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

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Abstract

G protein-coupled receptors have been well described to contribute to the regulation of glucosestimulated 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(Formula presented) 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(Formula presented) mice during hyperglycemic clamps. In ex vivo insulin secretion studies, we observed diminished GSIS from Ffar2(Formula presented) 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 Gα<inf>9/11</inf> or Gα<inf>i/o</inf>, 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 FFAR 2. 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. (Molecular Endocrinology 29: 1055–1066, 2015)

Original languageEnglish (US)
Pages (from-to)1055-1066
Number of pages12
JournalMolecular Endocrinology
Volume29
Issue number7
DOIs
StatePublished - Jul 1 2015

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ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Priyadarshini, M., Villa, S. R., Fuller, M., Wicksteed, B., Mackay, C. R., Alquier, T., Poitout, V., Mancebo, H., Mirmira, R. G., Gilchrist, A., & 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