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

## TL;DR

LGR4 deficiency in the pancreas reduces beta cell mass and impairs glucose metabolism, suggesting it could be a target for diabetes treatment.

## Contribution

This study identifies LGR4 as a key regulator of islet beta cell proliferation and survival through Wnt and RANKL signaling pathways.

## Key findings

- LGR4 deficiency in mice reduces islet beta cell mass and impairs glucose metabolism.
- LGR4 promotes beta cell proliferation via the Wnt-β-catenin-Ccnd1 axis and suppresses apoptosis through RANKL signaling.
- Inhibition of RANKL-RANK signaling reduces apoptosis in LGR4-deficient INS-1 cells.

## Abstract

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.

In islet β cells, LGR4 binds with Rspondin to activate the Wnt‐β‐catenin‐Ccnd1 axis, leading to a subsequent increase in cell proliferation. On the other hand, LGR4 also binds with RANKL, thus suppressing the phosphorylation of p44/p42 MAPK and p65 NF‐κB and subsequent cell apoptosis. LGR4 is thus a potential therapeutic target to regulate the flexibility of islet β cells and treat diabetes.