An acetate-specific GPCR, FFAR2, regulates insulin secretion

Medha Priyadarshini, Stephanie R Villa, Miles Fuller, Barton Wicksteed, Charles R Mackay, Thierry Alquier, Vincent Poitout, Helena Mancebo, Raghavendra G Mirmira, Annette Gilchrist, Brian T Layden

    Research output: Contribution to journalArticleResearchpeer-review

    47 Citations (Scopus)

    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 beta-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 Galphaq/11 or Galphai/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.
    Original languageEnglish
    Pages (from-to)1055 - 1066
    Number of pages12
    JournalMolecular Endocrinology
    Volume29
    Issue number7
    DOIs
    Publication statusPublished - 2015

    Cite this

    Priyadarshini, M., Villa, S. R., Fuller, M., Wicksteed, B., Mackay, C. R., Alquier, T., ... Layden, B. T. (2015). An acetate-specific GPCR, FFAR2, regulates insulin secretion. Molecular Endocrinology, 29(7), 1055 - 1066. https://doi.org/10.1210/me.2015-1007
    Priyadarshini, Medha ; Villa, Stephanie R ; Fuller, Miles ; Wicksteed, Barton ; Mackay, Charles R ; Alquier, Thierry ; Poitout, Vincent ; Mancebo, Helena ; Mirmira, Raghavendra G ; Gilchrist, Annette ; Layden, Brian T. / An acetate-specific GPCR, FFAR2, regulates insulin secretion. In: Molecular Endocrinology. 2015 ; Vol. 29, No. 7. pp. 1055 - 1066.
    @article{c95bc552b77e4de8a7bda52e753cccc2,
    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 beta-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 Galphaq/11 or Galphai/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.",
    author = "Medha Priyadarshini and Villa, {Stephanie R} and Miles Fuller and Barton Wicksteed and Mackay, {Charles R} and Thierry Alquier and Vincent Poitout and Helena Mancebo and Mirmira, {Raghavendra G} and Annette Gilchrist and Layden, {Brian T}",
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    Priyadarshini, M, Villa, SR, Fuller, M, Wicksteed, B, Mackay, CR, Alquier, T, Poitout, V, Mancebo, H, Mirmira, RG, Gilchrist, A & Layden, BT 2015, 'An acetate-specific GPCR, FFAR2, regulates insulin secretion', Molecular Endocrinology, vol. 29, no. 7, pp. 1055 - 1066. https://doi.org/10.1210/me.2015-1007

    An acetate-specific GPCR, FFAR2, regulates insulin secretion. / Priyadarshini, Medha; Villa, Stephanie R; Fuller, Miles; Wicksteed, Barton; Mackay, Charles R; Alquier, Thierry; Poitout, Vincent; Mancebo, Helena; Mirmira, Raghavendra G; Gilchrist, Annette; Layden, Brian T.

    In: Molecular Endocrinology, Vol. 29, No. 7, 2015, p. 1055 - 1066.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - An acetate-specific GPCR, FFAR2, regulates insulin secretion

    AU - Priyadarshini, Medha

    AU - Villa, Stephanie R

    AU - Fuller, Miles

    AU - Wicksteed, Barton

    AU - Mackay, Charles R

    AU - Alquier, Thierry

    AU - Poitout, Vincent

    AU - Mancebo, Helena

    AU - Mirmira, Raghavendra G

    AU - Gilchrist, Annette

    AU - Layden, Brian T

    PY - 2015

    Y1 - 2015

    N2 - 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 beta-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 Galphaq/11 or Galphai/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.

    AB - 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 beta-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 Galphaq/11 or Galphai/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.

    UR - http://press.endocrine.org/doi/pdf/10.1210/me.2015-1007

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    Priyadarshini M, Villa SR, Fuller M, Wicksteed B, Mackay CR, Alquier T et al. An acetate-specific GPCR, FFAR2, regulates insulin secretion. Molecular Endocrinology. 2015;29(7):1055 - 1066. https://doi.org/10.1210/me.2015-1007