Deficiency of Leucine‐Rich Repeat Containing G Protein‐Coupled Receptor 4 in Pancreas Reduces β Cell Mass

Although leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) is abundantly expressed in the pancreas, it is currently unknown whether LGR4 impacts pancreatic endocrine cells. Here, a critical role of LGR4 is demonstrated in islet β cell mass using a group of transgenic mice with LGR4 deficiency. Knock-out of Lgr4 in the pancreas and islet β cells significantly reduced islet β cell mass, and subsequently impaired glucose metabolism upon the challenge of a high-fat diet. Deficiency of LGR4 in these mice or in cultured INS-1 cells showed a significant reduction in islet β cell proliferation measured by Ki-67, EdU, and CCK-8 assay. Increase of islet β cell proliferation induced by Rspondin-LGR4 signaling occurred via Wnt-β-catenin-Ccnd1 axis. In addition, the deficiency of LGR4 in islet β cells significantly increased apoptosis. Inhibition of RANKL-RANK signaling by the TRAF-STOP inhibitor significantly attenuated apoptosis of cultured INS-1 cells induced by deficiency of LGR4. Overall, this work shows that deficiency of LGR4 reduces islet β cell mass via suppression of proliferation and concurrent increase of apoptosis. LGR4 in pancreatic islets is thus critical for the control of glucose homeostasis.