghavendra G
authors.initials: RG
authors.lastname: Mirmira
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (M.P., S.R.V., M.F., B.T.L.), Northwestern University, Chicago, Illinois 60611; Kovler Diabetes Center (B.W.), The University of Chicago, Chicago, Illinois 60637; Monash University (C.R.M.), Clayton, Victoria 3800, Australia; Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and Department of Medicine (T.A., V.P.), University of Montreal, Quebec, H2X 0A9 Canada; Multispan (H.M.), Hayward, California 94545; Department of Pediatrics and the Herman B Wells Center for Pediatric Research (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 4602; Department of Biochemistry and Molecular Biology (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Medicine (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pharmaceutical Sciences (A.G.), Midwestern University, Downers Grove, Illinois 60515; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Annette
authors.initials: A
authors.lastname: Gilchrist
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (M.P., S.R.V., M.F., B.T.L.), Northwestern University, Chicago, Illinois 60611; Kovler Diabetes Center (B.W.), The University of Chicago, Chicago, Illinois 60637; Monash University (C.R.M.), Clayton, Victoria 3800, Australia; Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and Department of Medicine (T.A., V.P.), University of Montreal, Quebec, H2X 0A9 Canada; Multispan (H.M.), Hayward, California 94545; Department of Pediatrics and the Herman B Wells Center for Pediatric Research (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 4602; Department of Biochemistry and Molecular Biology (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Medicine (R.G.M.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pharmaceutical Sciences (A.G.), Midwestern University, Downers Grove, Illinois 60515; and Jesse Brown Veterans Affairs Medical Center (B.T.L.), Chicago, Illinois 60612.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Layden
mesh_terms: D000085:Acetates / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D000078790:Insulin Secretion; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000819:agonists / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity
chemical_list: D000085:Acetates; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D007328:Insulin; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C473103:FFAR2 protein, human; C506481:Ffar2 protein, mouse