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.
Original language | English |
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Pages (from-to) | 3203-17 |
Number of pages | 15 |
Journal | Diabetes |
Volume | 64 |
Issue number | 9 |
DOIs | |
Publication status | Published - Sept 2015 |
Externally published | Yes |
Keywords
- 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