title: GPR43 Potentiates β-Cell Function in Obesity.
abstract: The intestinal microbiome can regulate host energy homeostasis and the development of metabolic disease. Here we identify GPR43, a receptor for bacterially produced short-chain fatty acids (SCFAs), as a modulator of microbiota-host interaction. β-Cell expression of GPR43 and serum levels of acetate, an endogenous SCFA, are increased with a high-fat diet (HFD). HFD-fed GPR43 knockout (KO) mice develop glucose intolerance due to a defect in insulin secretion. In vitro treatment of isolated murine islets, human islets, and Min6 cells with (S)-2-(4-chlorophenyl)-3,3-dimethyl-N-(5-phenylthiazol-2-yl)butanamide (PA), a specific agonist of GPR43, increased intracellular inositol triphosphate and Ca(2+) levels, and potentiated insulin secretion in a GPR43-, Gαq-, and phospholipase C-dependent manner. In addition, KO mice fed an HFD displayed reduced β-cell mass and expression of differentiation genes, and the treatment of Min6 cells with PA increased β-cell proliferation and gene expression. Together these findings identify GPR43 as a potential target for therapeutic intervention.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Joanne C
authors.initials: JC
authors.lastname: McNelis
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Yun Sok
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Mayoral
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Rik
authors.initials: R
authors.lastname: van der Kant
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Andrew M F
authors.initials: AM
authors.lastname: Johnson
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Wollam
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA jolefsky@ucsd.edu.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
mesh_terms: D000085:Acetates / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020869:Gene Expression Profiling; D059647:Gene-Environment Interaction; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D018345:Mice, Knockout; D064307:Microbiota; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000819:agonists / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D010738:Type C Phospholipases
chemical_list: D000085:Acetates; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D007328:Insulin; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D010738:Type C Phospholipases; C473103:FFAR2 protein, human; C506481:Ffar2 protein, mouse