GPR43 Potentiates β-Cell Function in Obesity

Joanne C McNelis, Yun Sok Lee, Rafael Mayoral, Rik van der Kant, Andrew M F Johnson, Joshua Wollam, Jerrold M Olefsky

Research output: Contribution to JournalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)3203-17
Number of pages15
Issue number9
Publication statusPublished - Sept 2015
Externally publishedYes


  • Acetates/metabolism
  • Animals
  • Diet, High-Fat
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Gene Expression Profiling
  • Gene-Environment Interaction
  • Glucose Intolerance/genetics
  • Humans
  • In Vitro Techniques
  • Insulin/secretion
  • Insulin-Secreting Cells/metabolism
  • Islets of Langerhans/drug effects
  • Mice, Knockout
  • Microbiota
  • Obesity/genetics
  • Receptors, Cell Surface/agonists
  • Receptors, G-Protein-Coupled/agonists
  • Type C Phospholipases


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