GPR43 Potentiates beta-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 (SCFA), as a modulator of microbiota-host interaction. Beta cell expression of GPR43 and serum levels of acetate, an endogenous SCFA, are increased with high fat diet (HFD). HFD GPR43 knock out (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 PA, a specific agonist of GPR43, increased intracellular IP3 and Ca2+ levels, and potentiated insulin secretion in a GPR43, Gαq, and phospholipase C dependent manner. In addition, HFD KO mice displayed reduced beta cell mass and expression of differentiation genes, and the treatment of Min6 cells with PA increased beta cell proliferation and gene expression. Together these findings identify GPR43 as a potential target for therapeutic intervention.